Novel Immuno-epigenetic Based Platform for Patients With Peripheral T-cell Lymphoma (PTCL) and Cutaneous T-cell Lymphoma (CTCL): an International Phase Ib Study of Pembrolizumab Combined With Decitabine and/or Pralatrexate
Phase: PHASE1
Conditions: PTCL, CTCL
Sponsor: University of Virginia

 
 
  
 
 
 
Official Title:  
 Novel immuno-epigenetic based platform for patients with peripheral T-cell lymphoma (PTCL) and 
cutaneous T-cell lymphoma (CTCL): an international phase Ib study of pembrolizumab combined with 
decitabine and/or pralatrexate 
 
NCT Number:  
 
NCT03240211 
 
Document Date:  
 
12 April 2024 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
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TITLE:  
Novel immuno-epigenetic based platform for patients with peripheral T-cell 
lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL): an international 
phase Ib study of pembrolizumab combined with decitabine and/or 
pralatrexate. 
 
 
Coordinating Center:          
Global T-cell Lymphoma Consortium (GTcLC)  
at the University of Virginia (UVA)  
 
 
 Principal Investigator:       
Enrica Marchi, M.D., Ph.D. 
Assistant Professor of Medicine, Microbiology, Immunology and Cancer 
Biology 
Co-Director, Program for T-Cell Lymphoma Research 
Division of Hematology-Oncology 
Department of Medicine 
University of Virginia 
email: EM5YT@hscmail.mcc.virginia.edu 
phone: 434-297-5529 
 
 
Co-Principal Investigator        Owen A. O’Connor, M.D., Ph.D. 
and IND Holder: 
 
Professor of Medicine 
Co-Director, Program for T-Cell Lymphoma Research 
                                               
oao2j@hscmail.mcc.virginia.edu 
                                                  
 
Participating Sites: 
 
Enrica Marchi, M.D., Ph.D. 
University of Virginia 
 
EM5YT@hscmail.mcc.virginia.edu 
 
 
John Lister, MD 
 
Chief, Division of Hematology and Cellular Therapy 
 
Professor of Medicine 
 
Allegheny Health Network Center Institute 
 
John.LISTER@ahn.org  
 
  
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is the property of the University of Virginia Cancer Center 
Office of Clinical Research and the Human Immune Therapy Center. Distributing, copying, or disclosing 
information contained in this document requires prior authorization from the University of Virginia Cancer 
Center, except that this document may be disclosed to the appropriate institutional review and representatives 
of the U.S. Food and Drug Administration or other regulatory agencies as required by law.   

 
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Contents 
STATEMENT OF COMPLIANCE ...................................................................................... 6 
1.0 
TRIAL SUMMARY.................................................................................................... 7 
2.0 
TRIAL DESIGN.......................................................................................................... 7 
2.1 
Trial Design ............................................................................................................. 7 
2.2 
Trial Diagram .......................................................................................................... 8 
3.0 
OBJECTIVES & HYPOTHESIS .............................................................................. 8 
3.1 
Primary Objectives & Hypothesis ......................................................................... 8 
3.2 
Secondary Objectives ............................................................................................. 8 
3.3 
Exploratory Objective ............................................................................................ 9 
4.0 
BACKGROUND & RATIONALE ............................................................................ 9 
4.1 
Background ............................................................................................................. 9 
4.2 
Rationale and Preclinical Data ............................................................................ 10 
4.2.1 Deciphering mechanisms of action of pralatrexate in PTCLs. ........................... 10 
4.2.2 Epigenetic Priming with the HMA, decitabine ................................................... 11 
4.2.3 Pralatrexate potently synergizes with epigenetic drugs in models of T-cell 
lymphoma. .......................................................................................................... 11 
4.2.4 Hypothesis ........................................................................................................... 12 
4.2.5 Rationale for the Trial and Selected Subject Population .................................... 12 
4.3 
Pharmaceutical and Therapeutic Background .................................................. 12 
4.3.1 Pembrolizumab ................................................................................................... 13 
4.3.2 Pralatrexate ......................................................................................................... 14 
4.3.3 Decitabine ........................................................................................................... 16 
5.0 
TREATMENT PLAN ............................................................................................... 17 
5.1 
Study Design .......................................................................................................... 17 
5.2 
Agents Administration ......................................................................................... 18 
5.2.1 Pembrolizumab ................................................................................................... 19 
5.2.2 Pralatrexate ......................................................................................................... 19 
5.2.3 Decitabine ........................................................................................................... 19 
5.3 
Dose Limiting Toxicities ....................................................................................... 19 
5.4 
Required Blood Parameters and Other Investigations Prior to Each Treatment
 ................................................................................................................................ 20 
5.5 
Efficacy Endpoints ................................................................................................ 20 
5.6 
Biomarker Research ............................................................................................. 20 

 
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6.0 
METHODOLOGY ................................................................................................... 21 
6.1 
Diagnosis/Condition for Entry into the Trial ..................................................... 21 
6.1.1 Subject Inclusion Criteria ................................................................................... 21 
6.1.2 Subject Exclusion Criteria .................................................................................. 22 
6.2 
Trial Treatments ................................................................................................... 23 
7.0 
Dose Selection/Delays/Modification ........................................................................ 25 
7.1 
Dose Selection ........................................................................................................ 25 
7.2 
Dose Delays ............................................................................................................ 25 
7.3 
Dose Modification ................................................................................................. 25 
7.3.1 Immune Related Adverse Events ........................................................................ 25 
7.3.2 Pralatrexate ......................................................................................................... 30 
7.4 
Timing of Dose Administration ........................................................................... 30 
7.5 
Trial Blinding/Masking ........................................................................................ 31 
7.6 
Randomization and Treatment Allocation ......................................................... 31 
7.7 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 31 
7.7.1 Acceptable Concomitant Medications ................................................................ 31 
7.7.2 Prohibited Concomitant Medications ................................................................. 31 
7.8 
Rescue Medications & Supportive Care ............................................................. 32 
7.8.1 Prophylactic Measurements and Supportive Care .............................................. 32 
7.8.2 Supportive Care Guidelines for Immune-related AEs ........................................ 33 
7.9 
Diet/Activity/Other Considerations ..................................................................... 36 
7.9.1 Diet ...................................................................................................................... 36 
7.9.2 Contraception ...................................................................................................... 36 
7.9.3 Use in Pregnancy ................................................................................................ 37 
7.9.4 Use in Nursing Women ....................................................................................... 37 
7.10 
Subject Withdrawal/Discontinuation Criteria ................................................... 37 
7.10.1 Discontinuation of Study Therapy after CR ....................................................... 38 
7.11 
Clinical Criteria for Early Trial Termination ................................................... 38 
8.0 
TRIAL FLOW CHART ........................................................................................... 39 
9.0 
TRIAL PROCEDURES ........................................................................................... 48 
9.1 
Trial Procedures ................................................................................................... 48 
9.1.1 Administrative Procedures .................................................................................. 48 
9.1.2 Inclusion/Exclusion Criteria ............................................................................... 49 
9.1.3 Medical History .................................................................................................. 49 
9.1.4 Prior and Concomitant Medications Review ...................................................... 49 
9.1.5 Disease Details and Treatments .......................................................................... 49 
9.1.6 Clinical Procedures/Assessments ........................................................................ 49 
9.1.7 Laboratory Procedures/Assessments................................................................... 51 

 
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9.1.8 Other Procedures ................................................................................................. 56 
9.1.9 Visit Requirements .............................................................................................. 56 
9.1.10 Subject Registration and Randomization ............................................................ 57 
9.2 
DATA REPORTING / REGULATORY REQUIREMENTS .......................... 57 
9.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety 
Event Information ............................................................................................... 58 
9.2.2 Pregnancy and Exposure During Breastfeeding ................................................. 61 
9.2.3 Events of Clinical Interest ................................................................................... 61 
9.2.4 Unanticipated Problems ...................................................................................... 61 
9.2.5 Data Breaches ..................................................................................................... 62 
9.2.6 Protocol Violations or Deviations ....................................................................... 62 
9.2.7 Method of Detecting AEs, SAEs, and Other Reportable Safety Events ............. 63 
9.2.8 Follow-up of AE, SAE, and Other Reportable Safety Event Information .......... 63 
9.2.9 Sponsor Responsibility for Reporting Adverse Events ...................................... 63 
9.3 
Other Regulatory, Monitoring and Quality Assurance/Quality Control 
Considerations ....................................................................................................... 64 
9.3.1 Foreign Sites ....................................................................................................... 64 
9.3.2 Compliance & Monitoring .................................................................................. 64 
9.3.3 Study Monitoring ................................................................................................ 64 
9.3.4 Study Records Retention ..................................................................................... 66 
10.0 
STATISTICAL ConSiderations .............................................................................. 66 
10.1 
Study Design .......................................................................................................... 66 
10.2 
Dose allocation ....................................................................................................... 68 
10.3 
Stopping rules and MTD definition .................................................................... 70 
10.4 
Sample size and accrual ....................................................................................... 70 
10.5 
Operating characteristics ..................................................................................... 71 
10.6 
Data Analysis Plan ................................................................................................ 73 
11.0 
APPENDICES ........................................................................................................... 73 
11.1 
ECOG Performance Status .................................................................................. 73 
11.2 
Modified Severity Weighted Assessment Tool (mSWAT) Worksheet ............. 73 
11.3 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ............... 74 
11.4 
Response Evaluation Criteria in Lymphoid Malignancies and CTCL ............ 74 
11.5 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................... 74 
11.5.1 Definition of AE ................................................................................................. 74 
11.5.2 Definition of SAE ............................................................................................... 75 
11.5.3 Additional Events Reported in the Same Manner as SAE .................................. 76 
11.5.4 Recording AE and SAE ...................................................................................... 76 

 
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12.0 
Summary of Changes ................................................................................................ 80 
13.0 
References .................................................................................................................. 88 
 
 
 

 
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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) sponsor, and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  All changes to the consent form will be IRB 
approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
 
 
 
Sponsor/Lead Principal Investigator 
 
 
_______________________  
_______________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 
 
 
Investigator 
 
 
_______________________  
_________________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 
 

 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
PDP (pembrolizumab plus decitabine plus pralatrexate) phase Ib 
study in relapsed/refractory PTCL and CTCL. 
Trial Phase 
Phase Ib 
Clinical Indication 
Relapsed, refractory peripheral T-cell Lymphoma (PTCL) and 
cutaneous T-cell lymphoma (CTCL). 
Trial Type 
Dose-escalation. 
Type of control 
N/A 
Route of administration 
Intra-venous (IV) 
Trial Blinding 
Open-label 
Treatment Groups  
Arm 
A 
(pembrolizumab 
plus 
pralatrexate); 
Arm 
B 
(pembrolizumab plus pralatrexate plus decitabine); Arm C 
(pembrolizumab plus decitabine). 
Number of trial subjects 
Maximum of 38 
Estimated enrollment period 
6-10 months 
Estimated duration of trial 
2 years  
Duration of Participation 
2 years plus 
Estimated average length of 
treatment per patient 
6 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an international, multicenter, multi-arm, phase Ib, model-based dose-escalation study. The primary 
objectives of the study in each arm is to determine the maximum tolerated dose (MTD), recommended 
phase 2 dose (RP2D), dose limiting toxicities (DLTs) and to evaluate the clinical efficacy at the MTD of 
various combinations of pembrolizumab, pralatrexate and decitabine.   
The safety and toxicity of these combinations will be evaluated throughout the entire study. Dose allocation 
in Arms A and C will be based upon a continual reassessment method (CRM)1, and combination allocation 
in Arm B will be conducted using a DLT-adapted partial order continual reassessment method (POCRM) 
for dose-finding with combinations of agents2.   
 

