Clinical trial NCT02650999
Conditions: CD19+ Diffuse Large B-cell Lymphomas Follicular Lymphomas Mantle Cell Lymphomas
Sponsor: Abramson Cancer Center at Penn Medicine
Start date: 2016-01-01; Completion date: 2020-06-12
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Single center, phase I/II trial of pembrolizumab after CTL019 for CD19+ lymphomas. Patients will have CD19+ diffuse large B-cell, follicular, or mantle cell lymphomas relapsed/refractory after CTL019. 12 total patients will be enrolled. Safety of pembrolizumab (primary endpoint) will be determined using a Bayesian monitoring rule for treatment-related adverse events causing drug discontinuation. Secondary efficacy endpoints include overall response rate and progression-free survival.

Detailed description:

Arms: arm 1: Single arm, pembrolizumab 200mg IV every 3 weeks until progression/toxicity
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: 200mg intravenously (IV)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Page 1 of 75 
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regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
 
 
 
TITLE: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after 
anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory 
CD19+ lymphomas 
 
IND NUMBER: IND Exemption provided by FDA 
 
Penn UPCC Protocol Number: 46415 
IRB Protocol Number: 823486 
Clinical trials.gov number: NCT02650999 
 
Principal Investigator: 
Stephen J. Schuster, MD 
 
 
 
 
Professor of Medicine 
 
 
 
 
Director, Lymphoma Program, Abramson Cancer Center 
 
 
 
 
University of Pennsylvania 
 
Co-Investigators: 
 
Elise A. Chong, MD 
 
 
 
 
Sunita D. Nasta, MD 
 
 
 
 
Jakub Svoboda, MD 
 
 
 
 
Daniel J. Landsburg, MD 
 
Statistician:  
 
Wei-Ting Hwang, PhD 
 
REGULATORY SPONSOR: Stephen J. Schuster, MD 
 
 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY................................................................................................ 710 
2.0 
TRIAL DESIGN...................................................................................................... 811 
2.1 
Trial Design ......................................................................................................... 811 
2.2 
Trial Diagram ...................................................................................................... 912 
3.0 
TRIAL OBJECTIVES & HYPOTHESES ........................................................... 912 
3.1 
Primary Objectives & Hypotheses .................................................................... 912 
3.2 
Secondary Objectives & Hypotheses ................................................................. 912 
3.3 
Exploratory Objective ...................................................................................... 1013 
4.0 
BACKGROUND & RATIONAL ........................................................................ 1114 
4.1 
Background ....................................................................................................... 1114 
4.1.1 Pharmaceutical and Therapeutic Background ................................................ 1114 
4.1.2 Preclinical and Clinical Trial Data .................................................................. 1215 
4.2 
Rationale ............................................................................................................ 1215 
4.2.1 Rationale for the Trial and Selected Subject Population ................................ 1215 
4.2.2 Rationale for Dose Selection/Regimen/Modification ..................................... 1316 
4.2.3 Rationale for Endpoints .................................................................................. 1417 
5.0 
METHODOLOGY ............................................................................................... 1518 
5.1 
Entry Criteria .................................................................................................... 1518 
5.1.1 Diagnosis/Condition for Entry into the Trial .................................................. 1518 
5.1.2 Subject Inclusion Criteria................................................................................ 1518 
5.1.3 Subject Exclusion Criteria .............................................................................. 1720 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
5.2 
Trial Treatments ............................................................................................... 1821 
5.2.1 Dose Selection/Modification .......................................................................... 1922 
5.2.2 Timing of Dose Administration ...................................................................... 2429 
5.2.3 Trial Blinding/Masking ................................................................................... 2529 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ................. 2529 
5.3.1 Acceptable Concomitant Medications ............................................................ 2529 
5.3.2 Prohibited Concomitant Medications.............................................................. 2530 
5.4 
Rescue Medications & Supportive Care ......................................................... 2631 
5.4.1 Supportive Care Guidelines ............................................................................ 2631 
5.4.2 Cytokine release syndrome and macrophage activation syndrome ................ 2936 
5.5 
Diet/Activity/Other Considerations ................................................................. 3340 
5.5.1 Diet .................................................................................................................. 3340 
5.5.2 Contraception .................................................................................................. 3340 
5.5.3 Use in Pregnancy ............................................................................................ 3441 
5.5.4 Use in Nursing Women ................................................................................... 3441 
5.6 
Subject Withdrawal/Discontinuation Criteria ............................................... 3441 
5.7 
Second Course ................................................................................................... 3644 
5.8 
Subject Replacement Strategy ......................................................................... 3744 
5.9 
Clinical Criteria for Early Trial Termination ............................................... 3744 
6.0 
TRIAL FLOW CHART ....................................................................................... 3846 
6.1 
Study Flow Chart .............................................................................................. 3846 
6.2 
Physical examination and adverse events ....................................................... 4250 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
6.3 
Imaging studies ................................................................................................. 4250 
6.4 
Laboratory studies ............................................................................................ 4250 
6.5 
Optional correlative studies ............................................................................. 4351 
7.0 
TRIAL PROCEDURES ....................................................................................... 4351 
7.1 
Trial Procedures ............................................................................................... 4351 
7.1.1 Administrative Procedures .............................................................................. 4452 
7.2 Clinical Procedures/Assessments .......................................................................... 4755 
7.1.2 Other Procedures ............................................................................................. 5159 
7.1.3 Visit Requirements .......................................................................................... 5159 
7.2 
Adverse Events .................................................................................................. 5362 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ..................................................................................... 5463 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ............. 5564 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.......... 5564 
7.3 
Reporting of Adverse events ............................................................................ 5665 
7.3.2 Evaluating Adverse Events ............................................................................. 6069 
7.3.3 Modification of CTC Grading scale for Cytokine Release Syndrome (CRS) 6372 
7.3.4 Sponsor Responsibility for Reporting Adverse Events including Deviations 
and Exceptions ................................................................................................ 6576 
8.0 
STATISTICAL ANALYSIS PLAN .................................................................... 6777 
8.1 
Statistical Analysis Plan ................................................................................... 6777 
8.1.1 Primary Objectives & Hypotheses .................................................................. 6777 
8.1.2 Secondary Objectives & Hypotheses .............................................................. 6878 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
8.1.3 Exploratory Objectives ................................................................................... 6979 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................. 6979 
9.1 
Investigational Product .................................................................................... 6979 
9.2 
Packaging and Labeling Information ............................................................. 6980 
9.3 
Clinical Supplies Disclosure ............................................................................. 7080 
9.4 
Storage and Handling Requirements .............................................................. 7080 
9.5 
Returns and Reconciliation .............................................................................. 7081 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ................................... 7081 
10.1 
Confidentiality ................................................................................................... 7081 
10.2 
Compliance with Law and Audits ................................................................... 7182 
10.3 
Compliance with Trial Registration and Results Posting Requirements .... 7182 
10.4 
Quality and Safety Management ..................................................................... 7182 
10.5 
Ethical Considerations ..................................................................................... 7283 
10.6 
Conflict of Interest ............................................................................................ 7384 
10.7 
Records Retention ............................................................................................. 7384 
11.0 
 References ............................................................................................................. 7485 
12.0 
APPENDICES ....................................................................................................... 7586 
12.1 
ECOG Performance Status .............................................................................. 7586 
12.2 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ........... 7586 
12.3 
Response Evaluation Criteria .......................................................................... 7586 
12.4 
Events of Clinical Interest Guidance Document ............................................ 7587 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
1.0 TRIAL SUMMARY 
Title 
Phase I/II study of pembrolizumab in patients failing to respond to or 
relapsing after anti-CD19 chimeric antigen receptor modified T cell 
therapy for relapsed or refractory CD19+ lymphomas 
Abbreviated Title 
Pembrolizumab after CTL019/CTL119 for relapsed/refractory CD19+ 
lymphomas 
Trial Phase 
Phase I / II 
Clinical Indication 
Relapsed / refractory CD19+ B cell lymphomas after CTL019/CTL119 
Trial Type 
Investigator-initiated 
Type of control 
None. Enrollment will be offered to subjects with an unmet medical need, 
which is no available effective, standard therapy for relapsed / refractory 
CD19+ lymphomas 
Route of administration 
Intravenous 
Trial drug, dose, route, regimen Pembrolizumab (Keytruda®) 200mg fixed dose IV every 3 weeks 
Trial Blinding 
None 
Treatment Groups  
Single group 
Number of trial subjects 
12 evaluable subjects 
Estimated enrollment period 
12 months (approximately January 2016-January 2017) 
Estimated duration of trial 
36 months (approximately January 2016-January 2019) 
Duration of Participation 
24 months (12 months treatment + 12 months follow-up) 
 
Objectives 
Primary Endpoints: 
1. Determine safety of pembrolizumab after CTL019/CTL119. This 
endpoint will be met if ≤ 30% of patients develop toxicity 
resulting discontinuation of pembrolizumab. 
2. Determine efficacy of pembrolizumab after CTL019/CTL119. 
This endpoint will be met if the ORR at 3 months is ≥ 35%. 
Statistical methodology 
Primary Endpoints: 
1. Safety endpoint will be assessed using a Bayesian monitoring 
rule to ensure probability of a patient developing toxicity 
resulting in discontinuation of pembrolizumab ≤ 30%  
Secondary Endpoints: 
1. ORR will be assessed using a one-sided binomial test 
2.  PFS, EFS, RD, and OS will be assessed using Kaplan Maier 
survival analysis. PFS after pembrolizumab will be compared to 
PFS after CTL019/CTL119 using a log rank test. 
 
 
 
 


 
 
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regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single center, open label trial of pembrolizumab in patients failing to respond 
to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy 
(CTL019/CTL119) for relapsed or refractory CD19+ lymphomas. 
Eligible patients will have CD19+ diffuse large B-cell, follicular, or mantle cell 
lymphomas with no available curative treatment options, a limited prognosis of several 
months to <2 years anticipated survival with currently available therapies, and 
progressive or relapsed disease after a single intravenous dose of 5 x 108 ± 20% 
CTL019/CTL119 administered on our currently enrolling clinical trial (NCT02030834). 
We anticipate enrollment of 12 total patients onto the present trial for patients not 
responding to, or relapsing after, CTL019/CTL119. 
The safety and efficacy of pembrolizumab in this group of patients will be determined 
using a fixed dose of 200mg IV. This dose was previously well-tolerated and effective 
for treatment of patients with metastatic melanoma and NSCLC. The primary safety 
endpoint will be determined by assessing the rate of pembrolizumab discontinuation as 
well as the rate of occurrence of treatment-related adverse events (AEs), defined as NCI 
CTCAE version 5 grade ≥ 3 AEs are possibly, probably, or definitely related to study 
treatment or grade 4 cytokine release syndrome. Secondary efficacy endpoints will be 
assessed, including overall response rate (ORR) and progression-free survival (PFS). 
History (adverse events), physical examination, assessment of performance status, and 
routine laboratory studies will be performed prior to first pembrolizumab dose and every 
3 weeks prior to pembrolizumab administration. Baseline tumor assessment by radiologic 
imaging will be performed within 6 weeks of starting pembrolizumab and then prior to 
week 12 after first dose of pembrolizumab, and then should be performed every 12 weeks 
from most recent imaging PET/CT, CT of chest/abdomen/pelvis, or MRI 
chest/abdomen/pelvis ± 2 weeks until 24 months after first dose of pembrolizumab. The 
duration of pembrolizumab administration will be one year; however, we plan to continue 
data collection regarding: (1) engraftment as long as patients are at risk (until evidence 
of loss of detectable transduced T cells); (2) disease-free survival until disease 
progression; (3) survival until time of death; or (4) until the patient withdraws consent 
for clinical data collection, as part of the follow-up data collection specified for the FDA 
for gene modified cell therapy clinical trials. 
 


 
 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
Peripheral blood, and when possible tumor biopsies, will be obtained prior to 
pembrolizumab and during therapy with pembrolizumab for correlative studies (see 
collateral research below). 
2.2 
Trial Diagram 
 
3.0 TRIAL OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
(1) Objective:  To determine the safety of pembrolizumab in patients failing to respond to 
or relapsing after CTL019/CTL119 for relapsed or refractory CD19+ lymphomas. 
Hypothesis:  Pembrolizumab will be safely tolerated with ≤ 30% of patients experiencing 
toxicities resulting in discontinuation of pembrolizumab 
3.2 
Secondary Objectives & Hypotheses 
(1) Objective:  To describe the overall response rate (ORR) at 3 months to pembrolizumab 
in patients failing to respond to or relapsing after CTL019/CTL119 for relapsed or 
refractory CD19+ lymphomas  To describe the clinical efficacy of pembrolizumab, 
including progression-free survival, disease-free survival, event-free survival, response 
duration, and overall survival (Cheson, 2007) in patients failing to respond to or 
CD19+ B cell lymphoma 
relapsed/refractory 
after CTL019 
Week 0              
12 
 
24 
 
39 
 
54 
Pembrolizumab 200mg IV q3 weeks for 18 doses until PD or toxicity 
Follow-up 
Assessment for adverse events every 3 weeks prior to pembrolizumab 
Response 
Assessment:  
Week 12 
Response 
Assessment: 
Week 24 
Response 
Assessment: 
Week 39 
Response 
Assessment: 
Week 52 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
relapsing after CTL019/CTL119. Efficacy comparisons will be made for ORR between 
CTL019/CTL119 and pembrolizumab. 
Hypothesis:  Pembrolizumab will enhance the efficacy of CTL019/CTL119 in patients 
failing to respond to or relapsing after CTL019/CTL119 for relapsed or refractory CD19+ 
lymphomas (John, 2013).  
(2) Objective: To describe the immunophenotypic and cytokine profiles of chimeric antigen 
receptor modified T cells in these patients before and after therapy with pembrolizumab 
Hypothesis:  Immunophenotypic profiles of tumor cells and chimeric antigen receptor 
modified T cells obtained pre and post pembrolizumab therapy will identify patients for 
whom pembrolizumab will enhance efficacy. 
3.3 
Exploratory Objective 
(1) 
Objective: To describe the baseline immunophenotypic profiles of tumor cells in these 
patients (see below chart). 
 