 
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2.2 
Trial Diagram 
 
*Pembrolizumab Day above (e.g. Day 1 and Day 8) refers only to cycle 1 of treatment. Pembrolizumab will 
be continued every 3 weeks following the first administration.  Please refer to Section 8.0 for detail.  
 
3.0 OBJECTIVES & HYPOTHESIS 
3.1 
Primary Objectives & Hypothesis 
 
• 
Determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and dose 
limiting toxicity (DLT) of the combinations of pembrolizumab and pralatrexate (Arm A), 
pralatrexate, decitabine and pembrolizumab (Arm B), and decitabine and pembrolizumab (Arm C) 
in patients with relapsed/refractory PTCL and CTCL. 
• 
Evaluate the safety and toxicity of the combination of pembrolizumab and pralatrexate (Arm A), 
pralatrexate, decitabine and pembrolizumab (Arm B), and decitabine and pembrolizumab (Arm C) 
in patients with relapsed/refractory PTCL and CTCL. 
 
• Evaluate the efficacy, as determined by the ORR (complete + partial response), of the combination 
of pembrolizumab and pralatrexate (Arm A), pralatrexate, decitabine and pembrolizumab (Arm B), 
and decitabine and pembrolizumab (Arm C) in patients with  relapsed/refractory PTCL and CTCL. 
 
Hypothesis: If pralatrexate and/or decitabine functions in an immunomodulatory fashion then priming and 
modulating the malignant cells and the microenvironment will enhance the antitumor activity of 
pembrolizumab in patients with PTCLs and CTCLs. 
3.2 
Secondary Objectives  
 
• 
Describe the anti-tumor activity of the combinations of pembrolizumab and pralatrexate (Arm A), 
pralatrexate, decitabine and pembrolizumab (Arm B), and decitabine and pembrolizumab (Arm C) 
in patients with relapsed/refractory PTCL and CTCL. 
• 
Evaluate the efficacy, as determined by the overall response rate (ORR), progression free survival 
(PFS), and duration of response (DOR), of the study population receiving the combinations of 
pembrolizumab and pralatrexate (Arm A), pralatrexate, decitabine and pembrolizumab (Arm B), 
and decitabine and pembrolizumab (Arm C) in patients with relapsed/refractory PTCL and CTCL. 
• 
Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (pre- and post- 
treatment). 
• 
Establish pharmacokinetic profile for pembrolizumab when administered with pralatrexate (Arm 
A), with decitabine (Arm C) and when given as a combination (Arm B) during cycle 1 only.  
• Obtain additional information regarding adverse events within the selected dose range. 

 
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• 
Estimate the OS, PFS of the combination in patients with relapsed/refractory PTCL and CTCL.   
• 
Estimate the DOR of patients with relapsed/refractory PTCL and CTCL on study. 
• 
Identify potential biomarkers of response to treatment.  
 
3.3 
Exploratory Objective 
We will determine the treatment related effects on host immune function and identify potential biomarker of 
response through the objectives below: 
Objectives:  
(1) Analyze the changes in the T cell repertoire in peripheral blood and primary tumor samples as a 
function of treatment with pembrolizumab and pralatrexate (Arm A), pembrolizumab, decitabine 
and pralatrexate (Arm B), pembrolizumab and decitabine (Arm C) in order to assess the 
contribution of epigenetic priming with decitabine in patients receiving treatment with 
pembrolizumab and pralatrexate. 
 
(2) Elucidate the immunomodulatory effect of the combinations of pembrolizumab with pralatrexate 
(Arm A), pralatrexate and decitabine (Arm B), and decitabine (Arm C) and identify biomarkers of 
response 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Mature T cell lymphomas, also known as peripheral 
T cell lymphomas (PTCL), comprise a heterogeneous 
group of lymphoid malignancies characterized by 
their rare frequency and unique clinicopathologic 
features3,4. The annual prevalence of non-Hodgkin 
lymphomas in the US is estimated to be 72,580, or 
approximately 
4.3% 
of 
all 
newly 
diagnosed 
malignancies. The mature T cell lymphomas 
represent about 5-10% of all newly diagnosed NHLs. 
The most common subtypes of PTCL are PTCL Not 
Otherwise specified (NOS) and angioimmunoblastic 
lymphoma (AILT), which when combined represent 
approximately 45% of all PTCLs (see figure above). 
Peripheral T-cell lymphomas also include the 
cutaneous T-cell lymphomas (CTCL) which are a 
mature post-thymic T-cell lymphoma. The two most 
common forms of CTCL are mycosis fungoides (MF) 
and Sézary syndrome (SS). Between 2,000 and 3,000 
new cases of CTCL occur in the United States each 
year. MF is categorized as limited stage (IA, IB, and 
IIA) or plaque/patch disease localized within the skin, and advanced stage (IIB to IVB), characterized by 
cutaneous tumors and involvement of the blood, lymph nodes, bone marrow, or visceral organs. SS is 
characterized by generalized erythroderma and the presence of abnormal lymphoid cells in the blood. 
The largest study conducted to date to evaluate the outcomes of patients with PTCL was the International T-
cell Lymphoma project5. This retrospective study of more than 1300 patients from North America, Europe 
and Asia revealed that outcomes of patients with PTCL were dismal, with the majority of patients dying 
from their disease (as noted in the Kaplan-Meier curve on the right). What was particularly important was 
the fact that majority of patients included in this study were treated with chemotherapeutic regimens that 

 
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were borrowed from B- cell lymphoma treatment paradigms such as CHOP and CHOP-like regimens. For 
CTCL patients, those with limited-stage disease may be effectively treated with skin-directed therapies 
including topical nitrogen mustard or psoralen plus ultraviolet A. However, in patients with an advanced 
disease, control is often short lived, and the disease is relentlessly progressive. Although response rates to 
cytotoxic chemotherapy range from 60 to 80% in patients with advanced disease, the median duration of 
response is usually measured in months. 
Clearly, there is an unmet need for novel therapeutic agents for both PTCL and advanced stage CTCL. 
Several newer medications have been approved by the FDA for treatment of PTCL and CTCL, including 
vorinostat6, romidepsin7,8, belinostat9 and pralatrexate10-12. The response for these single agents are seen in 
up to 1/3 of the patients despite having heavily treated disease. Possible strategies directed at improving 
their efficaciousness include combining novel agents in an effort to design new backbone (T cell specific 
regimen, analogous to CHOP for B cell aggressive lymphomas), and/or to identify novel biological agents 
that can complement their activity in a relative non-toxic fashion (in an attempt to replicate what rituximab 
has done for B cell NHL within a T cell lymphoma).    
4.2 
Rationale and Preclinical Data 
The peripheral T-cell lymphomas (PTCLs) are rare subtypes of Non-Hodgkin lymphoma (NHL) with 
unique clinicopathologic features and very unfavorable prognosis. Recently it has been demonstrated that 
PTCLs are characterized by recurrent mutations in epigenetic operators (e.g. TET2, DNMT3A, and IDH2) 
and escape from immune surveillance.  
4.2.1 Deciphering mechanisms of action of pralatrexate in PTCLs. 
In order to clarify the mechanism of action of 
pralatrexate compared to methotrexate, we 
performed gene expression profiling on 
multiple cell lines treated with equimolar 
concentrations 
of 
methotrexate 
and 
pralatrexate. Preliminary data produced by our 
group revealed that when using GEP profiling, 
pralatrexate induces radically different patterns 
of gene expression compared to methotrexate.  
Firstly, we demonstrated that pralatrexate 
induces differential expression of multiple 
genes including KDM3A, alias JMJD1A. 
KDM3A is a histone demethylase that 
specifically demethylates Lysine-9 residue of 
histone H3 (H3-K9), and plays a central role in the histone code (figure 1A). Existing data shows that 
epigenetic regulation through methylation and demethylation of H3-K9 at the locus encoding for interferon 
γ regulates T-helper differentiation and signaling. Furthermore, other evidence supports the notion that H3-
K9 demethylation contributes to transcriptional depression of the promoter region for the MAGE gene 
family, inducing expression of MAGE A2.  
Secondly, when we performed pathway analysis comparing methotrexate and pralatrexate we confirmed the 
hypothesis that pralatrexate specifically affects immune response signaling, cytokine production and 
lymphocyte activation pathways (figure 1B). We are presently expanding the repertoire of T-cell 
lymphomas treated with methotrexate and pralatrexate, to further elucidate the immunomodulatory 
functions of pralatrexate.  This data provides the basis for our hypothesis that pralatrexate would potently 
interact with the immune checkpoint inhibitor, pembrolizumab in restoring cytotoxic T-cell response 
affecting both the microenvironment and the tumor cells and would synergize with the HMA, decitabine, 
inducing interferon-mediated response and re-expression of MAGE family genes. 