Panels for polychromatic ﬂow cytometry 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
4.0 BACKGROUND & RATIONAL 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells 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).  The structure of 
murine PD-1 has been resolved.  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.  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.  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.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  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.  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, 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
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.  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.  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 disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
We are currently conducting a phase IIA clinical trial of redirected autologous T cells, 
engineered to contain anti-CD19 attached to 4-1BB and TCRζ signaling domains, in patients 
with chemotherapy relapsed or refractory CD19+ lymphomas (NCT02030834).  Briefly, 
autologous T cells collected from eligible patients with diffuse large B cell, follicular, and 
mantle cell lymphomas are transduced using a lentiviral vector to express a chimeric antigen 
receptor comprised of an extracellular single chain antibody (scFv) with specificity for CD19 
in tandem with an intracellular signaling domain comprised of 4-1BB and TCRζ signaling 
molecules.  The transduced T cells have specificity for cells expressing CD19, a molecule that 
is restricted in expression to the surface of B cell lymphoma cells as well as normal B cells.  
Therapy with anti-CD19 chimeric antigen receptor modified T cells has shown efficacy in 
chronic lymphocytic and acute lymphoblastic leukemias (Porter, 2011; Grupp, 2013; Maude, 
2014).  On our lymphoma trial, to date, 7 of 7 evaluable patients with relapsed or refractory 
follicular lymphoma have responded to anti-CD19 chimeric antigen receptor modified T cell 
therapy (100% response rate and at a median follow-up of 290 days, only one patient has had 
progression of disease [S. Schuster, preliminary data]), while only 6 of 12 evaluable patients 
with relapsed or refractory diffuse large B cell lymphoma have responded to therapy (50% 
response rate; 5 of 6 patients have ongoing complete responses at median follow-up of 274 
days [S. Schuster, preliminary data]).  We have preliminary evidence that the PD-1 receptor-
ligand pathway may have a role in patients failing to respond to chimeric antigen receptor 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
modified T cell therapy, since we have observed increased expression of PD-1 on 
CTL019/CTL119 with decreased TNF-α and IFN-γ levels in the setting of progressive disease.  
This has also been demonstrated in a laboratory model of CAR T cells in combination with 
PD-1 blockade (John, 2013). 
Based on this data, we have written this phase I/II clinical trial of pembrolizumab in patients 
failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell 
therapy for relapsed or refractory CD19+ lymphomas. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial evaluated the safety and clinical activity of single agent 
pembrolizumab (Hamid, et al., 2013; Garon, et al., 2015).  The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels. 
 
PK data analysis of pembrolizumab administered Q2W and every three week (Q3W) showed 
slow systemic clearance, limited volume of distribution, and a long half-life (refer to 
Investigator’s Brochure).  Pharmacodynamic data (IL-2 release assay) suggested that 
peripheral target engagement is durable (>21 days).  This PK and pharmacodynamic data 
provides scientific rationale for the FDA-approved Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has been found to have a wide 
therapeutic range based on the melanoma indication.  The differences in exposure for a 200 
mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are 
anticipated to remain well within the established exposure margins of 0.5 – 5.0 for 
pembrolizumab in the melanoma indication. The exposure margins are based on the notion of 
similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 
2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). 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 the FDA-approved indications and non-Hodgkin 
lymphoma. 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The change to a fixed dose regimen will simplify the dosing regimen to be more convenient 
for physicians and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce 
complexity in the logistical chain at treatment facilities and reduce wastage. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg Q3W will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose Q3W, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe. 
It is possible that cytokine release syndrome may occur given that these patients have received 
prior treatment with CLT019; thus, if cytokine release syndrome occurs, we have planned for 
dosing hold parameters and dosing modifications (see Section 5.2.1.2 and Section 5.4.2). 
4.2.3 Rationale for Endpoints 
4.2.3.1 Rationale for Efficacy Endpoints 
1) Primary Objective:  To determine the safety of pembrolizumab in patients failing to 
respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell 
therapy for relapsed or refractory CD19+ lymphomas. 
Although pembrolizumab has been approved for use in melanoma, there have been no 
studies in non-Hodgkin lymphoma and the transition to a fixed dose has not been well-
studied.  In previous studies of pembrolizumab, the rates of drug discontinuation due 
to an adverse event were 4.2% in melanoma and 2.6%% in non-small cell lung cancer 
and the rates of drug discontinuation for any reason were 9.4% in melanoma and 21.1% 
in non-small cell lung cancer (see Investigator’s Brochure).  Additionally, given that 
we hypothesize that pembrolizumab may re-activate quiescent chimeric antigen 
receptor T cells, there is the potential for additional toxicity in patients who have 
previously received chimeric antigen receptor T cells.  Thus, we will define safety as ≤ 
30% of patients experiencing toxicities resulting in discontinuation of pembrolizumab. 


 
 
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regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
1. Histologically confirmed follicular lymphoma grade 1-3A, diffuse large B cell 
lymphoma, or mantle cell lymphoma by WHO 2009 classification  
 
2. Relapsed/refractory lymphoma after CTL019/CTL119 
 
3.  No available curative treatment options, a limited prognosis of several months to <2 
years anticipated survival with currently available therapies, and progressive or 
relapsed disease 
 
5.1.2 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 age  18 years on day of signing informed consent. 
3. Have baseline imaging within 6 weeks of enrollment (CT, MR or PET/CT imaging) 
and have measurable disease on physical examination or imaging studies. Any lesion 
≥1.5 cm in long axis dimension is considered measurable. 
4. Have a performance status of 0-1 on the ECOG Performance Scale (Appendix 12.1). 
 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
5. Demonstrate adequate organ function as defined in Table 1Table 1, all screening labs 
should be performed within 14 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥50,000 / mcL 
Hemoglobin 
≥8 g/dL without transfusion or EPO dependency (within 7 days 
of assessment). Subject must demonstrate Hgb 8.0g/dL within 14 
days of treatment initiation and have a Hgb of ≥ 8g/dL 7 days or 
more from last PRBC transfusion 
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 
 
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 estimated per institutional standard. 
 
6. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
7. Female subjects of childbearing potential should 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 
Section5.5.2).  Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year.  
8. 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. 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
5.1.3 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. An exception will be made for patients 
who have received CTL019/CTL119 on experimental protocol; these patients will be 
eligible to enroll once progression of disease or failure to respond is documented by 
clinical or radiologic assessment. 
2.  Patient has received intervening therapy for lymphoma after CTL019/CTL119 
infusion. 
3. Has active cytokine release syndrome from CTL019/CTL119 infusion. 
4. Has a known history of active TB (Bacillus Tuberculosis). 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. Toxicities that are disease related 
will not exclude patients. 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention in the opinion of 
the Principal Investigator prior to starting therapy.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 


 
 
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lymphomas 
 
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. 
10. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. 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.  
11. Has known history of non-infectious pneumonitis that required steroids or has any 
evidence of active non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. 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.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. 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. 
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. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2Table 2 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
Table 2  Trial Treatment 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg  Q3 weeks IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
 
Trial treatment should begin on the day of enrollment or as close as possible to this date. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of the dose to be used in this trial is provided in Section 4.2.2– 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 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 5.4 and 
Events of Clinical Interest Guidance Document for supportive care guidelines, including use 
of corticosteroids. 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 
Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first, followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
Grade 4 
Permanently 
discontinue 
 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold1 
 Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue1 
 Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue2 
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue2 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 
Hypothyroidism 
 
Grade 2-4 
 
Continue  
 
 Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
 
 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs3 
Intolerable/ 
persistent Grade 2 
Withhold 
 Based on type and severity of AE 
administer corticosteroids  
 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1 For 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 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
3 “All other immune-related AEs” excludes hematologic AEs given that hematologic changes are not considered reportable AEs or treatment-limiting 
toxicity (Section 7.3, Section 8.1). For grade 3-4 hematologic toxicity at least possibly related to therapy, therapy will be held until toxicity resolves to 
grade 0-1 or subject’s baseline. 
 
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 
Dose modification for cytokine release syndrome: 
If patients develop cytokine release syndrome grades 1-3 after pembrolizumab, then pembrolizumab will be held until cytokine release 
syndrome resolves. Once cytokine release syndrome has fully resolved, the clinical investigator has the option of restarting 
pembrolizumab at ½ dose (100mg) every 3 weeks. If patients develop grade 4 cytokine release syndrome or require administration of 
tocilizumab, pembrolizumab will be stopped due to drug toxicity. 
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 Principal Investigator and the Data and Safety Monitoring Board. The 
reason for interruption should be documented in the patient's study record. 
5.2.2 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 6.0).  Trial treatment may be administered up to 3 days before or 3 days 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). 
The Pharmacy Manual contains specific instructions for the preparation of pembrolizumab infusion fluid and administration of infusion 
solution. 


 
 
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5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment administered. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing trial.  If there is a clinical 
indication for one of these or other medications or vaccinations specifically prohibited during the trial, discontinuation from trial therapy 
or vaccination may be required.  The investigator should discuss any questions regarding this with the Principal Investigator.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician.  
5.3.1 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 medications 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 and ECIs as defined in Section 7.2 and 7.3. 
5.3.2 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 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 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 used for adrenal insufficiency, treatment of shock, 
or for other indications approved after consultation with the Principal Investigator. 
 Note:  Hematopoietic growth factors, including G-CSF and EPO, are permitted 
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. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 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 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
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 5.2.1.2 for dose 
modification.  
Management of Infusion Related Reactions: Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
Table  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction associated with administration of 
pembrolizumab. 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild transient 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 
Therapy or infusion interruption 
indicated 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 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with, but is not 
limited to: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Corticosteroids 
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. 
 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (e.g., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening consequences; urgent 
intervention 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. 
**In cases of anaphylaxis, epinephrine should be 
used immediately 
Participant is permanently discontinued from 
further further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5 (CTCAE)  
 
5.4.2 Cytokine release syndrome and macrophage activation syndrome 
Given that pembrolizumab will be administered after patients have received CART-19 therapy, the possibility of re-activating CART-
19 cells with subsequent development of cytokine release syndrome exists. 
Overview and Clinical Manifestations: Patients treated with pembrolizumab who have previously received CART-19 may experience a 
cytokine release syndrome (CRS), which has correlated with disease response.    Clinical manifestations have included   high fevers, 
fatigue, anorexia, nausea, vomiting, headache, rash, hypotension (occasionally requiring pressor support)  tachypnea, hypoxia 
(occasionally requiring ventilator support), delirium and confusion (in several patients), evidence of disseminated intravascular 
coagulation as well as macrophage activation syndrome (MAS).  In some cases CRS, TLS and hypotension have led to acute kidney 
injury and several patients have required at least transient dialysis.  The CRS has been effectively abrogated with anti-cytokine directed 
therapy including tocilizumab in most patients. As of July 2014, three patients on another CART-19 trial have died of complications 
related to refractory CRS and intercurrent infections.  It is unclear if treating the CRS adversely impacts the anti-tumor response. 
Features consistent with MAS or HLH have been observed in patients treated with CART 19, coincident with clinical manifestations of 
the CRS. MAS appears to be a reaction to immune activation that occurs from the CRS, and therefore should be considered a 
manifestation of CRS.  
Macrophage activation syndrome (MAS) is similar to Hemophagocytic lymphohistiocytosis (HLH); it is a reaction to immune 
stimulation by infection, autoimmune diseases or other precipitants, but is distinguished from familial or genetically mediated HLH.  
There are no definitive diagnostic criteria for MAS, but it is typically diagnosed by meeting HLH criteria. 
Some but not all features of MAS are typically observed.  The clinical syndrome of MAS is characterized by high grade non-remitting 
fever, cytopenias affecting at least two of three lineages, and hepatosplenomegaly.  It is associated with biochemical abnormalities, 
such as high circulating levels of serum ferritin, soluble interleukin-2 receptor (sCD25), and triglycerides, together with a decrease of 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
circulating NK activity.  Other findings include variable levels of transaminases up to signs of acute liver failure and coagulopathy 
with findings consistent with DIC. A pathologic feature of MAS is the presence of hemophagocytic CD163+ macrophages (HPC) in 
bone marrow or lymph-node aspirates. 
 
Diagnosis of HLH is based on the fulfillment of criteria established in 2004101 for HLH associated with autosomal recessive disorders 
(familial HLH, fHLH).  
 
A diagnosis of non-familial HLH/MAS is made by having 5/8 criteria: 
 Fever 
 Splenomegaly 
 Cytopenias (affecting 2 or more lineages in the peripheral blood; hemoglobin <9 g/dL, platelets <100,000/L, Absolute 
neutrophil count <1000/L) 
 Fasting triglycerides >265 mg/dL , Fibrinogen   < 1.5 g/L 
 Hemophagocytosis in bone marrow or spleen or lymph nodes  
 Low or absent NK-cell activity 
 Ferritin  > 500 g/L 
 Soluble CD25R > 2400 U/L 
 
Supportive clinical criteria include neurologic symptoms and cerebrospinal ﬂuid pleocytosis, conjugated hyperbilirubinemia, and 
transaminitis, hypoalbuminemia and hyponatremia. Typically, high fevers, cytopenias, and when performed, hemophagocytosis in the 
bone marrow is observed (though marrow specimens at the time of the reaction are not often taken). Soluble CD25R and NK cell 
activity are not standard tests, though samples are taken for retrospective CD25R analysis.  Therefore, patients may not meet strict 
definition of HLH/MAS, but given the constellation of findings, and the consistent dramatic elevation in Ferritin, this is indeed the 
reaction associated with the CRS.   
 


 
 
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At this time it is still unknown whether CRS/MAS is beneficial or harmful to the antitumor response.  Research monitoring data showed 
that IL6 levels were extraordinarily high during the CRS, prompting us to use an anti-IL6 receptor antibody tocilizumab to treat the 
CRS/MAS.  The majority of patients treated with tocilizumab for CRS and MAS had rapid (within hours) resolution of dramatic fevers, 
and continuous improvement in hypotension and hypoxia over hours to several days, and showed improvement in biochemical evidence 
of CRS and MAS within 48 hours.  Adult patients were treated with tocilizumab 4mg/kg or 8mg/kg.  It is unclear if early treatment will 
negate the antitumor response.  Treatment and timing of treatment of this toxicity will be at the discretion of the patient’s physician and 
the study principal investigator, and occur in the setting of hemodynamic instability. 
Management of cytokine release syndrome 
Some patients who have responded to CART-19 cells have experienced a CRS. Cytokine production is required for the activation, 
expansion and cytolytic function of T cells and for CART-19 T cells.  Therefore some degree of CRS may be a desired clinical outcome. 
Premature or early intervention with anti-cytokine therapy may therefore abrogate the anti-tumor efficacy of CART-19. Subsequent to 
this experience, selective tocilizumab (an anti-IL6-receptor antibody) therapy has been utilized (described below) with effective toxicity 
management and successful ongoing CART-19 T cell expansion in patients. Please note, steroids or other immunosuppressant drugs 
should NOT be used as pre-medication for pembrolizumab but may be considered in the management of CRS.  
The moderate to severe cases of CRS observed required intervention with tocilizumab, with or without high dose corticosteroids, 
between 2 and 9 days after T cell infusion. This resulted in rapid reversal of the high persistent fevers associated with CRS in most but 
not all patients. 
Given the dramatic clinical improvement of most patients treated with anti-cytokine therapy, patients with moderate to severe cytokine 
toxicities should be first managed with administration of tocilizumab. 
Tocilizumab should be used as a weight-based dose of 8 mg/kg at the time of hemodynamic instability. This management approach is 
designed to avoid life-threatening toxicities, while attempting to allow the CART-19 cells to establish a proliferative phase that appears 
to correlate with anti-tumor efficacy. Thus, the timing of the tocilizumab should be individualized, in close consultation with the 
Principal Investigator and/or expert consultants for the trial.  Steroids have not always been effective in this setting and may not be 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
necessary given the rapid response to tocilizumab. Because steroids will interfere with CART-19 function and efficacy, if used, they 
should be rapidly tapered.  
Upon developing the prodrome of high-persistent fevers following CART-19 infusion, patients should then be followed closely. 
Infection and tumor lysis syndrome work up should be immediately undertaken.  The pharmacy should be notified of the potential need 
for tocilizumab.  Patient management in an intensive care unit may be required and the timing is dependent upon local institutional 
practice. In addition to supportive care, tocilizumab may be administered in cases of moderate to severe CRS, especially if the patient 
exhibits any of the following: 
 Hemodynamic instability despite intravenous fluid challenges and moderate stable vasopressor support 
 Worsening respiratory distress, including pulmonary infiltrates, increasing oxygen requirement including high-flow O2, 
and/or need for mechanical ventilation.  
 Any other signs or symptoms of rapid deterioration despite medical management 
 
The recommended dosing for tocilizumab is 8 mg/kg i.v. single dose. Not all Grade 4 CRS reactions following CART-19 have been 
immediately treated with tocilizumab and decisions are, in part, based upon the rapidity of the syndrome onset and underlying patient 
reserve. 
Other anti-cytokine therapies, such as repeat administration of tocilizumab or use of siltuximab or etanercept, may also be considered if 
the patient does not respond to the initial dose of tocilizumab.  If the patient experiences ongoing CRS despite administration of anti-
cytokine directed therapies, anti T-cell therapies such as Cytoxan, ATG, Campath may be considered.   
CRS has been associated with biochemical and physiologic abnormalities consistent with MAS.  Moderate to extreme elevations in 
serum C-reactive protein (CRP) and ferritin have been seen with CART-19 associated CRS, however the magnitude and kinetics vary 
greatly between individual patients.  CRS management decisions should be based upon clinical signs and symptoms and response to 
interventions, not these laboratory values per se. 


 
 
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persons without prior written authorization from the regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
CTCAE grading of CRS relates to its occurrence with acute infusional toxicities, whereas the CRS associated with CART-19 therapy is 
not acute, but rather delayed. Refer to Section 7.3.3 for modified definitions of grading of CART-19 delayed CRS events.  
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea or vomiting. 
5.5.2 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 7.2.2-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. 


 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
5.5.3 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 7.2.2. 
5.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab 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. 
5.6 
Subject Withdrawal/Discontinuation 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 trial plan is violated, or for administrative and/or other safety reasons.  Specific details regarding discontinuation or 
withdrawal are provided in Section 7.1.3– 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 radiographic disease progression 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
Note: For unconfirmed radiographic disease progression, if a biopsy is felt clinically necessary, patients may continue 
pembrolizumab until progression is biopsy confirmed. 
Progressive disease (PD): Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns with immunotherapy may extend beyond the typical 
course of responses seen with cytotoxic agents and can manifest as a clinical response preceded by initial increase in tumor 
burden, the appearance of new lesions, or a mixed response with some enlarging lesions while other lesions are regressing. 
Therefore, if the investigator feels the patient has clinical benefit, subjects may continue pembrolizumab until progression is 1) 
confirmed at follow-up imaging at next response assessment unless clinically indicated to perform sooner and 2) found to have 
progressive disease at a subsequent imaging evaluation. 
Evidence of PD will be based on a comparison with baseline (or nadir) scans or other evaluations. 
Subjects with PD on imaging should be managed as follows: 
Subjects will be permitted to continue pembrolizumab beyond first confirmed progressive disease as measured by the 2007 
Revised response criteria for malignant lymphoma as long as the following are true: 
• Investigator assessed clinical benefit 
AND 
• Subject is tolerating pembrolizumab 
 
Subjects that meet the above criteria and continue pembrolizumab must discontinue pembrolizumab upon the next documented 
event of PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the subject is clinically 
deteriorating and unlikely to receive any benefit from continued treatment. The decision to continue treatment should be 
discussed with the Principal Investigator and Medical Monitor and documented in the study records. 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 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 
 Completed 12 months of uninterrupted treatment with pembrolizumab or 18 administrations of study medication, whichever is 
later. 
Note: 12 months of study medication is calculated from the date of first dose. Subjects who stop pembrolizumab after 12 months 
may be eligible for up to one year of additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.3.5 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7.1.3 Visit Requirements.  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 in Section 7.2.3.1). 
5.7 
Second Course 
Additional details are provided in Section 7.1.3.5. 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
5.8 
Subject Replacement Strategy 
1. If a subject is enrolled, but does not receive any doses of pembrolizumab, they may be replaced, to allow for a total of 12 subjects 
treated with pembrolizumab who are assessed for response rate 
2. If a subject receives one dose of pembrolizumab but is removed from study for a reason aside from toxicity prior to receiving 4 
doses of pembrolizumab, this patient may be replaced to allow for a total of 12 subjects treated with pembrolizumab who are 
assessed for response rate. Patients removed prior to 3 months who have not experienced toxicity will be included for efficacy 
analyses but will not be included in toxicity analysis. 
5.9 
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 
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. 
 


 
 
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screenin
g 
Treatment cycles and week # 
 
End of 
Treatme
nt 
Treatment Cycle^^: 
Main 
Study 
Screening 
C1 
 
C2 
 C3 to C8 
C9 
onward
s 
Discon 
Safety 
Follow-up 
Visit 
Follow-up 
Day (relative to each cycle): 
-28 to -1 
D0 
(W0) 
D3 
D7 
D14 
D0 
D7 
D14 
D0 
D0 
 
 
 
Scheduling Window (Days): 
 
-3B 
 
±1 
± 3 
± 3 
± 3 
± 3 
±3  
± 3 
± 7 
At time 
of 
Discon 
30 days 
post 
discon 
± 2 weeks 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
 
 
Trial Treatment Administration 
 
x 
 
 
 
x 
 
 
x 
x 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Survival Status 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Review Adverse Events 
 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 
Full Physical Examination 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 


 
 
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persons without prior written authorization from the regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
Trial Period: 
Screenin
g 
Treatment cycles and week # 
 
End of 
Treatme
nt 
Treatment Cycle^^: 
Main 
Study 
Screening 
C1 
 
C2 
 C3 to C8 
C9 
onward
s 
Discon 
Safety 
Follow-up 
Visit 
Follow-up 
Day (relative to each cycle): 
-28 to -1 
D0 
(W0) 
D3 
D7 
D14 
D0 
D7 
D14 
D0 
D0 
 
 
 
Scheduling Window (Days): 
 
-3B 
 
±1 
± 3 
± 3 
± 3 
± 3 
±3  
± 3 
± 7 
At time 
of 
Discon 
30 days 
post 
discon 
± 2 weeks 
Vital Signs 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 
ECOG Performance Status (Appendix 12.1) 
x 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
 
Electocardiogram (EKG) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or Serum -HCG 
x 
xB 
 
 
 
x 
 
 
xE 
x 
 
x 
 
PT/INR and aPTT 
x 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
x 
xB 
xC 
xD 
xD 
x 
xD 
xD 
xE 
x 
 
x 
 
Comprehensive Serum Chemistry Panel,, 
LDH 
x 
xB 
xC 
xD 
xD 
x 
xD 
xD 
xE 
x 
 
x 
 
Uric acid, phosphate 
x 
xBD 
xC 
xD 
xD 
x 
xD 
xD 
xI 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
TSH with reflex to T4 
x 
xB 
 
 
 
x 
 
 
x 
xF 
 
x 
 
Tumor Imaging 
xA 
Week 12 then every 12 weeks from most recent imaging 
PET/CT, CT of chest/abdomen/pelvis, or MRI 
chest/abdomen/pelvis ± 2 wk for 24 months 
 
xA 
 
xA 
HIV, Hep B sAg/sAb/cAb, HCV Ab 
xG 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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persons without prior written authorization from the regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen 
receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
 
Trial Period: 
Screenin
g 
Treatment cycles and week # 
 
End of 
Treatme
nt 
Treatment Cycle^^: 
Main 
Study 
Screening 
C1 
 
C2 
 C3 to C8 
C9 
onward
s 
Discon 
Safety 
Follow-up 
Visit 
Follow-up 
Day (relative to each cycle): 
-28 to -1 
D0 
(W0) 
D3 
D7 
D14 
D0 
D7 
D14 
D0 
D0 
 
 
 
Scheduling Window (Days): 
 
-3B 
 
±1 
± 3 
± 3 
± 3 
± 3 
±3  
± 3 
± 7 
At time 
of 
Discon 
30 days 
post 
discon 
± 2 weeks 
Archival or Newly Obtained Tissue 
Collection (optional) 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
Correlative Studies Blood CollectionH 
(optional) 
x 
xB 
xH 
xD 
xD 
x 
xD 
xD 
through 
C4 
 
x 
 
 
^^Please note that for study purposes, Day 0 / Week 0 / Cycle 1 refers to the date of the first infusion 
A See Section 6.3 
BCycle 1, Day 0 labs will be drawn within 3 days prior to infusion; screening labs may double as Cycle 1, Day 0 labs if they are 
performed within this timeframe 
CLabs will be drawn Day 3 ± 1 day after Cycle 1 infusion 
DFor Cycles 1 and 2, labs will be drawn weekly ± 3 days at one week and two weeks after each infusion 
EFrom Cycle 3-8, labs will be drawn ± 3 days prior to each dose of pembrolizumab 


 
 
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FBeginning with Cycle 9 of pembrolizumab), labs may be drawn every odd-numbered cycle (i.e. prior to every other dose) ± 1 week 
until drug discontinuation. 
GWithin 3 months of enrollment 
HSee Section 6.5 
IOnly for Cycle 3 


 
 
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regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
 
6.2 
Physical examination and adverse events 
Physical examination including vital signs, as well as determination of ECOG performance 
status will be obtained prior to start of each cycle of pembrolizumab. 
Review of adverse events will be performed prior to start of each cycle of pembrolizumab. 
Review of concomitant medications will be performed prior to the start of each cycle of 
pembrolizumab. 
6.3 
 Imaging studies 
ABaseline imaging must be performed within 6 weeks of first dose of pembrolizumab. This 
may be obtained by contrast-enhanced CT, contrast-enhanced MRI, or PET/CT. Imaging for 
response assessment should be performed at week 12 after first dose of pembrolizumab, and 
then should be performed every 12 weeks from most recent imaging PET/CT, CT of 
chest/abdomen/pelvis, or MRI chest/abdomen/pelvis ± 2 weeks until 24 months after first dose 
of pembrolizumab. After 24 months, subjects who did not discontinue study due to progression 
of lymphoma or toxicity will transition to the follow-up period and be followed with imaging 
every 6 months ± 2 weeks until 60 months after first dose of pembrolizumab. 
Subjects will be reimaged at the time of pembrolizumab discontinuation ± 2 weeks unless they 
are coming off study for toxicity, coming off study with recently documented complete 
response (within 8 weeks), or coming off study after > 1 year of follow-up. 
6.4 
Laboratory studies 
 
Screening tests (within 28 days prior to enrollment): CBC with differential, CMP, uric 
acid, phosphate, TSH with reflex to T4, PT/PTT, HIV (to be performed within 3 months of 
enrollment), Hepatitis B surface antibody / surface antigen, core antibody (to be performed 
within 3 months of enrollment), Hepatitis C antibody (to be performed within 3 months of 
enrollment) urinalysis, urine or serum pregnancy test if the subject is a woman whose last 
menstrual period was < 18 months ago. EKG will also be obtained. 
Cycle 1, Day 0 (labs within 3 days prior to infusion; screening labs may double as Cycle 1, 
Day 0 labs if they are performed within this timeframe): CBC with differential, CMP, LDH, 
uric acid, phosphate, TSH with reflex to T4, urine or serum pregnancy test if the subject is a 
woman whose last menstrual period was < 18 months ago. 
 
Cycle 1, day 3 ± 1 day: CBC with differential, CMP, LDH, uric acid, phosphate 


 
 
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lymphomas 
 
 
Cycle 1 (labs one week and two weeks after cycle 1 infusion ± 3 days): CBC with 
differential, CMP, LDH, uric acid, phosphate 
Cycle 2 (labs within 3 days prior to the infusion): CBC with differential, CMP, LDH, 
uric acid, phosphate, TSH with reflex to T4, urine or serum pregnancy test if the subject is a 
woman whose last menstrual period was < 18 months ago.  
Cycle 2 (labs one week and two weeks after cycle 2 infusion ± 3 days): CBC with 
differential, CMP, LDH, uric acid, phosphate 
 
Cycles 3-8 (labs every 3 weeks within 3 days prior to each cycle): CBC with 
differential, CMP, LDH, uric acid (only for cycle 3), phosphate (only for cycle 3), TSH with 
reflex to T4, urine or serum pregnancy test if the subject is a woman whose last menstrual 
period was < 18 months ago. 
 