 
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4.2.2 Epigenetic Priming with the HMA, decitabine 
Preclinical data recently published by 
our group have added even more 
credence that these epigenetic drugs 
cooperate through both basic pathway 
interruption 
as 
well 
as 
through 
numerous immunologically mediated processes13,14.  We demonstrated major class effects between HDAC 
inhibitors and HMAs, where the IC10-20 of each drug in combination produced astounding synergy with 
synergy coefficients ranging between 0.0007 and 0.9.   Interestingly, the synergy was more dependent on 
the concentration of the HDAC inhibitor, rather than the hypomethylating agent, owing to the fact that 
higher doses of HMA kill cells primarily through a DNA damage response, while lower doses 
predominantly work by inhibiting DNMT3. These observations were also validated in a SCID beige mouse 
model of T-cell lymphoma.  We further investigated the effects of the various treatments on the gene 
expression and methylation profile. Whole genome gene expression profiling (GEP) and genome wide 
methylation analysis was performed through collaboration with the Bologna group. Our final analysis of 
this data demonstrated that the combination of romidepsin and decitabine ‘reversed’ the malignant GEP 
signature of all the T-cell lymphoma cell lines studied, with each individual drug having only a partial 
effect on the gene expression signature (published data, not shown here). These results served as the basis 
for a phase I/II clinical trial using oral 5-azacitidine and romidepsin in patients with relapsed or refractory 
PTCL that is currently ongoing (https://clinicaltrials.gov/show/NCT01998035). Interestingly, 4 of 5 patients 
with chemotherapy refractory and many with HDAC inhibitor refractory PTCL responded to the treatment, 
with 2 of the 4 responses being complete remission.  However, when we analyzed the methylation profile 
induced by either drug alone and in the combination, we found that decitabine produced a profound effect, 
inducing demethylation of 190 different gene regions corresponding to 175 genes and an additional 335 
loci. Consistent with previous findings, the 5 top ranked genes in terms of both gene expression and 
methylation modification upon treatment turned out to be predominantly affected by decitabine (figure 2A).  
A search for genes modulated by both gene expression and methylation found only 5 genes in common, 
which were mostly cancer testis antigens (GAGE2B, MAEL, TDRD9, GRIN1 and PNLDC1). Four out of 
five genes were also confirmed by RT-PCR (figure 2B). These genes modulated almost uniquely by 
decitabine, suggesting that the addition of the HDAC inhibitor could be avoided. Interestingly, other 
detailed studies of antigen presentation on the tumor cells revealed that another HMA, azacytidine, 
increased expression of multiple cancer testis antigens including multiple MAGE family proteins, whose 
expression have been shown to be suppressed by promoter hypermethylation. This finding is nearly 
identical to the one made by our group following treatment of T-cell lymphoma cell lines by the 
combination of romidepsin and decitabine.  In addition, recent data has demonstrated that low dose 
decitabine elicits an anti-tumor cytotoxic T lymphocyte response by the induction of CD80 expression via 
demethylation of CpG dinucleotide sites in the promoter of CD80 gene in preclinical model of T-cell 
lymphoma15. We hypothesize that prior exposure to HMA combined with pralatrexate can enhance “the 
priming effect” on patients undergoing treatment with the immune checkpoint inhibitor, pembrolizumab, 
increasing the expression of neoantigens on the surface of the neoplastic cells, restoring the T-cell cytotoxic 
response through upregulation of T-cell co-stimulatory molecules, inducing expression of the MAGE 
family proteins, de-repressing the transcription of human endogenous retrovirus (HERV) genes16 and 
modulating the malignant cells and the microenvironment to become more vulnerable to PD-1 blockade.  
4.2.3 Pralatrexate potently synergizes with epigenetic drugs in models of T-cell lymphoma.   
Accumulating work from our group continues to confirm that pralatrexate favorably combines with a 
number of drugs very active in PTCL, including bortezomib17, gemcitabine, and romidepsin18. The latter 
combination of pralatrexate and romidepsin is simply based on the empiric observation that these two drugs 
were the first approved for the treatment of patients with relapsed or refractory PTCL, with single agent 
activity that appears to be lineage specific. Mice treated at the MTD of each drug exhibited some regression 

 
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of tumor, with the best response seen with pralatrexate in this model. However, when given at 50% of the 
MTD for the single agent, the combination of pralatrexate and romidepsin induced complete remission not 
seen with single agents, and produced an overall survival benefit only for mice in the combination cohort.  
Given pre-clinical evidence of synergism, our group initiated a phase I/II trial of combined pralatrexate and 
romidepsin (https://clinicaltrials.gov/show/NCT01947140). Among 25 patients enrolled in phase 1 study, 
the combination was found to be highly tolerable, and produced an ORR in PTCL patients with very 
chemotherapy resistant disease of 77%, including 38% CR. 
4.2.4 Hypothesis 
We hypothesize that if pralatrexate serves as an immunomodulatory agent able to induce interferon-
mediated T-helper response signaling and contributes to promoter de-repression of MAGE family genes 
through KDM3A and decitabine induces the expression of T-cell co-stimulatory molecules (e.g. CD 80), 
MAGE family proteins, and triggers type-I interferon-mediated response through viral mimicry as described 
above19, then priming and modulating the malignant cells and the microenvironment with pralatrexate and 
decitabine before exposure to the PD-1 blockade with pembrolizumab will restore and enhance immune 
surveillance and ultimately augment the antitumor activity in patients with PTCL and CTCL. 
4.2.5 Rationale for the Trial and Selected Subject Population 
The peripheral T-cell lymphomas (PTCLs) are rare subtypes of Non-Hodgkin lymphoma (NHL) with 
unique clinicopathologic features and very unfavorable prognosis. Recently it has been demonstrated that 
PTCLs are characterized by recurrent mutations in epigenetic operators (e.g. TET2, DNMT3A, and IDH2) 
and escape from immune surveillance. The immune checkpoint inhibitor, pembrolizumab has shown 
marked activity as single agent in patients with PTCL and CTCL.  
4.3 
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 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
13 
 
with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  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. 
The peripheral T-cell lymphomas (PTCLs) are rare subtypes of Non-Hodgkin lymphoma (NHL) with 
unique clinicopathologic features and very unfavorable prognosis. Recently it has been demonstrated that 
PTCLs are characterized by recurrent mutations in epigenetic operators (e.g. TET2, DNMT3A, and IDH2) 
and escape from immune surveillance. The immune check point inhibitor, pembrolizumab has shown 
marked activity as single agent in patients with PTCL and CTCL.  
We hypothesize that if pralatrexate serves as an immunomodulatory agent able to induce interferon-
mediated T-helper response signaling and contributes to promoter de-repression of MAGE family genes 
through KDM3A and decitabine induces the expression of T-cell co-stimulatory molecules (e.g. CD 80), 
MAGE family proteins, and triggers type-I interferon-mediated response through viral mimicry, then 
priming and modulating the malignant cells and the microenvironment with pralatrexate and decitabine 
before exposure to the PD-1 blockade with pembrolizumab will restore and enhance immune surveillance 
and ultimately augment the antitumor activity in patients with PTCL and CTCL. 
4.3.1 Pembrolizumab 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity of 
single agent MK-3475.  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 
MK-3475 showed evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, was the dose and schedule utilized in Cohorts A, B, C and D of this protocol 
to test for initial tumor activity.  More recent data from other clinical studies within the MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 release assay) 
suggested that peripheral target engagement is durable (>21 days).  This early PK and pharmacodynamic 
data provides scientific rationale for testing a Q2W and 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 MK-3475 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.  MK-3475 has been found to have a wide 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
14 
 
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 MK-3475 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 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 indication settings. 
 
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 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 every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 
mg/kg dose every 3 weeks, 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.  
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. 
4.3.2 Pralatrexate 
Overview 
Pralatrexate is presently approved for the treatment of relapsed or refractory PTCL.  O’Connor el at in the 
pivotal study PROPEL showed that pralatrexate produced an overall response rate of 29% and a median 
duration of response of 10.4 months in a heavily pretreated group of patients. Pralatrexate is a novel 
antifolate that has been rationally designed to have increased affinity for the reduced folate carrier (RFC-1), 
allowing for better internalization into the cell. Pralatrexate is also a better substrate for polyglutamation by 
FPGS (folylpolyglutamyl synthetase) allowing for better retention in the cell compared to MTX.  In 
addition, the polyglutamate chains formed by pralatrexate tend to be longer than those formed on MTX, 
which appears to improve the inhibition of the target enzyme dihydrofolate reductase (DHFR). Collectively, 
these pharmacological attributes render pralatrexate a more potent cytotoxic agent in vitro and in vivo 
compared to MTX across a broad panel of lymphoma cell lines. Clinical trials to assess the efficacy of 
pralatrexate in other forms of lymphoma are ongoing including CTCL and B-cell malignancies. 
Interestingly, initial clinical experiences seemed to suggest that pralatrexate was more active in T- over B-
cell lymphomas, though; admittedly few patients with B-cell lymphoma have been treated.  Dedicated 
studies exploring the activity of pralatrexate in B-cell neoplasms on a weekly schedule are now ongoing 11. 
Some data has suggested that the activity in different lymphoid neoplasms may correlate with higher levels 
of RFC-1 in sensitive cells, suggesting that RFC-1 could be an important biomarker of activity.  While 
many laboratory studies are now ongoing to explore these relationships, it is clear that any up-regulation of 
RFC-1 could lead to marked improvement in the activity of pralatrexate.  Such pharmacologic strategies 
could lead to the generation of rational synergistic combinations.    
The regulation of RFC-1 is complex. The promoter site of RFC is known to be epigenetically regulated and 
known be hypermethylated in many tumor types 20. This observation has led to the hypothesis that RFC 
expression can be pharmacologically modulated by histone deacetylase inhibitors and hypomethylating 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
15 
 
agents, both of which are known to influence the epigenetic regulation of many genes.  These biological 
features of RFC regulation suggest that rational combinations of select agents known (or suspected of 
regulating RFC expression) may provide a basis for exploring the potential synergistic combinations of 
pralatrexate and HDACI or hypomethylating agents.  
 