Cycles 9-onwards, labs prior to every cycle of pembrolizumab within 1 week prior to 
each cycle: CBC with differential, CMP, LDH, urine or serum pregnancy test if the subject is 
a woman whose last menstrual period was < 18 months ago. 
 
Cycles 9-onwards (labs prior to each odd cycle of pembrolizumab within 1 week prior 
to each cycle): TSH with reflex to T4 
6.5 
Optional correlative studies 
Subjects will have blood drawn prior to the first infusion, then at 24 hours, 48 hours, and 72 
hours, as well as day 7, day 14, day 21, then prior to each successive dose of pembrolizumab 
through cycle 4.  Given that these are exploratory studies, the timing of these labs may be 
flexible.  The total amount of blood drawn at a single time will not exceed 30cc and the 
maximum volume drawn will not exceed 330cc. 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the 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 


 
 
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or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
The consent process will be documented for every subject. This process will involve a) 
documentation of the consent discussion and obtaining consent via the b) IRB approved 
Informed Consent Form.  
Documentation of the consent discussion will record that the study was explained to the subject 
along with the risks and benefits and that the subjects had no questions or all questions were 
answered and both the subject and person obtaining consent signed the consent form on “X” 
date and a signed copy was given to the subject for his/her records. 
Only designated members of the study team, who are qualified through education and 
experience and who have completed CITI certification will obtain consent from subjects. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   


 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
7.1.1.2 Adult subjects not competent to give consent 
This will be approached on a case-by-case basis by the Principal Investigator in consultation 
with the IRB, DSMB, and study supporter. 
Adult subjects who are deemed by informal assessment by the investigator to have concern for 
inability to give informed consent will be further evaluated for medical decision-making 
capacity to give consent by a study investigator. In the event the patient is unable to give 
informed consent, a "legally responsible party", will be advised when the patient's primary 
oncologist is considering enrollment on this clinical trial. The patient's legally responsible 
party, must give informed consent prior to participation. The following individuals may be 
considered legally authorized representatives of the subject and capable of providing surrogate 
consent (or surrogate HIPAA Authorization):  
 A court-appointed guardian authorized to consent to the subject's participation in the 
protocol in a current court order issued within the subject's jurisdiction 
 A health care agent appointed by the subject in a power of attorney 
 A "health care representative" when the subject cannot speak for themselves and where 
there has been no guardian appointed by the court or health care power of attorney 
designated by the patient 
Any member of the following classes, in descending order of priority, who is reasonably 
available may act as the subject’s health care representative: 
 The spouse (unless an action for divorce is pending) and adult child or children of 
another relationship. 
 Adult children (18 years of age or older). 
 A parent. 
 An adult sibling. 
 An adult grandchild 
 An adult who has knowledge of the patient’s preferences and values, including but not 
limited to religious and moral beliefs 


 
 
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Assent, will be obtained from the subject, if they are able to provide it, prior to participation. 
7.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.4 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.   
7.1.1.5 Prior and Concomitant Medications Review 
7.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 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.  
7.1.1.5.2 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 as 
defined in Section 7.2. 
7.1.1.6 Disease Details and Treatments 
7.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 


 
 
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lymphomas 
 
7.1.1.6.3 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 the first dose of the new therapy.  Once new anti-cancer 
therapy has been initiated the subject will move into survival follow-up (see Section 
7.1.3.4). 
7.2 Clinical Procedures/Assessments 
7.1.1.7 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 5.0 (see Section 12.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
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 (termed immune-related adverse 
events, or irAEs); see the separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.1.8 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,  
7.1.1.9 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart (i.e., cycles with 
an even number beginning with Cycle 4), the investigator or qualified designee will perform a 
directed physical exam as clinically indicated prior to trial treatment administration.   


 
 
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lymphomas 
 
7.1.1.10 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to and at the 
conclusion of the administration of each dose of trial treatment and at the time patient is 
removed from study as specified in the Trial Flow Chart (Section 6.0).  Vital signs should 
include temperature, pulse, and blood pressure.   
7.1.1.11 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Appendix 12.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.1.12 Tumor Imaging and Assessment of Disease 
Baseline imaging must be performed within 6 weeks of first dose of pembrolizumab. This may 
be obtained by contrast-enhanced CT, contrast-enhanced MRI, or PET/CT. Imaging for 
response assessment (Cheson, 2007) should be performed prior to week 12 after first dose of 
pembrolizumab, and then should be performed every 12 weeks from most recent imaging 
PET/CT, CT of chest/abdomen/pelvis, or MRI chest/abdomen/pelvis ± 2 weeks until 24 
months after first dose of pembrolizumab.  
At time of pembrolizumab discontinuation ± 2 weeks, subjects will be reimaged unless they 
are coming off study for toxicity, coming off study with recently documented complete 
response (within 8 weeks of most recent imaging), or coming off study after > 1 year of follow-
up. 
7.1.1.13 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 Blood may be optionally collected for correlative studies up to 3 days before pembrolizumab 
administration during cycles 1, 2, 3, and 4. Further optional blood draws may occur at time of 
routine laboratory study blood draws scheduled near time of imaging. These labs may be 
collected within 7 days before that week’s dose of pembrolizumab. 
7.1.1.14 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in the table: Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   
 


 
 
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
 
Absolute Neutrophil Count 
 
results are noted 
Thyroxine (T4) 
Absolute Lymphocyte Count 
 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
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.   
‡ If considered standard of care in your region. 
 


 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to the first dose of 
treatment.  Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  


 
 
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7.1.2 Other Procedures 
7.1.2.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 12 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.3 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.3.1 Screening Period 
Baseline imaging must be obtained within 6 weeks of first dose of pembrolizumab. Laboratory 
requirements for enrollment eligibility are listed in the study flow chart (Section 6.1) and entry 
criteria (Section 5.1).  
7.1.3.2 Treatment Period 
Subjects will receive pembrolizumab every 3 weeks for up to 18 cycles or 54 weeks, whichever 
is later. 
7.1.3.3 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days ± 1 week 
after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  If it is not medically safe to delay initiation of a new anti-cancer therapy 
until a safety follow-up visit is performed, it is permissible to have the safety visit soon after 
initiation of new anti-cancer therapy, but this should be noted in the patient’s record. 
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 


 
 
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days of the end of treatment or before initiation of a new anti-cancer treatment should also be 
followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab (as 
described in Section 7.1.3.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
7.1.3.4 Follow-up Visits 
Subjects who discontinue trial treatment for toxicity will be followed at least monthly or more 
frequently at the discretion of the study investigator until stabilization, return to baseline, 
resolution of toxicity, or initiation of a new cancer treatment. 
Subjects who discontinue trial treatment for a reason other than disease progression or toxicity 
(i.e., elective discontinuation of therapy) will move into the Follow-Up Phase and should be 
assessed depending upon time from first dose of pembrolizumab. If the patient is within 24 
months from first dose of pembrolizumab, follow-up imaging will occur  every 12 weeks from 
most recent imaging PET/CT, CT of chest/abdomen/pelvis, or MRI chest/abdomen/pelvis ± 2 
weeks until 24 months after first dose of pembrolizumab. After 24 months, subjects will be 
followed with imaging every 6 months ± 2 weeks until 60 months after first dose of 
pembrolizumab.  Adverse events will be collected and reported per adverse event sections 
7.2.3.1 and 7.3.  Information regarding post-study anti-neoplastic treatment will be collected 
if new treatment is initiated.  
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.3.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment. 
7.1.3.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to an additional 17 
cycles (approximately one year) pembrolizumab treatment if they progress after stopping study 
treatment from the initial treatment phase.  This retreatment is termed the Second Course Phase 
of this study and is only available if the study remains open and the subject meets the following 
conditions: 
 Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR, and 
 Was treated for at least 8 cycles with pembrolizumab before discontinuing 
treatment, and 


 
 
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 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 12 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of study treatment 
 The subject meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria 
 The study is ongoing 
A drug-related toxicity, objective response or disease progression that occurs during the 
Second Course Phase for a subject will not be counted as an event for safety or efficacy 
analyses in this study. 
*Note: patients must have measurable disease at the start of re-treatment to be eligible for 
this provision. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
7.2 
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 pembrolizumab, 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 


 
 
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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. 
Adverse events may occur during the course of the use of pembrolizumab 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 will not occur in screened subjects prior to receiving ANY dose of 
pembrolizumab. 
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 of first dose of pembrolizumab through 
completion of the Safety Follow Up Visit, and at each examination on the Adverse Event case 
report forms/worksheets. The reporting timeframe for adverse events meeting any serious 
criteria is described in sections 7.2 and 7.3. 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event. As was noted above, events related to 
the cytotoxic chemotherapy will be excluded from adverse event reporting.  
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
 
7.2.1 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. 


 
 
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If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of pembrolizumab 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) 
7.2.2 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) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
pembrolizumab 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); 


 
 
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 Is associated with an overdose; 
 Is an other important medical event  
Refer to Table 6 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 (i.e. last dose of 
pembrolizumab), or the initiation of new anti-cancer therapy, whichever is earlier, whether or 
not related to pembrolizumab, must be reported within 24 hours of discovery to the Sponsor 
(SJ Schuster, schustes@mail.med.upenn.edu or 215-662-400 / page Dr. Schuster). Dr. Schuster 
and the study team will be responsible for reporting SAEs to the University of Pennsylvania 
IRB, the medical monitor, and the DSMC per reporting of Adverse Events Section 7.3 below. 
Any serious adverse event must also be reported within 2 working days to Merck Global Safety 
in the form of a completed CIOMS I/Medwatch. All information shall contain the reporter’s 
name and the Study subject identifier code.  
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 pembrolizumab 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. 
7.3 
Reporting of Adverse events 
HEMATOLOGIC GRADE 3 OR GREATER ADVERSE EVENTS WILL NOT BE 
REPORTED unless they are determined by the Principal Investigator to be unanticipated and 
clinically significant.Penn IRB Reporting: 
(1) Unanticipated problems including suspected adverse reactions and adverse reactions 
 An event is considered a “suspected adverse reaction” when there is reasonable 
possibility that the drug/investigational product caused the adverse event.  For these 
reporting purposes, reasonable possibility means there is evidence to suggest a causal 
relationship between the drug/investigational product and the event. 
 An event is considered probably or definitely related to the research procedures. 
(2) In addition to unanticipated problems, the IRB also requires prompt reporting of the 
following events:  
 Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 


 
 
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 Violation or deviation (meaning an accidental or unintentional change to the IRB 
approved protocol) only when: one or more participants were placed at increased risk 
of harm, or, the event has the potential to occur again, the event represents serious or 
continuing noncompliance.  
 Breach of confidentiality. 
 Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to 
remain on the study. 
 
REPORTS MUST BE SUBMITTED ELECTRONICALLY at:  
https:\\medley.isc-seo.upenn.edu\hsProtocol\jsp\fast.do 
 
The IRB requires investigators to submit reports within 10 working days (with one 
exception) of events that meet the definition of an unanticipated problem involving risks to 
subjects or others.  Exception: If the adverse event involved a death and indicates that 
participants or others are at increased risk of harm, investigators are required to submit a 
report to the IRB within 3 days. 
 
Penn DSMC Reporting: 
 All grade 3 or higher events (unless listed as exclusionary) within ten business days 
of knowledge 
 All unexpected deaths within two business days of knowledge 
 All others deaths within 30 days of knowledge. Deaths of subjects off-study for 
greater than 90 days from the last study treatment/intervention are not reportable 
 
REPORTS MUST BE SUBMITTED ELECTRONICALLY VIA VELOS. 
Events will be reported for 30 days following the last study intervention (i.e., last dose of 
pembrolizumab), or for the protocol defined follow-up if greater than 30 days after the last 
study intervention. 
Penn Medical Monitor Reporting: 
 All events reported to the Penn DSMC or non-serious Events of Clinical Interest reported 
to Merck Global safety will be reported within the same required timeframes as for the 
Penn DSMC and Merck reporting requirements, respectively. If there are conflicting 
timeframes, the shorter timeframe will be used. 


 
 
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lymphomas 
 
 A summary of SAEs and therapy-limiting toxicities will be forwarded to the medical 
monitor for review after every 3 patients are enrolled and receive at least 4 doses of 
therapy or every 3 months, whichever occurs first. 
Merck: SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number: +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
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. 
7.3.1.1 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 of discovery 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 pembrolizumab, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
1. Additional adverse events: 


 
 
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lymphomas 
 
 
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”).  This document can be found in Appendix 4 and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs.   
 
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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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
 
7.3.2 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 5.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the adverse event case report forms/worksheets. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to 
Grades 1-4, will be used. Subjects will be monitored by medical histories, physical examinations, and blood studies to detect potential 
toxicities from the treatment. 
 
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V5.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mild 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 of hospitalization indicated; 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 pembrolizumab 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 


 
 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
 
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 pembrolizumab to be discontinued? 
Relationship to 
test drug  
Did pembrolizumab cause the adverse event? The determination of the likelihood that pembrolizumab 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 pembrolizumab and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely pembrolizumab caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to pembrolizumab such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of pembrolizumab?  
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 
Pembrolizumab 
(continued)  
Dechallenge 
Was pembrolizumab 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 pembrolizumab; or (3) the trial is a single-dose drug trial); or (4) pembrolizumab is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to pembrolizumab 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) pembrolizumab is used only one time). 


 
 
 
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receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY PEMBROLIZUMAB, OR IF REEXPOSURE TO PEMBROLIZUMAB 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 pembrolizumab 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 pembrolizumab relationship). 
Yes, there is a reasonable 
possibility of pembrolizumab 
relationship. 
There is evidence of exposure to pembrolizumab.  The temporal sequence of the AE onset relative to the administration of pembrolizumab is 
reasonable.  The AE is more likely explained by pembrolizumab than by another cause. 
No, there is not a reasonable 
possibility pembrolizumab 
relationship 
Subject did not receive pembrolizumab OR temporal sequence of the AE onset relative to administration of pembrolizumab is not reasonable OR 
there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


 
 
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lymphomas 
 
7.3.3 Modification of CTC Grading scale for Cytokine Release Syndrome (CRS) 
The CTCAE grading system was developed to capture a cytokine release syndrome occurring 
during infusional therapy and is inadequate to capture the delayed CRS that occurs after 
CART-19 infusions.  We propose to modify the CTC grading specifically to capture toxicity 
for protocols using CART-19 cells (Table 7.2.5a). Related definitions can be found in Table 
7.2.5b. 
Recipients of CART-19 cells may develop a cytokine release syndrome.  Data from small 
numbers of patients show marked elevations in IL6, IFN-g, and less intensely TNF among 
other cytokines.  Elevations in clinically available markers of inflammation including ferritin 
and CRP have also been observed to correlate with the clinical CRS syndrome. 
Symptoms usually occur 1-14 days after cell infusion, but the syndrome is not defined by the 
timing of the reaction.  Patients developing any symptoms attributable by the investigator as 
related to cytokine release should be reported as having had a CRS. Symptoms may include: 
 High fevers 
 Rigors 
 Sweating 
 Nausea 
 Vomiting 
 Anorexia 
 Fatigue 
 Headache 
 Myalgia/arthralgia 
 Hypotension 
 Dyspnea 
 Tachypnea 
 Hypoxia 
 Altered mental status 
 End organ dysfunction 
 Signs of macrophage activation syndrome including hemophagocytosis and hemolysis 
For the purposes of reporting and grading on clinical trials using CART-19 cells, we will 
use the following grading for CRS Toxicity.  The start date of CRS is a retrospective 
assessment of the date of onset of persistent fevers and/or myalgia consistent with CRS 
and not explained by other events (i.e. sepsis). The stop date of CRS is defined as the date 
when the patient has been afebrile for 24 hours and off vasopressors for 24 hours. 
 
 


 
 
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lymphomas 
 
 
Table 7.2.5a - CRS Toxicity Grading 
1 
2 
3 
4 
5 
Mild 
reaction: 
Treated 
with 
supportive 
care such 
as anti-
pyretics, 
anti-
emetics 
Moderate reaction 
requiring IV 
fluids or 
parenteral 
nutrition; some 
signs of organ 
dysfunction (i.e. 
grade 2 creatinine 
or grade 3 liver 
function tests 
([LFTs] related to 
CRS and not 
attributable to any 
other condition).   
Hospitalization 
for management 
of CRS related 
symptoms 
including fevers 
with associated 
neutropenia.  
More severe reaction: 
Hospitalization required for 
management of symptoms 
related to organ dysfunction 
including: 
 grade 4 LFTs 
 grade 3 creatinine related to 
CRS and not attributable to 
any other conditions 
 hypotension requiring 
multiple fluid boluses for 
blood pressure support or 
low-dose pressors (see 
Table 7.2.5b) 
 coagulopathy requiring 
fresh frozen plasma or 
cryoprecipitate 
 hypoxia requiring 
supplemental oxygen (nasal 
cannula oxygen, high flow 
oxygen, Continuous 
Positive Airway Pressure 
[CPAP] or Bilateral 
Positive Airway Pressure 
[BiPAP]) 
Patients admitted for 
management of suspected 
infection due to fevers and/or 
neutropenia may have grade 2 
Life-threatening 
complications 
such 
as 
hypotension 
requiring 
high-
dose 
pressors 
(see 
Table 
7.2.5b) 
or 
hypoxia 
requiring 
mechanical 
ventilation 
Death 


 
 
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lymphomas 
 
Table 7.2.5a - CRS Toxicity Grading 
CRS and this excludes 
management of fever or 
myalgias 
 
Table 7.2.5b High Dose Vasopressor Use 
Definition of “High-Dose” Vasopressors 
Vasopressor 
Dose for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 20 mcg/kg/min 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 200mcg/min 
Epinephrine monotherapy 
≥ 10 mcg/min 
If on vasopressin 
High-dose if vaso +  Norepinephrine Equivalent (NE) of 
>10 mcg/min (using Vasopressin and Septic Shock Trial 
(VASST) formula) 
If 
on 
combination 
vasopressors (not vasopressin) 
Norepinephrine equivalent of ≥ 20 mcg/min (using VASST 
formula) 
Vasopressin and Septic Shock Trial (VASST) Equivalent Equation: 
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine 
(mcg/min)] + [phenylephrine (mcg/min) ÷10] 
7.3.4 Sponsor Responsibility for Reporting Adverse Events including Deviations and 
Exceptions 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  


 
 
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Reportable Events: 
Any accidental or unintentional deviation from the approved protocol, identified 
retrospectively, that in the opinion of the investigator or as defined by the protocol, placed one 
or more participants at increased risk, compromises the rights or welfare of subjects, and/or 
disrupts the study design, is considered a reportable event and must be reported to the Study 
Principal Investigator, Study Medical Monitor, IRB, and ACC DSMC within 10 working days 
of notification. Principal Investigator and Medical Monitor approval/acknowledgement must 
be received first and included in with the IRB/DSMC submission. Deviations to protect 
subjects from immediate harm/danger should be reported immediately following the event to 
the entities outlined above. 
 
Exceptions (Prospective action): 
An exception is defined as a one-time, intentional action or process that departs from the IRB 
and CTSRMC approved study protocol, intended for one occurrence. If this action disrupts the 
study progress, such that the study design or outcome (endpoints) may be compromised, or the 
action compromises the safety and welfare of study subjects (i.e., requests to enroll and/or treat 
subjects outside of the current protocol criteria), advance documentation of Medical 
Monitor, IRB, and DSMC approval is required. Principal Investigator and Medical Monitor 
approval must be received first and included in with the IRB/DSMC submission. All entities 
should be given sufficient time to evaluate this request. 
Deviations (Retrospective action): 
A one time, unintentional action or process that departs from the IRB and CTSRMC approved 
study protocol, involving one incident and identified retrospectively, after the event occurred. 
If the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or 
compromises the safety and welfare of the subjects, the deviation must be reported to the 
DSMC within 5 business days and the IRB within 10 business days.  
For reportable deviations, documentation of the Medical Monitor response must be submitted 
to the DSMC with the report. 
Deviations that do not meet the definition above of “reportable” will be explained in a memo 
to file or recorded on a deviation log and will contain documentation of the PI’s assessment 
of the impact of the deviation on safety and study outcomes. 
 


 
 
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8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan 
8.1.1 Primary Objectives & Hypotheses 
(1) Objective:  To determine the safety of pembrolizumab in patients failing to respond to 
or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for 
relapsed or refractory CD19+ lymphomas. Safety will be assessed by adverse event 
monitoring. Patients who have received at least one dose of pembrolizumab will be 
considered evaluable for safety. In this trial, success will be defined as receiving at least 
one dose of pembrolizumab and the lack at least possibly related adverse events leading 
to permanent discontinuation of pembrolizumab. Patients who experience Grade 3 or 
higher non-hematologic toxicity leading to permanent pembrolizumab discontinuation 
or any Grade 4 non-hematologic toxicity or cytokine release syndrome at least possibly 
related to pembrolizumab will be considered toxicity failures. 
Methodology: We will use a Bayesian monitoring rule to assure that the failure rate is 
no greater than 30%. Monitoring will begin with the first patient. Because little 
information is available on the safety of this drug in lymphoma, we will assume a non-
informative Beta(1, 1) prior distribution for the failure rate. We will denote the rate of 
pembrolizumab discontinuation as failure rate, FR, and will use the following 
monitoring rule in the interest of patient safety: we will stop the trial if at any time:  
Pr[FR > 0.30 | data from the trial] >= 97.5%  
That is, if at any time during the study, we can conclude that there is at least a 97.5% chance 
that the failure rate is greater than 30%, we will stop the study. The stopping boundaries 
corresponding to this probability criterion are to terminate the trial if:  
(# of patients that experience failure) / (# of patients evaluated) ≥ 3/3, 3/4, 4/5, 4/6, 5/7, 
5/8, 6/9, 6/10, 7/11, 7/12. Any patient who has received at least one dose of pembrolizumab 
will be included in this denominator for evaluable patients if they have received at least 4 
doses of pembrolizumab and not experienced toxicity OR if they have experienced any 
toxicity with any dose of pembrolizumab. 
If the study is not terminated early, it will continue until all patients have been treated with 
pembrolizumab and completed all follow up evaluations.  
Hypothesis:  Pembrolizumab will be safely tolerated with ≤ 30% of patients experiencing 
toxicities resulting in discontinuation of pembrolizumab 


 
 
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8.1.2 Secondary Objectives & Hypotheses 
Any patient who receives at least one dose of pembrolizumab will be included in efficacy 
analyses. 
(1) Objective:  To describe the overall response rate (ORR) to pembrolizumab in patients 
failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified 
T cell therapy for relapsed or refractory CD19+ lymphomas.  
Methodology: For efficacy, a sample size of 12 patients achieves an 80% power to detect 
a difference (P1 0.35 – P0 0.05) of 0.30 using a one-sided binomial test for ORR.  The 
target of significance level is 0.05.  This response rate prediction of 35% is based on the 
reported 28% response rate reported for nivolumab, another anti-PD1 blocking antibody, 
in patients with B cell lymphoma.  This also assumes that a 5% response rate would be 
seen if pembrolizumab does not have efficacy in this population. If the response rate is 3 
or more, the hypothesis that the ORR is ≤ 0.05 is rejected. If the number of responses is 2 
or less, the hypothesis that ORR is ≥ 0.35. 
Hypothesis: The response rate after pembrolizumab will be 3 or more, allowing us to reject 
the null hypothesis that pembrolizumab after CTL019/CTL119 has an ORR ≤ 0.05 
(2) Objective:  To describe the clinical efficacy of pembrolizumab, including progression-
free survival, disease-free survival, event-free survival, response duration, and overall 
survival (Cheson, 2007) in patients failing to respond to or relapsing after anti-CD19 
chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas. Efficacy comparisons will be made with both most recent prior therapy as 
well as with CTL019/CTL119. 
Methodology: Kaplan Meier survival analysis will be used to estimate progression-free 
survival, event-free survival, response duration, and overall survival. For patients with 
initial responses to both CTL 019 and pembrolizumab, progression-free survival, event-
free survival, and response duration, patients’ response to CTL 019 therapy will be 
compared to their response to pembrolizumab using the log-rank test, with p ≤ 0.05 
considered statistically significant. 
Hypothesis:  Pembrolizumab will enhance the efficacy of CTL019/CTL119 in patients 
failing to respond to or relapsing after chimeric antigen receptor modified T cell therapy 
for relapsed or refractory CD19+ lymphomas.  


 
 
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8.1.3 Exploratory Objectives 
(1) Objective: To describe the immunophenotypic and cytokine profiles of chimeric 
antigen receptor modified T cells in these patients before and after therapy with 
pembrolizumab 
Hypothesis:  Immunophenotypic profiles of tumor cells and chimeric antigen receptor 
modified T cells obtained pre and post pembrolizumab therapy will identify patients for 
whom pembrolizumab will enhance efficacy. 
(2) Objective: For immunologic correlative studies, within subject comparisons of baseline 
to post pembrolizumab measures will be conducted. These analyses will be descriptive 
and considered exploratory; thus, power will not be considered for these paired 
comparisons. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
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. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 


 
 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
 
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or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ 
lymphomas 
 
9.3 
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. 
9.4 
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. 
9.5 
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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 


 
 
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• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
10.2 Compliance with Law and Audits 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
the supporter, government regulatory bodies, and University compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
10.3 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.     
10.4 Quality and Safety Management 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of 
adverse events as noted above, as well as the construction and implementation of a site data 
and safety-monitoring plan.  This will include a regular assessment of the number and type of 
serious adverse events. 
The investigator will permit study-related monitoring, audits, and inspections by the DSMC, 
IRB, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 


 
 
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regulatory sponsor. 
 
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lymphomas 
 
instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  
Interim analyses of toxicity are to be performed quarterly or every three patients on-study. The 
Abramson Cancer Center Data and Safety Monitoring Committee will conduct in-house safety 
audits as per their guidelines. 
 
During the course of the trial, safety and data quality monitoring will be performed in an on-
going manner by the Principal Investigator. The principal investigator will monitor data 
integrity. This includes ensuring that all source documents exist for the data on the case 
report forms, ensuring that all fields are competed appropriately, all corrections are done 
according to GCPs and any inconsistencies / deviations are documented.  The Principal 
Investigator will also review all Adverse Event forms in “real-time” to ensure 
appropriateness of the data and timeliness of reporting.  
 
 
The Medical monitor for this study will be Alfred L. Garfall, M.D., who is not directly 
involved in the trial and is not collaborating with the sponsor or study supported in any 
other trial.  In this role, the medical monitor will review all AEs including grading, 
toxicity assignments, all other safety data and activity data.  The medical monitor may 
recommend reporting of adverse events and relevant safety data not previously reported 
and may recommend suspension or termination of the trial.   The Medical Monitor will be 
asked to review study data at least quarterly (every 3 months) or more frequently 
depending on enrollment. 
 
10.5 Ethical Considerations 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  This study is to be conducted according to US and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures.   
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study.  See Appendix I for a copy of the Subject Informed Consent Form.  This consent 
form will be submitted with the protocol for review and approval by the EC/IRB for the study.  
The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by 
the subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  Documentation of the informed consent process should be 


 
 
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regulatory sponsor. 
 
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recorded in the subject’s source documents.  The original consent form signed and dated by 
the subject and by the person consenting the subject prior to the subject’s entry into the study, 
must be maintained in the Investigator’s study files. 
10.6 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study 
supporter prior to participation in this study.  All University of Pennsylvania investigators will 
follow the University conflict of interest policy. 
 
10.7 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period if required by an 
agreement.  In such an instance, it is the responsibility of the sponsor to inform the institution 
as to when these documents no longer need to be retained.  The Investigator agrees to adhere 
to the document/records retention procedures by signing the protocol. 
 
 
 


 
 
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transmitted, reproduced, published, or used by other persons without prior written authorization from the 
regulatory sponsor. 
 
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lymphomas 
 
 
11.0 REFERENCES 
Cheson, B. P. (2007). Revised response criteria for malignant lymphoma. Journal of Clinical 
Oncology, 25, 579-586. 
Garon, E., Rizvi, N., Hui, R., Leighl, N., Balmanoukian, A., & al, e. (2015). Pembrolizumab 
for the treatment of non-small cell lung cancer. New England Journal of Medicine, 1-
11. 
Grupp, S. K. (2013). Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. 
New England Journal of Medicine, 368(16), 1509-1518. 
Hamid, O., Robert, C., Daud, A., Hodi, S., Hwu, W., & al, e. (2013). Safety and tumor 
responses with lambrolizumab (anti-PD-1) in melanoma. New England Journal of 
Medicine, 369(2), 134-144. 
John, L. D. (2013). Anti-PD-1 antibody therapy potently enhances the eradication of 
established tumors by gene-modified T cells. Clinical Cancer Research, 19(20), 5636-
5646. 
Lesokhin, A., Ansell, S., Armand, P., Scott, E., Halwani, A., & al, e. (2014). Preliminary 
Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or 
Refractory Lymphoid Malignancies. Blood, 124(21), Abstract #291. 
Maude, S. F. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. 
New England Journal of Medicine, 371(16), 1507-1517. 
Porter, D. L. (2011). Chimeric antigen receptor-modified T cells in chronic lymphocytic 
leukemia. New England Journal of Medicine, 365(8), 725-733. 
 