Mechanism of Action 
Pralatrexate is a unique antifolate that has been rationally designed to have a high affinity for the reduced 
folate receptor (RFC-1) and the enzyme folylpolyglutamy synthetase 21. This allows the drug to be 
selectively accumulated in tumor cells. RFC expression is induced by various oncogenes, including H-ras 
and c-myc, which results in an increase in the rate of internalization of radio-labeled antifolate11. Several 
studies have shown greater cytotoxic properties for pralatrexate compared to methotrexate, but its precise 
mechanism of action and T-cell specificity remain objects of research. Preliminary gene expression 
profiling and pathway analysis comparing methotrexate and pralatrexate demonstrated that pralatrexate 
specifically affects immune response signaling, cytokine production and lymphocyte activation pathways.  
 
Clinical Pharmacokinetics 
Non-compartmental and population PK (POPPK) analyses showed that pralatrexate R and S diastereomers 
follow apparent first-order PK with the area under the curve to infinity (AUC∞) increasing in a near linear 
manner with dose. Total, renal, and non-renal clearance as well as volume of distribution were constant 
within (nominal) doses ranging from 30 mg/m2 to 325 mg/m2. Comparing the 2 diastereomers, plasma 
exposures of the R diastereomer exceed those of the S diastereomer by approximately 2-fold; the reason for 
this is unclear at this point. S and R diastereomer clearance were reduced by 0.128 and 0.0778 L/hour per 1 
mL/min reduction in creatinine clearance for patients with a creatinine clearance less than 80 mL/min. 
Although the estimated effects of creatinine clearance appeared to be clinically insignificant, few patients 
with moderate to severe renal impairment were enrolled in these studies, making characterization of the 
effects of renal impairment on pralatrexate disposition difficult. Based on clearance parameters, it appears 
that renal tubular and hepatobiliary drug transporters may play an important role in the elimination of 
pralatrexate.  
In vitro plasma protein binding studies showed that pralatrexate was 67-86% bound to human plasma 
protein, with human serum albumin being a significant contributor to the total binding. Pralatrexate did not 
compete with plasma protein binding of 6 drugs that were selected as reference compounds for different 
plasma protein binding sites. These studies suggest that pralatrexate at clinically relevant concentrations is 
not likely to cause displacement of other drugs from plasma proteins. Of note is that the reciprocal study 
also showed that 6 selected reference agents did not displace pralatrexate from plasma proteins. These 
results collectively suggest that a plasma protein binding displacement drug interaction is unlikely.  
 
Safety 
The most frequent AEs, regardless of causality, reported in single-agent studies of hematologic 
malignancies were fatigue (n=86, 47%), nausea (n=74, 41%), mucosal inflammation (n=67, 37%), 
stomatitis (n=66, 36%), and constipation (n=65, 36%). 
Patients with ATLL and HTLV-1 will be closely monitored by both the principle investigator and the 
DSMB. 
Patients receiving pralatrexate should be monitored closely because AEs may occur at any time during 
therapy. For detailed information about the safety profile of pralatrexate, refer to the current pralatrexate IB 
and/or package insert. 
 
Efficacy in Non-Hodgkin’s Lymphoma 
Pralatrexate is FDA approved for the treatment of PTCL. There are data published by our group that 
suggest that pralatrexate is strongly synergistic in combination with bortezomib and other agents including 
romidepsin and hypomethylating agents in the treatment of PTCLs. Pralatrexate used in combination with 
romidepsin and hypomethylating agents represent a novel and potentially important platform for the 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
16 
 
treatment of T-cell malignancies. Early clinical phase I/II trials exploring the value of the doublet 
combination of pralatrexate plus romidepsin and azacytidine plus romidepsin are currently ongoing with 
very promising results. 
4.3.3 Decitabine 
Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent thought to exert its antineoplastic effects 
after phosphorylation and direct incorporation into DNA. This process leads to DNA methyltransferase 
irreversible inhibition, causing hypomethylation of DNA and resulting in cellular differentiation or 
apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not 
cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may 
restore normal function to genes that are critical for the control of cellular differentiation and proliferation. 
In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent 
adducts between DNA methyltransferase and decitabine incorporated into DNA. Nonproliferating cells are 
relatively insensitive to decitabine.  
 
Mechanism of Action of Decitabine 
Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into 
DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular 
differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at 
concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation 
in neoplastic cells may restore normal function to genes that are critical for the control of cellular 
differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be 
attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated 
into DNA. Non-proliferating cells are relatively insensitive to decitabine.  
 
Nonclinical Pharmacology of Decitabine - pharmacodynamics and pharmacokinetics 
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there have been 
no studies of decitabine-induced hypomethylation and pharmacokinetic parameters. Pharmacokinetic 
parameters were evaluated in patients. Eleven patients received 20 mg/m2 infused over 1 hour 
intravenously (treatment Option 2). Fourteen patients received 15 mg/m2 infused over 3 hours (treatment 
Option 1). PK parameters are shown in Table 3. Plasma concentration-time profiles after discontinuation of 
infusion showed a biexponential decline. The CL of decitabine was higher following treatment Option 2. 
Upon repeat doses there was no systemic accumulation of decitabine or any changes in PK parameters. 
Population PK analysis (N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 
2.3.2. The exact route of elimination and metabolic fate of decitabine is not known in humans. One of the 
pathways of elimination of decitabine appears to be deamination by cytidine deaminase found principally in 
the liver but also in granulocytes, intestinal epithelium and whole blood.  
 
Nonclinical Toxicology of Decitabine 
Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine 
was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y 
mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA 
of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. The 
effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered 
a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of 
gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced 
relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice 
exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed 
decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice given 
IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
17 
 
dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological 
measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed 
and significant decreases in sperm number were found at doses ≥0.3 mg/m2. In females mated to males 
dosed with ≥0.3 mg/m2 decitabine, pregnancy rate was reduced, and preimplantation loss was significantly 
increased. 
 
Safety of Decitabine 
Most common adverse reactions (>50%) are neutropenia, thrombocytopenia, anemia, and pyrexia. 
Following the first cycle of DACOGEN treatment, if any of the following non-hematologic toxicities are 
present, DACOGEN treatment should not be restarted until the toxicity is resolved: 1) serum creatinine ≥2 
mg/dL; 2) SGPT, total bilirubin ≥2 times ULN; 3) and active or uncontrolled infection. 
 
Efficacy of Decitabine 
A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with myelodysplastic 
syndromes (MDS) meeting French American-British (FAB) classification criteria and International 
Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Eighty-
nine patients were randomized to DACOGEN therapy plus supportive care (only 83 received DACOGEN), 
and 81 to Supportive Care (SC) alone. Patients with Acute Myeloid Leukemia (AML) were not intended to 
be included. Of the 170 patients included in the study, independent review (adjudicated diagnosis) found 
that 12 patients (9 in the DACOGEN arm and 3 in the SC arm) had the diagnosis of AML at baseline. 
Baseline demographics and other patient characteristics in the Intent-to-Treat (ITT) population were similar 
between the 2 groups. Patients randomized to the DACOGEN arm received DACOGEN intravenously 
infused at a dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle was 
repeated every 6 weeks, depending on the patient’s clinical response and toxicity. Supportive care consisted 
of blood and blood product transfusions, prophylactic antibiotics, and hematopoietic growth factors. The 
study endpoints were overall response rate (complete response + partial response) and time to AML or 
death. Responses were classified using the MDS International Working Group (IWG) criteria; patients were 
required to be RBC and platelet transfusion independent during the time of response. The overall response 
rate (CR+PR) in the ITT population was 17% in DACOGEN-treated patients and 0% in the SC group 
(p<0.001). The overall response rate was 21% (12/56) in DACOGEN-treated patients considered evaluable 
for response (i.e., those patients with pathologically confirmed MDS at baseline who received at least 2 
cycles of treatment). The median duration of response (range) for patients who responded to DACOGEN 
was 288 days (116-388) and median time to response (range) was 93 days (55-272). All but one of the 
DACOGEN-treated patients who responded did so by the fourth cycle. Benefit was seen in an additional 
13% of DACOGEN-treated patients who had hematologic improvement, defined as a response less than PR 
lasting at least 8 weeks, compared to 7% of SC patients. DACOGEN treatment did not significantly delay 
the median time to AML or death versus supportive care. All patients with a CR or PR were RBC and 
platelet transfusion independent in the absence of growth factors. Responses occurred in patients with an 
adjudicated baseline diagnosis of AML. 
5.0 TREATMENT PLAN 
5.1 
Study Design 
In Arm A and Arm C, because there are non-overlapping toxicities between pralatrexate or decitabine and 
pembrolizumab, a classic 3 x 3 dose escalation design will not be applied. Rather, in Arm A and Arm C, we 
will start at the known MTD for each drug and use a CRM design for dose escalation and de-escalation. In 
Arm B, a CRM design for escalation of more than one agent (POCRM) will be applied.  
 
Pralatrexate and decitabine will be administered as described every 28 days (Q4W).  
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
18 
 
Pembrolizumab will be administered at the fixed dose of 200 mg every 3 weeks (Q3W) based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 
200 mg every 3 weeks will provide exposures that: (1) are optimally consistent with those obtained with the 
2 mg/kg dose every 3 weeks; (2) will maintain individual patient exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and, (3) will maintain individual 
patient exposure in the exposure range established in melanoma that are well tolerated and safe. As noted 
above, the different drugs used in this trial will be administered following different schedule, every 3 weeks 
(Q3W) for pembrolizumab and every 4 weeks (Q4W) for pralatrexate and decitabine. Each cycle is 28 days. 
The trial schema for the first 12 weeks of treatment is provided below.  
Participants will be enrolled only onto Arms A and C until the required number of patients are accrued  to 
both arms. Enrollment onto Arm A or Arm C will be based on investigators’ choice. Once enrollment onto 
Arm A or Arm C is completed, the next participant(s) will be assigned to the open Arm (A or C). Arm B 
will be the last Arm enrolling patients as important toxicity information could be learned from treating 
patients on the doublet combinations in Arm A and Arm C. 
 