 


 
 
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regulatory sponsor. 
 
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12.0 APPENDICES 
12.1 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. 
 
12.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.3 Response Evaluation Criteria 
The Revised Response Criteria for Malignant Lymphoma will be utilized for response 
assessment in this study (Cheson, 2007). 
12.4 Events of Clinical Interest Guidance Document 
Events of Clinical Interest (ECI) Guidance Document Version 5 will guide pembrolizumab 
administration, discontinuation, and specific event reporting. Please refer to attached 
document. 
 

ICF_001.pdf: 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT INFORMED CONSENT 
AND HIPPA AUTHORIZATION FORM 
 
 
Protocol Title:   
Phase I/II study of pembrolizumab in patients 
failing to respond to or relapsing after anti-CD19 
chimeric antigen receptor modified T cell therapy 
for relapsed or refractory CD19+ lymphomas 
Principal 
Investigator: 
Stephen J. Schuster, M.D. 
Lymphoma Program, Abramson Cancer Center 
University of Pennsylvania 
Office phone: 215-614-1846 
Emergency 
Contact: 
Stephen J. Schuster, M.D. 
215-662-4000, ask operator to page Dr. Schuster 
or the emergency oncologist on call 
  
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study because you have a 
type of cancer called non-Hodgkin lymphoma and have had your cancer 
progress after receiving chimeric antigen receptor modified T cell therapy 
targeting CD19 (CART 19). Your participation is voluntary which means you can 
choose whether or not you want to participate. If you choose not to participate, 
your clinical care will not be affected and there will be no loss of benefits to 
which you are otherwise entitled.  
Before you can make your decision about participating in this study, you will 
need to know what the study is about, the possible risks and benefits of being in 
this study, and what you will have to do in this study. This document describes 
the purpose, procedures, benefits, risks, discomforts, and precautions of the 
study. It also describes the alternative procedures that are available to you and 
your right to withdraw from the study at any time. The research team is going to 
talk to you about the research study, and they will give you a copy of this 
consent form to read. You may also decide to discuss it with your family, 


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friends, or family doctor. You may find some of the medical language difficult to 
understand. Please ask the study doctor and/or the research team for about this 
form and for more information. If you decide to participate, you will be asked to 
sign this form. If you decide to participate, you can later change your mind at 
any time and withdraw from this study. 
 
What is the purpose of this research study? 
The purpose of this study is to determine the safety and tolerability of 
pembrolizumab in people with lymphoma who have previously received chimeric 
antigen receptor modified T cells. This study will also determine how well patients 
with your type of lymphoma respond to pembrolizumab. Although pembrolizumab 
has been approved by the U.S. Food and Drug Administration (FDA) for 
treatment of melanoma, a type of skin cancer, the use of pembrolizumab to treat 
lymphoma is investigational. This means that pembrolizumab has not been 
approved by the FDA for treatment of your type of cancer. 
 
Who is sponsoring this study?  
Dr. Stephen Schuster, the Principal Investigator, is the physician who developed 
this specific protocol and is also the sponsor (entity responsible for the design, 
conduct, and regulatory oversight of the study).  Merck Sharp & Dohme Corp. is 
the manufacturer of pembrolizumab and will be providing drug during this 
research study. Dr. Schuster and the University of Pennsylvania will receive 
payments to cover some research costs such as the cost of pembrolizumab, 
pembrolizumab infusion costs, performing research-related tests, and collecting 
and reporting study information. 
 
How long will I be in the study? How many other people will be 
in the study? 
 
You will come to the doctor’s office to received treatment once every 3 weeks. 
You can continue to receive study treatment for up to 1 year as long as your 
lymphoma is not getting worse, you do not need a different treatment for your 
lymphoma, or you do not have bad side effects from pembrolizumab. 
 
After completing treatment with pembrolizumab, you will come in for a safety 
follow-up visit about 30 days after your last dose of pembrolizumab or before you 
start a new treatment for your lymphoma. If you stop getting the study drug and 


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your lymphoma has not gotten worse, you will continue to come in for study 
follow-up visits until you start a new treatment or your disease gets worse. If you 
stopped receiving study drug because you had a bad side effect, you will 
continue to come in for follow-up visits as needed until your side effect is better 
or you have started a new cancer treatment. You may be observed for up to 2 
years after stopping the study treatment. 
 
You may stop participating at any time. If you decide to stop participating, we 
encourage you to talk to your doctor first. It is important to tell your doctor if you 
are considering stopping so that your doctor can discuss what follow-up care and 
testing will be best for you. Leaving the study will not affect your medical care. 
 
Your doctor may stop you from participating in this study at any time if she or he 
believes that it is in your best interest, if you do not follow the study rules, or if the 
study is stopped. If new information becomes available that might affect your 
choice to stay in the study, your study doctor will notify you as soon as possible. 
 
Twelve patients are expected to participate in this study. This study will only be 
conducted at the University of Pennsylvania Abramson Cancer Center. 
 
What am I being asked to do? 
If you meet all of the criteria for being in the study, you can participate and 
receive study treatment with pembrolizumab. The study is broken down into three 
periods: screening, treatment, and follow-up. The following procedures and 
treatments will take place as an outpatient if you decide to participate in the 
study. 
 
Screening period and procedures: 
The purpose of the screening period is to make sure that it is safe for you to 
participate in this study and to evaluate your lymphoma and overall health. These 
exams, tests, and procedures are part of regular cancer care and may be done 
even if you do not take part in this study. If you have had some of these tests 
recently, they may not need to be repeated. These need to be done within 28 
days of entry onto this study, with the exception of imaging studies. 
You will have the following tests and procedures to make sure you are eligible for 
participation in this study: 


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• Review of your medical history including a detailed cancer history, the 
medications you have taken, and your current medications 
• Assessment of how able you are to get around (performance status) 
• Physical examination as well as vital signs  
• Blood tests, including: 
o Blood cell counts (CBC), blood chemistry tests (kidney and liver 
function), thyroid function tests, and blood clotting function tests. 
• Urine sample for urinalysis 
• Electrocardiogram (EKG) will be performed to check your heart function 
• If you are a woman of reproductive potential, either a blood or urine 
pregnancy test will be performed 
• Optional: You may be asked to provide additional tumor biopsy samples 
and / or blood samples during the study. These samples will be used for 
special studies that can be used to measure the progress of disease or 
the effects of treatment. This is optional. You will be asked to sign a 
separate authorization for these samples. 
• Optional: You will also be asked to take part in optional future biomedical 
research. You will be given a separate informed consent to describe this 
research. 
Treatment period: 
If you have been found eligible to participate in this study and you decide to 
participate, you will be scheduled to start treatment on this study. Each dose of 
pembrolizumab is given as a 30 minute infusion into a vein. You will receive 
pembrolizumab every three weeks at a dose of 200mg intravenously (IV). Every 
patient will receive the same dose of pembrolizumab. This dose is the same dose 
that is approved in the United States for treatment of other types of cancer. 
If you stop treatment because your lymphoma gets better, you may be able to re-
start pembrolizumab treatment for 1 year if your lymphoma returns within 2 years 
of stopping treatment and you meet certain criteria. Your study doctor will discuss 
this with you. 
Study tests / procedures: 
You will be asked to come to the outpatient clinic every three weeks for certain 
tests and procedures. Some of these exams, tests, and procedures are part of 
your routine cancer care but may be done more often because you are in this 
study. 


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Prior to every dose of pembrolizumab, you will have the following obtained 
(research study visits): 
• Vital signs, and a physical examination performed. 
• Review of how you are feeling, if you have had any side effects, and any 
medications you are taking 
o Taking 
other 
drugs 
(including 
alcohol, 
over-the-counter 
medications, herbal medications, nutritional supplements, or illegal 
drugs) may cause additional side effects or even life threatening 
reactions when combined with the drugs in this study. It is important 
to check with your study doctor before starting any new 
medications. 
o It is also important to contact your study doctor or a study team 
member if you experience any changes in your health or any side 
effects between study visits 
Laboratory tests and other procedures (considered standard of care): 
• After first dose of pembrolizumab, performed 3 days after first dose of 
pembrolizumab, then weekly for 5 weeks after first dose of pembrolizumab 
o Blood counts, blood chemistries (kidney and liver function) 
• Prior to every cycle of pembrolizumab, prior to pembrolizumab infusion for 
first 6 months of pembrolizumab (through week 21 / cycle 8): 
o Blood counts, blood chemistries (kidney and liver function), thyroid 
function tests,  
o If you are a woman whose last menstrual period was < 18 months 
ago, urine or serum pregnancy test  
• After 6 months of pembrolizumab, prior to every cycle of pembrolizumab 
(beginning week 24 / cycle 9), prior to pembrolizumab infusion: 
o Blood counts, blood chemistries (kidney and liver function) 
o If you are a woman whose last menstrual period was < 18 months 
ago, urine or serum pregnancy test  
• After 6 months of pembrolizumab, prior to every odd cycle of 
pembrolizumab (beginning week 24 / cycle 9), within 7 days prior to 
pembrolizumab infusion: 
o Blood counts, blood chemistries (kidney and liver function), thyroid 
function tests 
 
Optional research blood draws 
• These blood tests are optional and are being performed for research 
purposes. These would not normally be done as part of your standard 
care. When done, they will require about 2 tablespoons of additional blood 
drawn per blood draw. The maximum number of tablespoons of blood that 
may be taken for the duration of the study is 22 tablespoons. With the 


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exception of the blood draws marked with an asterisk * this blood can be 
drawn when your normal standard care lab work is drawn 
o Prior to first dose of pembrolizumab after you have consented to 
participate in this study, *24 hours after first dose of 
pembrolizumab, *48 hours after first dose of pembrolizumab, 3 
days after first dose of pembrolizumab, weekly for 3 weeks after 
first dose of pembrolizumab, then prior to each cycle of 
pembrolizumab through week 12, and at the time you withdraw 
from or complete study. If cytokine release syndrome occurs, this 
schedule of blood draws may be shifted, but the maximum amount 
of blood drawn for a single blood draw will not be more than 2 
tablespoons. The overall total will not be more than 22 tablespoons. 
 
Imaging studies (considered standard of care): 
• Imaging with CT scan, PET / CT, or MRI as determined by your study 
physician to assess the status of your lymphoma will be performed at 
weeks 12, 24, 39, 54, 66, 78, 93, and 104 until 24 months after your first 
dose of pembrolizumab 
• At the time of stopping pembrolizumab, you will be re-imaged unless you 
are withdrawing from study due to side effects, have had imaging within 
the last 4 weeks, or have not received pembrolizumab within 1 year 
 
Follow-up period and procedures: 
You may receive pembrolizumab for up to one year as long as your disease is 
not getting worse, you do not need a different treatment, or you do not have bad 
side effects. When you do stop receiving treatment on this study, you will come in 
for an end-of-treatment visit. 
 
The tests and procedures at the end of treatment visit include: 
• Physical examination vital signs (research visit) 
• Functional status assessment and review of medications and feel of how 
you have been feeling (research visit) 
• Blood tests for blood counts, blood chemistry (kidney and liver function), 
thyroid function, (standard of care) 
• Imaging study (CT scan, PET/CT, or MRI) to measure your lymphoma 
(standard of care) 
 


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Study follow-up: 
You will come in for a safety follow-up visit about 30 day after your last dose of 
pembrolizumab or before you start a new cancer treatment, whichever is first. 
If you stop treatment due to a bad side effect, then you will be followed at least 
monthly or more frequently at study investigator discretion until stabilization of 
the side effect, resolution of the side effect, or until you start a new cancer 
treatment. 
If you stop treatment for a reason other than lymphoma progression or due to a 
bad side effect, your follow-up is as follows: 
• Within 12 to 24 months of the first dose of pembrolizumab, follow-up 
imaging occurs every 3 months until 24 months after first dose of 
pembrolizumab 
 
This study does not replace or substitute for the long-term follow-up procedures 
or study visits related to the chimeric antigen receptor-modified T cells (CAR T-
cells) or CTL019 protocol. The procedures and study visits in this protocol are 
separate from those related to CAR T-cells. 
 
What are the possible risks or discomforts?  
 
There are risks to taking part in any research study. One risk is that you may get 
a drug that does not help treat your disease or that makes your condition or 
disease worse. Another risk is that there may be side effects. This research study 
may involve risks or other side effects that are not known or unforeseeable and 
not listed below. 
 
While on the study, you are at risk for the following side effects. Some of these 
side effects may be potentially serious or life-threatening, and may include death. 
You should discuss these with the study doctor.  If you experience side effects 
from this treatment, your study doctor may delay or skip a dose of the study drug, 
or ask you to stop study treatment. Everyone taking part in the study will be 
watched carefully for any side effects. Your doctor may also give you drugs to 
help lessen these side effects. Many side effects go away shortly after the 
treatment is stopped, but in some cases side effects can be serious, long lasting 
or permanent. You should talk to your study doctor about any side effects that 
you have while taking part in this study. 
 
Information about pembrolizumab: 
 


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Pembrolizumab is approved in the USA and some other countries to treat several 
different cancers, but may not be approved to treat your type of cancer. 
 
Pembrolizumab works by helping your immune system to fight your cancer. 
 
However, pembrolizumab can also cause your immune system to attack normal 
organs and tissues in your body and can affect the way they work, which can 
result in side effects. These side effects may become serious (i.e. cause 
hospitalization or be life-threatening), may result in death, and/or may occur after 
you stop taking pembrolizumab. 
 
What side effects could pembrolizumab cause? 
 
 
Risk of IV administration of pembrolizumab 
An IV line will be used to administer pembrolizumab through a vein in your arm. 
The use of an IV line may cause discomfort, irritation, mild bruising, bleeding, 
leakage of drug solution, and rarely infection, nausea, and lightheadedness. 
Because pembrolizumab is an antibody, there is the possibility that you may 
experience an acute infusion reaction.  These are side effects that develop 
during or immediately after the administration of pembrolizumab. Side effects 
may include:  
Blood pressure changes (increase or decrease) 
Cough 
Dizziness 
Fast heart beat 
Feeling cold 
Feeling that your tongue is swelling or your airway is closing and you have 
trouble breathing 
Fever 
Headache 
Joint pains 
Muscle pains 
Nausea 
Rash, hives, or itching 
Shortness of breath 
Sweating 
Tiredness 
Vomiting 
 
VERY COMMON, out of 100 people who receive pembrolizumab, 20 or more 
people may have the following:  
• Itching of the skin 
• Loose or watery stools 
• Cough  
 


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COMMON, out of 100 people who receive pembrolizumab, at least 5 but 
less than 20 people may have the following: 
• Joint Pain  
• Fever  
• Back pain 
• Rash 
• Pain in your belly 
• Loss of skin color 
• Not enough thyroid hormone so you may feel tired, gain weight, feel cold, 
have infrequent or hard stools. 
• Low level of salt in the blood that may cause you to feel tired, confused, 
headache, muscle cramps, or sick to your stomach 
 
UNCOMMON, out of 100 people who receive pembrolizumab, at least 1 but 
less than 5 people may have the following: 
• Too much thyroid hormone so you may feel anxious, angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery 
stools 
• Inflammation of the lungs so you may feel short of breath and cough. 
• Inflammation of the bowels / gut that may cause severe pain in your belly 
with loose or watery stools, and black, tarry, sticky stools or stools with 
blood or mucus.  
• Infusion reaction, where you may feel dizzy or faint (have low blood 
pressure), feel flushed, get a rash, have a fever, feel short of breath, or 
sick to your stomach at the time of receiving your infusion (IV) or just after, 
or pain at the site of infusion. 
• Inflammation of the skin so you may have peeling of the skin, itchiness, 
and/or skin redness. The skin inflammation (i.e. peeling, itching, and 
redness) could also be widespread throughout your body. More severe 
skin reactions may involve the inside of your mouth, the surface of your 
eye and genital areas, and/or may cause the top layer of your skin to peel 
from all over your body which can cause severe infection. 
 
RARE, out of 100 people who receive pembrolizumab, less than 1 person 
may have the following: 
• Inflammation of the liver that may make you feel sick to your stomach and 
vomit, feel like not eating, feel tired, have a mild fever, have pain in the 
right side of your belly, yellow eyes and skin, and dark urine 
• Inflammation of the pituitary gland (a gland in the head) which may cause 
you to feel sick to your stomach or have headaches,  changes in your 
behavior, double vision, few to no menstrual cycles, weakness, vomiting, 
dizziness, or fainting. 
• Adrenal glands (glands on top of the kidneys) that may not make enough 
hormone, which could cause tiredness, weight loss, muscle weakness, 
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watery stools, fever, salt craving, rapid heart rate, and sometimes 
darkening of the skin like a suntan 
• Inflammation of the kidneys so you may pass less urine, have cloudy or 
bloody urine, swelling and low back pain 
• Inflammation of the muscles so you may feel weak or pain in the muscles 
• Inflammation of the pancreas (a gland in your abdomen that controls 
sugar levels) so you may have severe pain in the top part of your belly that 
may move to your back, feel sick to your stomach, and have vomiting that 
gets worse when you eat. 
• Type 1 diabetes, a condition that can cause too much sugar in your blood, 
feeling thirstier than usual, frequent urination, and weight loss. You  are 
likely to need regular insulin shots.   
• Inflammation of the eye so you may have eye redness, blurred vision, 
sensitivity to light, eye pain, see floaters, or have headaches 
• Inflammation of the nerves that may cause pain, weakness or tingling in 
your hands and feet, and may spread to your legs, arms and upper body 
leading to severe muscle weakness and possible paralysis 
• Inflammation of the middle layer of your heart wall that may cause your 
heart to have difficulty pumping blood throughout your body, which can 
cause chest pain, shortness of breath and swelling of the legs. You may 
experience a fast or irregular heartbeat that may cause dizziness or 
fainting. 
• Inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your heart rate, blood 
pressure, body temperature, and the rate at which food is converted to 
energy. 
• A condition that may make you feel weak and tired and might have 
drooping of the eyelids, blurred or double vision, difficulty swallowing, 
slurred speech, weakness in your arms and legs, or difficulty breathing. 
• The formation of small clusters of immune cells (called granulomas) in 
parts of your body such as your lymph nodes, eyes, skin, or lungs 
• Inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality 
and behavior, difficulty speaking, weakness or loss of movement in some 
parts of your body, and loss of consciousness. 
 
 
If you have had an allogeneic stem cell transplant (a procedure in which a 
person receives blood-forming stem cells from a donor), you may experience 
graft versus host disease (GvHD), which may include diarrhea, skin rashes, and 
liver damage, after receiving pembrolizumab.  Sometimes this condition can 
lead to death. 
 
Patients treated with pembrolizumab BEFORE going on to receive an allogeneic 
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cells from a donor), should inform their transplant physicians that they have 
received pembrolizumab in the past. 
In patients with any hematologic malignancy (cancers of the blood like Hodgkin 
lymphoma, multiple myeloma): there is a potential for an increased risk of severe 
complications following allogeneic stem cell transplant in patients who previously 
received pembrolizumab BEFORE an allogeneic stem cell transplant.  
Reports of clotting of blood within the liver and severe graft versus host disease 
(which can include skin, liver and gastrointestinal symptoms), including death, 
have been received for patients who received pembrolizumab BEFORE an 
allogeneic stem cell transplant after pembrolizumab therapy.  
 
If you have had a solid organ transplant (for example, if you have received a 
kidney or a heart transplant), you may experience rejection of the transplanted 
organ. Your doctor will monitor you and should tell you what signs and symptoms 
you should report depending on the type of organ transplant that you have had. 
 
Other serious side effects from pembrolizumab include: 
• Swelling of the tumor causing localized pressure (rarely this might lead to 
death) 
• Pseudoprogression: symptoms of progression in the absence of actual 
disease progression (rarely this might lead to death) 
 
Additionally, since pembrolizumab was approved, the following side effects have 
been reported by people who received pembrolizumab. These side effects were 
voluntarily reported from a group of people of unknown size. It is not possible to 
estimate the frequency of this side effect: 
• Inflammation of the joints, which may include joint pain, stiffness, and/or 
swelling 
 
Because pembrolizumab has never been studied in people who have 
received chimeric antigen receptor-modified T cells (CART cells), there may 
be additional risks related to interactions between pembrolizumab and 
CART cells. 
 
 
Other study-related risks: 
 
Risks of blood draws: 
Blood samples will be taken for tests throughout this study.  The amount of blood 
to be taken by these blood draws is very small, and may be associated with 
discomfort and/or bruising at the site where the needle is inserted; and less 
commonly, fainting, the formation of a small blood clot or swelling of the vein and 
surrounding tissue, bleeding, and infection from the injection site.   
 
You will have about 5 tablespoons of blood drawn at each visit for routine blood 
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up to 2 tablespoons of blood drawn at some visits for research blood tests that 
would not be done if you were not taking part in this study. 
 
Imaging studies: 
During your participation in this study, you will undergo routine radiology tests to 
assess your disease.  These can include CT, PET/CT, or MRI scans. These 
types of scans and the frequency at which they are being performed are 
considered part of your routine cancer care. 
 
CT and PET/CT scans involve exposure to radiation. The amount of radiation 
exposure you may receive from these tests is considered small and will not 
adversely affect the treatment of your disease. You may be exposed to more 
radiation because you are taking part in the study.  At the doses you will receive, 
it is very likely that you will see no effects at all. 
 
The known risks associated with a Magnetic Resonance Imaging (MRI) are 
minimal.  The procedure uses radio waves and a magnetic field to take pictures.  
The greatest risk of having an MRI is the chance of metal objects flying through 
the air toward the magnet and hitting you.  To reduce this risk, all people involved 
with the study are instructed to remove all metal from their clothing and all metal 
objects from their pocket.  You must tell your study doctor if you have any metal 
plates or clips in your body.  No metal objects are allowed to be brought into the 
magnet room at any time. Metal objects inside your body can affect the test 
results and could lead to injury.  Because the magnetic field of the MRI scanner 
attracts metal, these studies will not be performed on anyone with a pacemaker 
or any non-removable metallic foreign objects in their body. If you have any such 
object on your body, you will not receive the scan.  You may feel claustrophobic 
(fear of being closed in) or anxious.  You may experience some discomfort and 
fatigue from lying in a confined space.  There are no known effects from 
exposure to the magnetic fields.   
 
The use of IV contrast or dye in these scans is preferred, but not required.  Your 
doctor will determine if the use of IV contrast or dye is ok for you based on 
routine clinical care. It is important to inform your study doctor if you have had an 
allergic reaction to IV contrast material or dye in the past. IV contrast material 
(dye) is often associated with feelings of discomfort, warmth, or pain. Serious, 
life-threatening, and fatal reactions have been associated with the administration 
of iodine containing contrast agents. If a more severe allergic reaction such as 
irregularity of the heartbeat, drop in blood pressure, or difficulty breathing, were 
to occur, the radiologist and other hospital specialists would initiate treatment 
immediately. Complications such as heart attack or death have been 
documented although they are extremely rare. Acute kidney failure is also one of 
these rare side effects. If you have a history of kidney disease, please inform the 
study staff. In addition, some mild side effects such as nausea, vomiting, 
headache, rash or hives, dizziness, diarrhea, and taste alteration have been 
documented when IV contrast is administered. 
 


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Risks of electrocardiogram (EKG): 
The electrocardiogram (EKG) is a noninvasive test used to measure the electrical 
activity of the heart. By positioning leads (electrical sensing devices) on the body 
in set locations, information about many heart conditions can be learned by 
looking for patterns on the EKG.  You may develop a slight rash or skin irritation 
in the locations where these leads (electrodes) were placed on your skin. There 
are no other known risks associated with an EKG. 
 
Reproductive risks:   
Because of the effects of this drug/device, there could be serious harm to unborn 
children or children who are breast-feeding. These effects could also harm the 
mother.  It is also possible that harmful side effects that are not yet known could 
happen to both the mother and unborn or breast-feeding child.  If you are 
currently pregnant, it is important that you inform the investigator because you 
will not be able participate in the study.  If you are currently breast-feeding, you 
may not continue breast-feeding while on this study.  
 
Female Participants: If you are able to become pregnant, you will be given a 
serum or urine pregnancy test before entry into the study.  You must agree to 
not have sex (abstinence) or to use 2 birth control methods during the course of 
the study and for at least 4 months after your final study treatment. The two 
birth control methods can be either 2 barrier methods or 1 barrier method plus 1 
hormonal method to prevent pregnancy. Barrier methods include diaphragm, 
condom, copper intrauterine device (IUD), sponge, or spermicide; hormonal 
methods include hormonal contraceptives, such as the birth control pill. Your 
study doctor must approve your form of birth control.  Ask your study doctor 
about the contraceptive methods that are available and which might be the best 
for you.   
Even when you use an approved contraceptive method, there is always a small 
risk that you could still become pregnant. If you do become pregnant during the 
course of this study, you must discontinue study treatment, tell the investigator 
immediately, and consult an obstetrician or maternal-fetal specialist.   
You may be considered postmenopausal if you are greater than 45 years old 
and have not had a menstrual cycle for more than 18 months. 
 
If you become pregnant during the study or within 4 months of completing study 
treatment with pembrolizumab, you must notify the study doctor right away.  The 
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contacted monthly until the pregnancy has been completed or terminated. The 
data collected will be obtained by your study doctor, who may collect the data 
from your gynecological physicians via self-report and medical records review.  
The data collected will include data as to your health during pregnancy, any 
complications during your pregnancy, and the status of your child when it is born. 
The study doctor will report the pregnancy outcome to the study Sponsor. 
Male Participants: You should not become pregnant or father a child while on this 
study or for 4 months after your last dose of pembrolizumab. If your partner has 
the potential to become pregnant, you must agree to not have sex (abstinence) 
or to use 2 birth control methods during the course of the study and for at least 4 
months after your final study treatment with pembrolizumab. The two birth control 
methods can be either 2 barrier methods or 1 barrier method plus 1 hormonal 
method to prevent pregnancy. Barrier methods include diaphragm, condom, 
copper intrauterine device (IUD), sponge, or spermicide; hormonal methods 
include hormonal contraceptives, such as the birth control pill. Your study doctor 
must approve your form of birth control.  Ask your study doctor about the 
contraceptive methods that are available and which might be the best for you. 
You should also inform your partner of the potential harm to an unborn child. If 
your partner becomes pregnant during the study or within 4 months of you 
completing study treatment with pembrolizumab, you must notify the study doctor 
right away. Your partner will be contacted monthly until the pregnancy has been 
completed or terminated. The data collected will be obtained by your study 
doctor, who may collect the data from your partner’s gynecological physicians via 
self-report and medical records review.  The data collected will include data as to 
your partner’s health during pregnancy, any complications during the pregnancy, 
and the status of your child when it is born. The study doctor will report the 
pregnancy outcome to the study Sponsor. 
 
If you are male and your partner is pregnant, you must agree to use a condom 
and no other method of birth control is required for your pregnant partner. 
 
What if new information becomes available about the study? 
During the course of this study, we may find more information that could be 
important to you.  This includes information that, once learned, might cause you 
to change your mind about being in the study.  If we discover or learn new 
information about the study drug that could affect your decision to stay in the 
study, we will notify you as soon as possible if such information becomes 
available. 


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What are the possible benefits of the study?  
 
Taking part in this study may or may not make your health better. It is possible 
that your disease and/or health may worsen as a result of participating in this 
study. 
 
What other choices do I have if I do not participate?  
Your participation in this study is entirely voluntary. Other possible treatments 
include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another clinical trial 
• Not receiving any treatment at this time 
• Getting symptom-focused or comfort care. This is also called palliative 
care. This type of care helps reduce pain, tiredness, appetite problems, 
and other problems caused by cancer. It does not treat the cancer directly, 
but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in 
this study. It is completely your decision whether or not you want to be part of this 
study.  If you decide to participate in this study you can change your mind at any 
time and withdraw from the study. 
 