 
5.2 
Agents Administration 
Details regarding study drug administrations are reported in the sections below (Section 5.2.1, Section 5.2.2 
and Section 5.2.3). Dose modifications are detailed in Section 7.3.  
Refer to FDA approved package insert and//or investigator’s brochure for each study drug for anything not 
specifically mentioned in the protocol. 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
19 
 
5.2.1 Pembrolizumab 
Pembrolizumab will be administered at the fixed dose of 200 mg every 3 weeks (Q3W) in all the study 
arms. In Arm A, pembrolizumab will be started on day 1 of cycle 1. In Arm B and Arm C, pembrolizumab 
administration will be started on day 8 of cycle 1 to allow respectively sensitization with pralatrexate and 
decitabine.  
5.2.2 Pralatrexate 
In Arm A, pralatrexate will be administered at the entry dose of 30 mg/m2 day 1, 8, 15 Q4W which 
represents the MTD identified in the PROPEL trial. Allocation of participants to doses of Pralatrexate will 
be conducted according to the study design described in Section 10: Statistical Considerations. 
In Arm B, pralatrexate will be administered at the entry dose of 20 mg/m2 day 1, 8, 15 Q4W and 
subsequently de-escalated (if applicable) following the study design described in the Statistical 
Considerations. 
All patients receiving pralatrexate will receive folic acid at the dose of 1,000 mg orally daily and vitamin 
B12 intramuscularly every 2 cycles (8 weeks) as recommended in the package insert of the product. The 
vitamin supplementation will start prior to the first dose of pralatrexate as recommended in the drug 
package insert. Leucovorin will be used to decrease the risk of mucositis in all patients receiving treatment 
with pralatrexate. Leucovorin will be given at the dose of 15 mg orally twice daily and should be held the 
day before, the day of and the day after pralatrexate treatment. Leucovorin is mandatory for patients on 
trial.  
5.2.3 Decitabine 
In Arm B, decitabine will be administered at the entry dose of 10 mg/m2 day 1 to day 5 (day 1 -> day 5) 
Q4W and de-escalated (if applicable) following the study design described in the Statistical Considerations. 
In Arm C, decitabine will be administered at the entry dose of 20 mg/m2 day 1 to day 5 (day 1 -> day 5) 
Q4W and allocation of participants to doses of decitabine will be conducted according to the study design 
outlined in the Statistical Considerations. 
For any additional information refer to FDA-approved package insert. 
5.3 
Dose Limiting Toxicities 
A dose limiting toxicity (DLT) is defined as any toxicity that occurs that is considered at least “possibly 
related to the study drug administration”. Only DLT’s that occur prior to initiation of cycle 2 will be used to 
determine dose escalation/de-escalation decisions. 
DLT criteria are defined as follows:  
 
1. Any non-hematologic toxicity greater and/or equal to grade 3, except for:   
• 
Alopecia  
• 
Untreated nausea or vomiting;  
• 
Untreated constipation or diarrhea; 
• 
Untreated dehydration or fatigue uncontrolled; 
• 
Any liver function test including AST/ALT, GGT, Alkaline phosphatase elevation that has 
returned to grade 1 or baseline by day1 of cycle 2; 
 
2. Grade 4 neutropenia lasting more than 5 days despite GCS-F support;  
3. Febrile neutropenia (ANC < 1000/mm3 with a single temperature of > 38.3°C or sustained temperature 
of ≥ 38°C for over one hour); 
4. Any grade 4 thrombocytopenia or grade 3 thrombocytopenia with clinically significant bleeding or any 
grade-3 thrombocytopenia requiring platelet transfusion  
5. Grade 4 anemia unexplained by underlying disease involvement; 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
20 
 
6. Failure to meet the required blood parameters for cycle 2 day 1. 
 
Management and dose modifications associated with adverse events will be described in the following 
sections 7.0, 7.1, 7.2 (Dose selection, dose delays, dose modification). 
5.4 
Required Blood Parameters and Other Investigations Prior to Each Treatment 
Before the start of each cycle, patients should be reassessed, and the following criteria must be fulfilled:  
• 
Absolute neutrophil count (ANC)  > 1000/μL 
• 
Platelet count ≥ 50,000/μL   
• 
Serum creatinine concentration ≤ 2.0 × institutional ULN or ≤ baseline, or creatinine clearance > 50 
ml/min or baseline 
• 
AST and ALT ≤ 2.0 × ULN or ≤ 3.0 × institutional ULN or baseline in presence of demonstrable 
lymphoma involvement of liver 
• 
Bilirubin concentration ≤ 1.5 x ULN or direct bilirubin ≤ULN for patients with total bilirubin levels 
>1.5 × ULN 
• 
Recovery of any drug-related non-hematological AE to grade ≤ 1, unless otherwise indicated     
• 
The above blood parameters are required to start day 1 treatment of every cycle with decitabine but 
do not need to be evaluated on day 2, day 3, day 4 and day 5 of each cycle unless clinically 
indicated. 
5.5 
Efficacy Endpoints 
The primary endpoints of this study are safety, tolerability, and efficacy (anti-tumor activity) that will be 
obtained at completion of the study. The study will provide additional data regarding safety, anti-tumor 
activity and efficacy of the combinations and will suggest possible biomarkers of response. 
. 
The plan is to evaluate the overall response rate (ORR), progression free survival (PFS), and duration of 
response (DOR) of the study population receiving the combinations of pembrolizumab and pralatrexate 
(Arm A), pralatrexate, decitabine and pembrolizumab (Arm B), and decitabine and pembrolizumab (Arm 
C). 
5.6 
Biomarker Research 
The trial will aim to identify biomarkers that may correlate with clinical activity of pembrolizumab through 
the following steps: 
• 
Analyze the changes on T cell repertoire in peripheral blood and primary tumor samples as a 
function of treatment with pralatrexate, decitabine and pembrolizumab and assess the contribution 
of epigenetic priming with decitabine in patients receiving treatment with pembrolizumab and 
pralatrexate. 
 
Standard flow cytometry to assess CD3, CD4, CD8, CD25, CD80, PD1, PD-L1, PD-L2 and Foxp3 will be 
performed in peripheral blood mononuclear cells. In addition, peripheral blood T lymphocytes will be 
analyzed by flow cytometry for CD45 RA, CCR7, CD62L to understand changes in the T cell repertoire. 
Correlation in between changes and response to treatment will be made. 
 
Paraffin embedded primary tumor samples will be obtained pre- and post-treatment as defined below and 
OpalMultiplexing “MANTRA” will be performed. MANTRA is a tissue evaluation technique, which uses a 
fluorescent signal amplification probe to permit serial immunohistochemistry and compared to conventional 
immunohistochemistry permits multiplex detection. Opal Multiplexing MANTRA will be used to determine 
changes in the microenvironment (TILs, NK-cell and antigen-presenting cells) as a function of treatment.  
The following set of 6 markers will be analyzed on each tissue biopsy: CD3, CD7, CD4, CD8, PGM1, IDO; 
CD3, CD7, CD4, CD8, CD20, FOXP3; CD3, CD7, CD4, CD8, PD-1, PD-L1; CD3, CD7, CD4, 
CD8, CD56, Granzyme B. 
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
21 
 
• 
Elucidate the immune modulatory effect of pralatrexate and decitabine and identify biomarker of 
response accounting for heterogeneity and dynamic changes. 
 
Gene expression profiling (GEP) analysis will be obtained on primary tumor samples pre- and post-
treatment. Changes of gene expression profiling as a function of treatment with pralatrexate and decitabine 
will be analyzed. Specific attention will be placed on defined gene-signature already described and 
predictive of response to pembrolizumab (e.g. interferon-γ-related genes including CXCL9, CXCL10, 
IDO1, IFNG, HLA-DRA, STAT1). Additional signature associated with clinical outcome will be 
investigated.   
 
Genome wide methylation analysis will be performed to identify and quantify changes in methylation pre- 
and post-treatment. Specific attention will be placed on decitabine contribution in de-repressing and 
inducing transcription of multiple DNA hypermethylated human endogenous retrovirus (HERV) genes 
triggering a type I interferon-response. 
 
GEP and methylation wide methylation profiling will be analyzed, and correlation will be made to identify 
biomarkers of response. The data gathered from the GEP and genome wide methylation will be used to 
create an algorithm of regulatory networks within PTCLs. The analysis of these data will provide 
information on etiology of PTCLs and will suggest possible targetable oncogenic pathways.  
6.0 METHODOLOGY 
6.1 
Diagnosis/Condition for Entry into the Trial 
Patients must have histologically confirmed diagnosis of relapsed and refractory (R/R) peripheral T-cell 
lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). 
6.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease as defined by the Lugano Criteria for PTCL (Cheson et al., 2014)22 and by 
the Global Response Score for CTCL (Olsen et al., 2011)23. 
4. Patient must have histologically confirmed relapsed or refractory Peripheral T-cell lymphoma 
(PTCL) or cutaneous T-cell Lymphoma (CTCL) as per WHO criteria and TNMB classification and 
staging.  
5. There is no upper limit for the number of prior therapies. Patient may have relapsed after prior 
autologous stem cell transplant. 
6. Patients who had prior treatment for their disease, as long as there is radiographic evidence of 
refractory or relapsed disease and the patient meets all other clinical and laboratory criteria for 
study treatment. 
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Be 
willing to provide FNA of a tumor lesion.  Newly-obtained is defined as a specimen obtained up to 
6 weeks (42 days) prior to initiation of treatment on Day 1.  Subjects for whom newly obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived 
specimen only upon agreement from the Sponsor. 
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
9. Demonstrate adequate organ function as defined in Table 6, all screening labs should be performed 
within 10 days of treatment initiation.   
 
 
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
22 
 
Table 6: Adequate Organ Function Laboratory Values. 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥75,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
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 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. Female subjects 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.   
11. Female subjects of childbearing potential (Section 7.7.9.2) must be willing to use an adequate 
method of contraception as outlined in Section 7.9.2 – Contraception for the course of the study 
through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
12. Male subjects of childbearing potential (Section 7.9.2) must agree to use an adequate method of 
contraception as outlined in Section 7.9.2- Contraception, starting with the first dose of study 
therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
6.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has lack of resolution of adverse events (AE) due to previously administered antineoplastic therapy 
to grade 1 or less according to National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE), version 5.0  
2. Had prior therapy with PD-1 inhibitors.  

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
23 
 
3. Has a diagnosis of immunodeficiency or has been receiving any immunosuppressive therapy within 
7 days prior to the first dose of trial treatment. Use of steroid equivalent to prednisone 10 mg/day 
does not constitute an exclusion criterion. 
 
4. Has a known history of active TB (Bacillus Tuberculosis) 
5. Hypersensitivity to pralatrexate, or decitabine or pembrolizumab or any of its excipients. 
6. Has received prior allogeneic stem cell transplant.  
7. 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. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to trial treatment.  This 
exception does not include carcinomatous meningitis which is excluded regardless of clinical 
stability.   
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment. The following are 
exceptions to this criterion: subjects with vitiligo or alopecia; subjects with hypothyroidism (e.g., 
following Hashimoto syndrome) stable on hormone replacement; subjects with psoriasis not 
requiring systemic treatment; patients with autoimmune phenomena secondary to active lymphoma. 
10. Has known history of, or any evidence of non-infectious pneumonitis/interstitial lung disease that 
required steroids or has current pneumonitis/interstitial lung disease. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
14. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after the last 
dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
18. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study 
therapy. Administration of killed vaccines is allowed. 
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. 
6.2 
Trial Treatments 
The treatment arms to be used in this trial are outlined in Table 7, Table 8 and Table 9 below. 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
24 
 
 
 
Table 7: Trial Treatment – Arm A 
Agent 
Premedication 
Precautions 
Dose 
Route 
Schedule A 
Cycle Length  
Pembrolizumab 
N/A 
200 mg  
(flat dose)  
IV  
Administered 
first during 
cycle 1 
Days 1* 
Q3W 
 
 
Pralatrexate  
B12 and Folate 
supplementation 
(to be started 
within one week 
before initiation 
of 
treatment), 
and leucovorin 
(LV) as outlined  
 
20 or 30 mg/m2** 
IV push 
 
Days 1, 8, 15 
Q4W 
*Day 1 for pembrolizumab administration refers only to cycle 1 of treatment. Pembrolizumab will be 
continued every 3 weeks following the first administration. 
** Doses as appropriate for assigned dose level. Pralatrexate dose will be calculated using weight at cycle 
1 day 1, unless weight has changed more that 10%. If so, the total dose should be calculated on the 
updated weight. 
 
 
Table 8: Trial Treatment – Arm B  
Agent 
Premedication 
Precautions 
Dose 
Route 
Schedule B 
Cycle Length  
Decitabine  
Antiemetic  
10 mg/m2* 
IV  
 
Days 1, 2,3,4,5 
Q4W 
Pralatrexate  
B12 and Folate 
supplementatio
n (to be started 
within one 
week before 
initiation of 
treatment) and 
leucovorin 
(LV) 
 
20 mg/m2 * 
IV push 
 
Days 1,8,15 
Pembrolizumab 
N/A 
200 mg  
(Flat dose) 
IV 
Day 8** 
Q3W 
* Doses as appropriate for assigned dose level. Pralatrexate and decitabine dose will be calculated using 
weight at cycle 1 day 1, unless weight has changed more that 10%. If so, the total dose should be calculated 
on the updated weight. 
**Day 8 for pembrolizumab administration refers only to cycle 1 of treatment. Pembrolizumab will be 
continued every 3 weeks following the first administration. 
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
25 
 
Table 9: Trial Treatment – Arm C 
Agent 
Premedication 
Precautions 
Dose 
Route 
Schedule C 
Cycle Length  
Pembrolizumab 
N/A 
200 mg  
(flat dose) 
IV  
(Administered 
first during 
cycle 1) 
 
Days 8* 
 
Q3W 
Decitabine  
Antiemetic 
 
20 mg/m2 ** 
IV  
  
 
Days 1,2, 3, 4, 5  
 
Q4W 
 *Day 8 for pembrolizumab administration refer only to cycle 1 of treatment. Pembrolizumab will be 
continued every 3 weeks following the first administration. 
**Doses as appropriate for assigned dose level. Decitabine dose will be calculated using weight at cycle 1 
day 1, unless weight has changed more that 10%. If so, the total dose should be calculated on the updated 
weight. 
All patients receiving pralatrexate will receive folic acid at the dose of 1,000 mg orally daily and vitamin 
B12 intramuscularly every 2 cycles (8 weeks) as recommended in the package insert of the product.  The 
vitamin supplementation will start prior to the first dose of pralatrexate as recommended in the drug 
package insert. If leucovorin is being used for rescue, this should be used at the dose of 15 mg orally twice 
daily and should be held the day before, of and after pralatrexate. 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on which 
treatment is allocated/assigned. 
7.0 DOSE SELECTION/DELAYS/MODIFICATION 
7.1 
Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0– Background and 
Rationale.   
7.2 
Dose Delays 
These dose delays apply to all drugs and patients on all study arms. Additional delays may apply for 
specific drugs (see sections 7.3.1 and 7.3.2 below).  
• 
Study drugs can be administered within 48 hours of their scheduled time. 
• 
Study drugs will be held for DLT and any grade 3/4 toxicity not addressed in section 5.3 until the 
AE returns to grade ≤ 2 unless otherwise specified in the sections below. 
• 
If the interruption lasts for more than 14 days, study treatment will be discontinued. 
7.3 
Dose Modification 
If the administration of a study drug combination (Arm A, Arm B, or Arm C) leads to a toxicity beyond 
cycle 1 at a given dose level, dose modifications may occur in accordance with the drug FDA approved 
package insert, or as outlined in the dose de-escalation tables. This post-cycle 1 DLT will not count towards 
the overall determination of MTD for this study. 
7.3.1 Immune Related Adverse Events 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure, including 
coadministration with additional compounds, may represent an immunologic etiology.  These adverse 
events may occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based on 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
26 
 
existing clinical study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab/combination treatment, administration of corticosteroids and/or other supportive care. For 
suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. 
Dose 
modification 
and 
toxicity 
management 
guidelines 
for 
irAEs 
associated 
with 
pembrolizumab/combination treatment are provided in Table 10 below. See Section 7.8 for supportive care 
guidelines, including use of corticosteroids. 
 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity event to the 
assigned treatment combination, to pralatrexate alone (Arm A or B), to decitabine alone (Arm B or C) or to 
pembrolizumab alone, for adverse events listed in Table 10, both (all, for Arm B) interventions must be 
held according to the criteria in Table 10 Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events. 
 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-related, both 
(all for Arm B) interventions should be held according to recommended dose modifications. 
 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab in this 
study, as described in Table 10. 
• 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions. 
• 
If the toxicities do resolve and conditions are aligned with what is defined in Table 10, the assigned 
treatment combination (based on Arm assignment) may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the assigned treatment combination, to 
only the combination of decitabine and pralatrexate (Arm B only), or to decitabine or pralatrexate 
alone, re-initiation of pembrolizumab either as a monotherapy or, for Arm B only, combined with 
decitabine or pralatrexate if the AE is not attributed to one of the drugs, may be considered if the 
principal investigator’s agrees. 
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
27 
 
Table 10: Dose Modification Guidelines for Immune-Related Adverse Events Associated with 
Monotherapy and IO Combinations. For further details please see section 7.8.2 
General instructions: 
1. The Corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study intervention treatment.  
3. If study intervention has been withheld, study intervention may resume after the irAE decreased to 
≤ Grade 1 after corticosteroid taper.  
4. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral 
steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids. 
 
Immune-
related AEs 
Toxicity 
grade 
(CTCAE 
v5.0) 
Action with 
pembrolizumab 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Pneumonitis  Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• Add 
prophylactic 
antibiotics for 
opportunistic 
infections 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
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). 
• 
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. 
Recurrent 
Grade 3, 
or Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Grade 2a 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
• 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
28 
 
bilirubin 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
value returned to baseline or is 
stable 
Grade 3b 
or 4c  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia 
 
New onset 
T1DM or  
Grade 3 or 
4 
hyperglyc
emia 
associated 
with 
evidence 
of -cell 
failure 
Withholdd 
• 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. 
Hypophysiti
s 
Grade 2 
Withhold 
• Administer 
corticosteroid
s and initiate 
hormonal 
replacements 
as clinically 
indicated.   
 
• 
Monitor for signs and symptoms 
of hypophysis’s (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 
4  
Withhold or 
permanently 
discontinued  
Hyperthyroi
dism  
Grade 2 
Continue  
• Treat with 
nonselective 
beta-blockers 
(e.g., 
propranolol) 
or thionamides 
as appropriate  
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 
4  
Withhold or  
permanently 
discontinued 
Hypothyroid
ism 
Grade 2, 3 
or 4 
Continue  
• Initiate 
thyroid 
replacement 
hormones 
(e.g., 
levothyroxine 
or 
liothyronine) 
per standard 
of care 
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
29 
 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to 
study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's study record. 
Nephritis 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
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 
Neurologica
l Toxicities 
Grade 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 
Myocarditis 
Grade 1  
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 
or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologi
c Conditions 
Suspected 
SJS, TEN, 
or DRESS 
Withhold 
• Based on type 
and severity 
of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Confirmed 
SJS, TEN, 
or DRESS 
Permanently 
discontinue 
All other 
irAEs 
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 evente 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 
IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes 
mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin: >1.5 to 3.0 x ULN if 
baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin: >3.0 to 10.0 x ULN if 
baseline normal; >3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: > 10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e  Events that require discontinuation include, but are not limited to: encephalitis, and other clinically important irAEs (e.g. 
vasculitis and sclerosing cholangitis). 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
30 
 
7.3.2 Pralatrexate 
Patient treated with pralatrexate are at risk of developing mucositis. The risk of developing mucositis can be 
lowered by pretreating patient with leucovorin 15 mg PO BID that has to be held the day before, day of and 
day after pralatrexate administration. The treatment with leucovorin will be given with treatment as noted 
above but can be given at the treating physician’s discretion for pralatrexate related mucositis (i.e. in 
schedule delays).  Pralatrexate and decitabine can induce hematologic toxicity that should be address with 
Neupogen/Neulasta support at the treating physician’s discretion and as suggested in Table 12 and Table 
13.  
Doses may be omitted or reduced based on patient tolerance.  Omitted doses will not be made up for at the 
end of the cycle; once a dose reduction occurs for toxicity, there will be no re-escalation. For dose 
modifications and omissions, use the suggested guidelines in Table 11, Table 12 and Table 13 below.  
Table 11: Suggested Guidelines for Pralatrexate Dose Modifications for Mucositis after Cycle 1 
Mucositis Gradea on the Day of 
Treatment  
Action 
Dose upon recovery to Grade  1 
Grade 2 
Omit dose 
Maintain dose level 
Grade 2 recurrence 
Omit dose 
Reduce to one dose level below 
Grade 3 
Omit dose 
Reduce to one dose level below  
Grade 4 
Stop therapy 
No further treatment with pralatrexate 
a Per NCI CTCAE, Version 3.0     
   