Will I be paid for being in this study? 
You will not be paid for participation in this study. 
 
Will I have to pay for anything? 
 
The study drug, pembrolizumab, is not approved for non-Hodgkin lymphoma and 
its cost and the cost of pembrolizumab infusion will be covered by the study. The 
cost of study visits related to this clinical trial as well as blood work that is 
considered non-standard of care (e.g., blood collected for research purposes) will 
be covered by the study.  
 
You and/or your insurance provider will be responsible for standard tests, exams, 
or procedures that would be done even if you were not in this study. You are 
responsible for any deductibles or applicable co-pays for routine office visits, 
scans and blood work. Some health plans will not pay the costs of tests, exams, 
and procedures for people taking part in studies. Please talk to your doctor and 
study team about putting you in touch with a financial counselor to determine 
exactly what the deductible and co-pay will be for you; this is highly variable 
depending on your type of insurance. 


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For more information on clinical trials and insurance coverage, you can visit the 
National Cancer Institute’s Website at: 
http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a 
copy of the “Clinical Trials and Insurance Coverage” information from this 
Website. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) 
and ask them to send you a free copy. 
  
 
What happens if I am injured from being in the study?  
 
For all side effects, injuries or illnesses that occur while you are taking part 
in this research study 
If you have a medical emergency during your participation on this study, you 
should go to the nearest emergency room. You should contact the Principal 
Investigator or Emergency contact listed on page one of this form. You may also 
contact your own doctor, or seek treatment outside of the University of 
Pennsylvania. Be sure to tell the doctor or his/her staff that you are in a research 
study being conducted at the University of Pennsylvania. Ask them to call the 
telephone numbers on the first page of this consent form for further instructions 
or information about your care. 
 
The University of Pennsylvania will offer you the care needed to treat side effects 
and/or injuries that occur while you are taking part in this research.  We may bill 
your insurance company or other third parties, if appropriate, for the costs of the 
care you get for the injury, but you may also be responsible for some of them. 
There are no plans for the University of Pennsylvania to pay you or give you 
other compensation for the injury. 
 
If you think you have been injured as a result of taking part in this research study, 
contact Dr. Schuster, the principal investigator of the research study as soon as 
possible.  His contact information, including phone number, is listed in the 
consent form. 
 
Research-related injuries or illnesses that occur while you are taking part 
in this research study  
In the event of a bodily injury or illness directly resulting from the study drug or a 
medical procedure required for this study, Merck Sharp & Dohme Corp. will cover 
the cost of all reasonable, unreimbursed, and necessary medical expenses to 
treat this injury or illness.  Merck Sharp & Dohme Corp. will not provide payment 
for injuries unrelated to the study drug, or which are a result of your underlying 
disease or any pre-existing medical conditions. If you have an illness or injury 
during this research trial that is not directly related to your participation in this 


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study, you and/or your insurance will be responsible for the cost of the medical 
care of that illness or injury. 
 
You may receive bills for injuries/illnesses that occur during your participation in 
this study. If you have questions about these bills and whether or not they are 
covered by the research study, please bring copies of these bills to a member of 
the study team and they will be able to answer your questions. 
 
Financial compensation for such things as disability or discomfort due to injury is 
not available. 
 
You will not lose any of your legal rights when you sign this form. 
 
When is the Study over?  Can I leave the Study before it ends? 
You can receive treatment on this study for up to 1 year and be followed on this 
study for up to a total of two years after first dose of pembrolizumab as long as 
your disease is not getting worse, you do not need a different treatment, or you 
do not have bad side effects.  
This study is expected to end after all participants have completed all visits, and 
all information has been collected.  This study may also be stopped at any time 
by your physician, the study Sponsor, or the Food and Drug Administration (FDA) 
without your consent because: 
• 
The Primary Investigator feels it is necessary for your health or 
safety.  Such an action would not require your consent, but you 
will be informed if such a decision is made and the reason for 
this decision. 
• 
You have not followed study instructions.  
• 
The Sponsor, the study Principal Investigator, or the Food and 
Drug Administration (FDA) has decided to stop the study. 
If you are removed from this research study, your study doctor will explain to 
you why you were removed. 
 
If you decide to participate, you are free to leave the study at anytime.  Leaving 
this study will not interfere with your future care.   
 
Your participation in this study is completely voluntary.  Leaving the study, or 
choosing not to take part, with not affect your future treatment or your 
relationship with your study doctor, and will not result in any penalty or loss of 


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benefits to which you are entitled. If you leave the study for any reason, the 
study doctor may ask you to have some end-of-study tests completed. 
It is important to tell the study doctor if you are thinking about stopping so any 
risks from the study drug can be evaluated by your doctor.  Another reason to 
tell your doctor that you are thinking about stopping is to discuss what follow-up 
care and testing could be most helpful for you. Should you choose to 
discontinue your treatment, you may be asked by the study doctor to have a 
final visit to complete some of the end of study tests/procedures.  In addition, 
information may continue to be obtained from your medical record for study 
follow-up purposes. You will also be asked to continue to participate in follow-up 
phone calls after you stop taking the study drug. 
 
Who can see or use my information?  How will my personal 
information be protected?   
If you decide to participate in this study, the study doctor and staff will collect 
medical and personal information about you as part of completing the study.  
We will do our best to make sure that the personal information in your medical 
record will be kept private.  However, we cannot guarantee total privacy.  Your 
personal information may be given out if allowed by law. If information from this 
study is published or presented at scientific meetings, your name and other 
personal information will not be used. This study is being overseen by the Food 
and Drug Administration (FDA); therefore they may review your research 
records.  Please refer to the information below which explains more specifically 
how your personal information will be protected.  If you do not want to allow 
these uses, you should not participate in this study. Information identifying you 
will be kept confidential as described below. 
What personal health information is collected and used in this study, and might 
also be disclosed?  
The following personal health information will be collected and used for the 
purposes of this study: 
• Name, address, telephone number, gender, date of birth 
• The history and diagnosis of your disease 
• Specific information about the treatments you received, including previous 
treatment(s) you may have had 
• Information about other medical conditions that may affect your treatment 
• Medical data including laboratory test results, health status, tumor 
measurements, CT scans, MRIs, and pathology results 


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• Information on side effects (adverse events) you may experience, and 
how these were treated 
• Long-term information about your general health status and the status of 
your disease. This may include information from other health care 
providers 
• Data that may be related to tissue samples that may be collected from you 
• Numbers or codes that will identify you, such as your medical record 
number 
• Information related to study visits and other tests/procedures performed 
while you are participating on this study. 
 
While collected as part of this study by your study doctor and study team, 
identifying information (including your name, address, telephone number, 
medical record number, or any number/codes that will directly identify you) will 
be kept as confidential as possible and will not be routinely disclosed outside of 
the University of Pennsylvania. 
 
You will be assigned a unique subject registration number upon enrollment.  
This number and your initials will be used to identify you throughout the course 
of this study so that your identity is protected.  The key to this code (which links 
your name back to the personal health information collected during this study) 
will be stored in a secure area and only the University of Pennsylvania study 
team will have access to this code. However, some of the study data (e.g. date 
of birth) could be used in combination with other information, in order to identify 
you.  If you have questions about the specific information that will be released, 
you should ask your study doctor.  
As part of standard study screening procedures, we will test for human 
immunodeficiency virus (HIV), hepatitis B, and hepatitis C. If you test positive 
for HIV, hepatitis B, or hepatitis C, by law we have to report the infection to the 
City of Philadelphia Health Department/PA Department of Health. We would 
report your name, gender, racial/ethnic background, and the month and year 
you were born.  
 
The reason that HIV is reported to the Department of Health is to keep track of 
how many people in the U.S. have HIV infection. It is also to make sure that 
states get enough money from the federal government to support the medical 
care of people living with HIV. The Health Department does not share the 


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names of HIV infected people with anyone else. It removes all personal 
identifiers, such as your name, before giving information on the number of HIV 
infections to the federal government. 
 
Why is your personal health information being used?  
Your personal contact information is important for the research team to contact 
you during the study. Your personal health information and results of tests and 
procedures are being collected as part of this research study, and will be used 
to conduct and oversee this research study, and to help guide your medical 
treatment.    
 
Electronic Medical Records and Research Results  
 
What is an Electronic Medical Record?  
 
An Electronic Medical Record (EMR) is an electronic version of the record of your 
care within a health system. An EMR is simply a computerized version of a paper 
medical record.  
  
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study,  results of research-
related procedures (i.e. laboratory tests, imaging studies and clinical procedures) 
may be placed in your existing EMR maintained by UPHS. .  
 
Once placed in your EMR, these results are accessible to appropriate UPHS 
workforce members that are not part of the research team.  Information within 
your EMR may also be shared with others who are determined by UPHS to be 
appropriate to have access to your EMR (e.g. health insurance company, 
disability provider, etc).  
 
Which of our personnel may use or disclose your personal health information? 
The following individuals may use or disclose your personal health information for 
this research study:  
• The Principal Investigator and the Investigator’s study team 
• Authorized members of the workforce of the UPHS and the School of 
Medicine, and University of Pennsylvania support offices, who may need 
to access your information in the performance of their duties (for example: 
for research oversight and monitoring, to provide treatment as part of this 
study or as part of your routine care, to manage accounting or billing 
matters, etc.).  This includes members of the Institutional Review Board 
(IRB), an Ethics Committee at the University of Pennsylvania who are 


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responsible for reviewing and overseeing research studies to ensure that 
they are safe and being well managed.  
 
Who, outside of UPHS and the School of Medicine, might receive your personal 
health information? 
 
As part of the study, the Principal Investigator, the study team and others listed 
above, may disclose your study-related records, including the results of the 
research study tests and procedures, to those listed below. This study data may 
be processed and transmitted using secure computer systems. In all disclosures 
outside of the University of Pennsylvania Health System and School of Medicine, 
you will not be identified by name, medical record number, address, telephone 
number, or any other direct personal identifier unless disclosure of the direct 
identifier is required by law. In records and information disclosed outside of the 
University of Pennsylvania Health System and School of Medicine, you will be 
assigned a unique code number.  
 
Your original medical records also may be reviewed by the sponsor of this study 
or its designated representatives, the Institutional Review Board overseeing this 
study, and any of the regulatory or safety oversight organizations outlined below.  
They may review these records for the purpose of checking data collected for the 
study, to make sure the study is being done properly, and to analyze the results 
of the study.  
 
Individuals or organizations responsible for supporting the study:  
• Merck Sharp & Dohme Corp., the study sponsor, and its authorized 
agents 
 
Regulatory and safety oversight organizations  
• The U.S. Food and Drug Administration (FDA) 
• Other regulatory agencies and/or their designated representatives 
• Public Health agencies and other government agencies (including non-
U.S.) as authorized or required by law 
 
Once your personal health information is disclosed to others outside of UPHS or 
the School of Medicine, it may no longer be covered by United States federal 
privacy protection regulations and your information may be re-disclosed without 
your permission.   
 
The Principal Investigator or study staff will inform you if there are any additions 
to the list above during your active participation in the trial. Any additions will be 
subject to University of Pennsylvania procedures developed to protect your 
privacy. 
 
How long may UPHS and the School of Medicine be able to use or disclose your 
personal health information? 


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Your authorization for use of your personal health information for this specific 
study does not expire. If you sign this form, we will collect your health information 
until the end of the research study.  We may collect some information from your 
medical records even after you finish taking part in this study or after your death. 
We will keep all of the information forever in case we need to look at it again. We 
will protect this information and keep it confidential. 
 
Your information may be held in a research database.  However, UPHS and the 
School of Medicine may not re-use or re-disclose information collected in this 
study for a purpose other than this study unless: 
• You have given written authorization to do so 
• The University of Pennsylvania’s Institutional Review Board grants 
permission after ensuring that appropriate privacy safeguards are in place 
• As permitted by law 
 
The data from this study may be published or used for teaching purposes, 
however you will not be personally identified in any publication.  Your identity will 
remain confidential unless disclosure is required by law. 
 
What if you decide not to give permission to use and give out your health 
information?  
Then you will not be able to be in this research study. 
 
Can you change your mind?  
You have the right to withdraw your permission for the use of your personal 
health information, but if you do so, you must stop taking part in this study. You 
must do so in writing to the Principal Investigator at the address on the first page. 
Even if you withdraw your permission, your personal health information that was 
collected before we received your written request may still be used and 
disclosed, as necessary for the study. If you withdraw your permission to use 
your personal health information, you will also be withdrawn from the research 
study and no new information will be collected.  However, even if you do 
withdraw your permission to use the data about you, we are required by the FDA 
and other national regulatory authorities to record anything that relates to the 
safety of the investigational drug under study. 
 
Will you be able to access your research records?  
You have the right to see and get a copy of your medical records kept by the 
University of Pennsylvania. However, you will not be able to review or receive 
some of your records related to the study until after the entire study has been 
completed.  When the study is over, you may write to the study doctor to ask to 
see or copy all of your medical information that was collected during the study.  
You also have the right to say how your medical information may be used, and to 
have any incorrect data about yourself updated or corrected. 
 


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Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric 
antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, 
as required by US Law.  This website will not include information that can identify 
you. At most, the website will include a summary of the results.  You can search 
this website at any time. 
 
By signing this document you are permitting the UPHS and the School of 
Medicine to use and disclose personal health information collected about you for 
research purposes as described above. 
 
Who can I call with questions, complaints or if I’m concerned 
about my rights as a research subject? 
If you have questions, concerns or complaints regarding your participation in 
this research study or if you have any questions about your rights as a research 
subject, you should speak with the Principal Investigator listed on page one of 
this form.  If a member of the research team cannot be reached or you want to 
talk to someone other than those working on the study, you may contact the 
Office of Regulatory Affairs with any question, concerns or complaints at the 
University of Pennsylvania by calling (215) 898-2614. 
 
When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer.  Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that personal health 
information to outside organizations or people involved with the operations of 
this study. 
A copy of this consent form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 
 
For subjects unable to give authorization, the authorization is given by the 
following authorized subject representative:  


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________________________       _____________________________________ 
Authorized subject                      Authorized subject   
 
 
Date 
representative [print]  
representative Signature   
 
 
Provide a brief description of above person authority to serve as the subject’s 
authorized representative:__________________________________________