Table 12: Suggested Guidelines for Pralatrexate Dose Modifications for Hematologic Toxicities 
Blood Counts on the Day 
of Treatment 
Duration of 
Toxicity 
Action 
Dose upon re-start 
Platelets < 50,000/L 
1 week 
Omit dose 
Continue prior dose 
2 weeks 
Omit dose 
Reduce to one dose level below 
>2 weeks 
Stop therapy 
No further pralatrexate 
ANC 500-1,000/L and no 
fever 
1 week 
Omit dose 
Continue prior dose 
ANC 
500-1,000/L 
with 
fever (a single temperature 
of > 38.3°C or sustained 
temperature of ≥ 38°C for 
over one hour) 
or  
ANC <500/L 
1 week 
Omit dose, give G-
CSF or GM-CSF 
Continue prior dose with G-CSF 
or GM-CSF support 
2 weeks or 
recurrence 
Omit dose, give G-
CSF or GM-CSF 
Reduce to one dose level below 
with G-CSF or GM-CSF support 
>2 weeks or 
2nd recurrence 
Stop therapy 
No further pralatrexate 
Table 13: Suggested Guidelines for Pralatrexate Dose Modifications for All Other Treatment Related 
Toxicities 
Toxicity Grade a on the Day of Treatment 
Action 
Dose upon recovery to Grade  2  
Grade 3 
Omit dose 
Reduce to one dose level below 
Grade 4 
Stop therapy 
No further pralatrexate 
a Per NCI CTCAE, Version 3.0) 
7.4 
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 8.0).  Trial treatment may be administered up to 2 
days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as 30-minute IV infusion every 3 weeks (21 days).  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 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
31 
 
(i.e., infusion time is 30 minutes: -5 min/+10 min). Pralatrexate will be administered as a 3-5 minute IV 
infusion at day 1, day 8 and day 15 of a 28-day cycle. Decitabine will be administered as a 1-hour (+ 60  
minutes) IV continuous infusion from day 1 to day 5 of a 28-day cycle. 
In Arm A, pembrolizumab should precede the administration of pralatrexate on the days that both infusions 
are scheduled (refer to trial schema in section 5.1). In Arm B,  decitabine should be infused first, 
pembrolizumab second and pralatrexate third when the three drugs are given together. On days where 
pembrolizumab is not due, decitabine should precede pralatrexate. When only two drugs are scheduled on 
the same day, decitabine should be infused first followed by pembrolizumab and pralatrexate should always 
be infused last (refer to trial schema 5.1). In Arm C, decitabine should precede the administration of 
pembrolizumab (refer to trial schema 5.1).  
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
7.5 
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered. 
7.6 
Randomization and Treatment Allocation 
Participants will be enrolled only onto Arms A and C until the required number of patients are accrued  to 
both arms. Enrollment onto Arm A or Arm C will be based on investigators’ choice. Once enrollment onto 
Arm A or Arm C is completed, the next participant(s) will be assigned to the open Arm (A or C).  
Enrollment to Arm B will begin once enrollment onto Arms A and C is completed.  
7.7 
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 Merck Clinical team.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  
7.7.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at the 
discretion of the investigator in keeping with the community standards of medical care.  All concomitant 
medication will be recorded on the case report form (CRF) including all prescription, over the counter 
(OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF.  
Systemic glucocorticoids are allowed within 4 weeks of study treatment, as long as the steroids are stopped 
or reduced to a dose of no more than prednisone 10 mg/day or equivalent within 10 days of study drug 
initiation. 
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 9.2. 
7.7.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
32 
 
• 
Investigational agents other than pembrolizumab or pralatrexate (for participants assigned to an arm 
including pralatrexate) 
• 
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.  
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. 
7.8 
Rescue Medications & Supportive Care 
7.8.1 Prophylactic Measurements and Supportive Care 
Patients will be permitted to receive appropriate supportive care measures as deemed necessary by the 
treating physician including but not limited to the items outlined below:   
• 
Diarrhea: Diarrhea should be treated promptly as it could represent an immune-related adverse 
event due to pembrolizumab administration. Please follow section 7.8.2 for supportive care 
guidelines for immune-related adverse events in case of diarrhea.  
• 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, with agents such as 
prochlorperazine, metoclopramide, 5-HT-3 inhibitors, or benzodiazepines.  Patients should be 
strongly encouraged to maintain liberal oral fluid intake during therapy, especially during the initial 
14 days of each treatment cycle. 
• 
Fatigue:  May be cumulative with increasing cycles of therapy.  Can be treated as 
recommended in the NCCN Guidelines 2017 available online. 
• 
Anemia: Transfusions or erythropoietin may be utilized as clinically indicated for the treatment 
of symptomatic anemia but should be clearly noted as concurrent medications.  
• 
Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. Dose 
modification for thrombocytopenia is allowed. Prophylactic folic acid and vitamin B12 
supplements may be necessary to reduce hematologic toxicity as indicated in section and should be 
used as detailed in section 5.2.2.  
• 
Neutropenia: Prophylactic use of colony-stimulating factors including granulocyte colony 
stimulating factor (G-CSF), pegylated G-CSF or granulocyte-macrophage colony stimulating factor 
(GM-CSF) may be utilized if clinically indicated and as suggested in Table 12 and Table 13. 
• 
Hypokalemia or hypomagnesemia should be corrected prior to administration of study drugs, 
and consideration should be given to monitoring potassium and magnesium in patients experiencing 
side effects potentially affecting serum electrolytes (e.g. patients with nausea, vomiting, diarrhea, 
fluid imbalance or cardiac symptoms.) 
• 
Oral Mucositis: Pralatrexate may cause mucositis, including stomatitis or mucosal 
inflammation of gastrointestinal and genitourinary tracts; prophylactic folic acid and vitamin B12 
supplements are necessary to reduce treatment-related mucositis; dosage modification may be 
required. Please see section 5.2.2 and the FDA approved package insert for any clarification.  
• 
Hepatotoxicity:  Liver function test abnormalities have been observed with pralatrexate use. 
Persistent abnormalities may indicate hepatotoxicity and may require dosage modification as 
indicated in table 13 and in the FDA package insert.  

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
33 
 
7.8.2 Supportive Care Guidelines for Immune-related AEs 
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. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.   Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab (see section 7.3.1).  
Note: if after the evaluation the event is determined not to be related, the investigator does not need to 
follow the treatment guidance (as outlined below). Refer to Section 5.0 and 7.0 for dose modification, 
escalation and de-escalation rules. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• 
Pneumonitis:  
o Grade 2 events withhold treatment and treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
o For Grade 3-4 events and recurrent grade 2, immediately treat with intravenous steroids.  
Permanently discontinue treatment. Administer additional anti-inflammatory measures, as 
needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis,  withhold treatment and administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids. Permanently discontinued treatment.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ 
Withhold treatment. Insulin replacement therapy is recommended for Type I 
diabetes mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
▪ 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o For Grade 2 events, withhold treatment and treat with corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
34 
 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. Withhold or permanently discontinue treatment, at discretion of the 
investigator or treating physician. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) or thinamides, as 
appropriate, are suggested as initial therapy. Continue treatment.  
▪ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
Withhold or permanently discontinue treatment, at discretion of the investigator or 
treating physician. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.  
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
▪ 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
Permanently discontinue treatment for grade 4 or grade 3 toxicity. 
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
• 
For Grade 2 events, withhold treatment and treat with corticosteroids. 
• 
For Grade 3-4 events, treat with systemic corticosteroids. Permanently discontinue 
treatment. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks 
 
• 
For other immune related adverse events (IRAE) including myocarditis, encephalitis and Gullian-
Barre and further clarification of the above mention IRAE refer to table 10 and section 
7.3.1Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Treatment guidelines for subjects who experience an infusion reaction associated with administration of 
pembrolizumab are in Table 14 below. 
 
Table 14: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires infusion 
Stop Infusion and monitor 
symptoms. 
Subject may be premedicated 1.5h (± 
30 minutes) prior to infusion of 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
35 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr. to 50 mL/hr.).  
Otherwise dosing will be held until 
symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po (or 
equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently 
discontinued from further trial 
No subsequent dosing 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
36 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
 
 
7.9 
Diet/Activity/Other Considerations 
7.9.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea or vomiting. 
7.9.2 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.   
Both pralatrexate and decitabine can cause fetal harm when administered to a pregnant woman.  There are 
no adequate and well-controlled studies of either agent in pregnant women. 
Women of childbearing potential will be advised to avoid becoming pregnant while receiving treatment 
with pembrolizumab combined with pralatrexate and/or decitabine. 
For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia 
(whether due to having had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in 
women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a post-menopausal state in women not using hormonal contraception or 
hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating 
a partner, respectively, while receiving study drug and for 120 days after the last dose of study drug by 
complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
37 
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it 
is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable 
by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, 
symptom-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study.  In order to participate in the study subjects of 
childbearing potential must adhere to the contraception requirement (described above) from the day of 
study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial therapy.  If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
7.9.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, pralatrexate and/or 
decitabine the subject will immediately be removed from the study treatment. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor 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/UVA CC/GTcLC  within 24 hours of awareness of the event (see study reference manual) and to 
Merck (see section 9.2.1.1) and followed as described above and in Section 9.2.2. 
7.9.4 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. 
7.10 
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 9.1.8– Other Procedures. 

 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
38 
 
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 
Note: For unconfirmed radiographic disease progression, please see LYRIC criteria 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 7.11 
• 
Unacceptable adverse experiences as described in Section 7.3 
a. Note: if any drug in the combination for the assigned arm is discontinued and/or is required 
to be held for an adverse event per section 7.0 for >2 weeks, all study treatment should be 
discontinued.  
• 
Treatment needs to be held (based on section 7.0) for an adverse event delaying treatment for > 2 
weeks 
• 
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 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of 
pembrolizumab, whichever is later. 
• 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 8.0 (Protocol Flow Chart) and 
Section 9.1.9 (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 9.2.1).  Subjects who discontinue for reasons other than progressive disease will 
have post-treatment follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up.  After documented disease progression each 
subject will be followed by telephone for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
7.10.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that have 
been treated for at least 24 weeks with pembrolizumab and had at least two treatments with pembrolizumab 
beyond the date when the initial CR was declared.   
7.11 
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 drugs 
In the event of Merck decision to no longer supply pembrolizumab, ample notification will be provided so 
that appropriate adjustments to subject treatment can be made. 
 
 

 
39 
 
 
 
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39 
 
8.0 TRIAL FLOW CHART 
 
STUDY FLOW CHART – ARM 
A 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: Screeni
ng 
(Visit 1) 
1&4 
 
2&5 
 
 
3&6  
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 D8 D15 
 
 
 
D22 
D1 D8 D15 D1 D8 D15 
At time of 
Discon 
30 days 
post discon 
Every 8 
weeks post 
discon 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
x 
x--------------------------------------------------------------x 
x 
x 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x12 
Review Adverse Events 
 
x---------------------------------------------------------------x 
x 
x 
x15  
Physical Examination 
x 
x2 
x2 
x2 
 x2 
x 
 
 
x 
 
 
x 
x 
 
Vital Signs and Weight 
x 
x-----on all days with physical exam or infusion-------x 
x 
x 
 
ECOG Performance Status 
X 
x3 
x3 
x3 
x3 
x3 
 
 
x 
 
 
x 
x 
 
Pregnancy Test – Urine or Serum β-
HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
x10 
 
 
 
x 
 
 
x 
 
 
 
 
 
CBC with Differential 
x 
x10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 

 
40 
 
 
 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
40 
 
STUDY FLOW CHART – ARM 
A 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: Screeni
ng 
(Visit 1) 
1&4 
 
2&5 
 
 
3&6  
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 D8 D15 
 
 
 
D22 
D1 D8 D15 D1 D8 D15 
At time of 
Discon 
30 days 
post discon 
Every 8 
weeks post 
discon 
Chemistry13 
x 
x10 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
 
EBV PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
x10, 
14 
 
 
 
x14 
 
 
x14 
 
 
x 
X 
 
Tumor Imaging4 
x4 
 
 
 
 
x4 
 
 
x4 
 
 
 
 
 
mSWAT and photograph of skin 
involvement5 
x5 
x5 
 
 
 
x5  
 
 
x5   
 
 
 
 
 
Archival/Newly Obtained Tissue 
Collection 
x6 
 
 
 
 
 
 
 
x7 
 
 
 
 
 
Correlative Studies Blood 
Collection 
 
x 
x11 
x11 
 
x 
 
 
x 
 
 
X 
 
 
Pharmacokinetics (PKs)8 
 
x 
x11 
x11 
 
 
 
 
 
 
 
 
 
 
Pralatrexate IV push 
 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Pembrolizumab Infusion 
 
x9 
 
 
X 
 
 
x 
 
x 
 
 
 
 
X1 After cycle 6, cycle 7 will follow the calendar for cycle 1&4, cycle 8 will follow the calendar for cycle 2&5, cycle 9 will follow the calendar for 
cycle 3&6 etcetera 

 
41 
 
 
 
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41 
 
X2 Physical exam will be performed weekly ONLY during cycle 1. Physical Exam will be performed only at D1 of each subsequent cycle beyond 
cycle 1. 
X3 ECOG will be performed weekly ONLY during cycle 1. ECOG will be performed only at D1 of each subsequent cycle beyond cycle 1. 
X4 CT/PET or CT will be performed at screening within 4 weeks from treatment start date and after cycle 2; then it will be repeated every 3 to 4 
cycles at the discretion of the treating physician. 
X5 mSWAT and standardized photographs of skin involvement are strongly recommended at screening or cycle 1 day 1 not at both timepoints. 
mSWAT is required to be performed after cycle 2 and then it will be repeated every 3 to 4 cycles at the discretion of the treating physician. 
mSWAT will be performed along with CT/PET or CT evaluation. 
X6 Blood samples and tissue collection should be obtained in the screening phase of the study  
X7 Tissue collection of the tumor lesion (including possible FNA or ultrasound when indicated per standard care) should be obtained, if possible, 
at screening or within Cycle 1 (please refer to section 6.1.1: Subject Inclusion Criteria number 7). An optional biopsy may be performed post 
Cycle 3 or 4.   
X8 Pharmacokinetics (PKs) blood draws are only for patients at UVA. See section 9.1.7.3 for details.  
X9 Pembrolizumab will be administered every 3 weeks (Q3W). In Arm A, pembrolizumab administration will be started on day 1 of cycle 1 as 
described in section 5.2.1. 
X10 For cycle 1 day 1, laboratory screening tests can be considered valid for treatment on cycle 1 day 1 as long as they are performed within the 
screening laboratory test window (10 days). After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
X11 Pharmacokinetics (PKs) and correlative study blood draws at Days 8 and 15 in a cycle are only for Cycle 1 (not cycles 4, 7, etc.) 
X12 For subjects who have an allogeneic SCT within 24 months of last study treatment, transplant parameters will be collected and specific events 
will be collected for 18 months from the date of the allogeneic transplant to include graft-versus-host-disease (acute and/or chronic), veno-
occlusive disease, febrile syndrome (a steroid-requiring febrile illness without an infectious cause), and encephalitis, for all grades, and regardless 
of relationship to study drug.   Additional medically important adverse events post-allogeneic SCT may be submitted at the Investigator’s 
discretion. 
 
X13See table in section 9.1.7 for list of tests to include (not just the comprehensive metabolic panel) 
X14Thyroid blood tests are only required every other cycle (e.g. day 1 only for odd cycles) 
X15After 30 day safety visit, only new SAEs considered related to study intervention need to be collected and assessments (as applicable) may be 
by phone or videoconference. Active AEs at the time of 30 day safety visit should be followed through resolution or stability.  
 

 
42 
 
 
 
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42 
 
 
STUDY FLOW CHART – ARM 
B 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: Scree
ning 
(Visit 
1) 
1&4 
 
2&5 
 
3&6 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 D8 D15 
 
 
D22 D1 D8 D15 
 
 
D22 D1 D8 D15 
At time of 
Discon 
30 days post 
discon 
Every 8 
weeks post 
discon 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
 
x------------------------------------------------------------x 
x 
x 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x14 
Review Adverse Events 
 
 
x-----------------------------------------------------------x 
x 
x 
x17  
Physical Examination 
X 
x2 
x2 
x2 
 
x 
 
 
 
x 
 
 
x 
x 
 
Vital Signs and Weight 
X 
 
x-----on all days with physical exam or infusion----x  
x 
x 
 
ECOG Performance Status 
X 
x3 
x3 
x3 
 
x 
 
 
 
x 
 
 
x 
x 
 
Pregnancy Test – Urine or Serum -
HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
x12 
 
 
 
x 
 
 
 
x 
 
 
 
 
 
CBC with Differential 
X 
x12 
x 
x 
x19 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Chemistry 18 
X 
x12 
x 
x 
 
x 
x 
x 
x16 
x 
x 
x 
x 
x 
 
EBV PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
43 
 
 
 
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43 
 
STUDY FLOW CHART – ARM 
B 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: Scree
ning 
(Visit 
1) 
1&4 
 
2&5 
 
3&6 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 D8 D15 
 
 
D22 D1 D8 D15 
 
 
D22 D1 D8 D15 
At time of 
Discon 
30 days post 
discon 
Every 8 
weeks post 
discon 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
x12, 
15 
 
 
 
x15 
 
 
 
x15 
 
 
x 
x 
 
Tumor Imaging4 
x4 
 
 
 
 
x4 
 
 
 
x4 
 
 
 
 
 
mSWAT and photograph of skin 
involvement5 
x5 
x5 
 
 
 
x5 
 
 
 
x5 
 
 
 
 
 
Archival/Newly Obtained Tissue 
Collection 
x6 
 
 
 
 
 
 
 
 
x7 
 
 
 
 
 
Correlative Studies Blood 
Collection 
 
x 
x13 
x13 
 
x 
 
 
 
x 
 
 
X 
 
 
Pharmacokinetics (PKs)8 
 
x9 
x13 
x13 
 
 
 
 
 
 
 
 
 
 
 
Pralatrexate 
 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
x 
 
 
 
Decitabine 
 
x10 
 
 
 
x10 
 
 
 
x10 
 
 
 
 
 
Pembrolizumab 
 
 
x11 
 
 
x 
 
 
x 
 
 
x 
 
 
 
X1 After cycle 6, cycle 7 will follow the calendar for cycle 1&4, cycle 8 will follow the calendar for cycle 2&5, cycle 9 will follow the calendar 
for cycle 3&6 etcetera. 
X2 Physical exam will be performed weekly only during cycle 1. It will be performed ONLY at D1 of each subsequent cycle beyond cycle 1. 
X3 ECOG should be only performed at D1 of each cycle beyond cycle 4. 

 
44 
 
 
 
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44 
 
X4 CT/PET or CT will be performed at screening within 4 weeks from treatment start date and after cycle 2;, then it will be repeated every 3 to 4 
cycles at the discretion of the treating physician. 
X5 mSWAT and standardized photographs of skin involvement are strongly recommended at screening or cycle 1 day 1 not at both timepoints. 
mSWAT is required to be performed after cycle 2 and then it will be repeated every 3 to 4 cycles at the discretion of the treating physician. 
mSWAT will be performed along with CT/PET or CT evaluation 
X6 Blood samples and tissue collection should be obtained in the screening phase of the study. 
X7 Tissue collection of the tumor lesion (including possible FNA or ultrasound when indicated per standard care) should be obtained, if possible, 
at screening or within Cycle 1 (please refer to section 6.1.1: Subject Inclusion Criteria number 7).  An optional biopsy may be performed post 
Cycle 3 or 4.  
X8 The pharmacokinetics (PKs) blood draw are only for patients at UVA. See section 9.1.7.3 for details. . 
X9 Cycle 1 only. Additional pharmacokinetics sample (only for patients at UVA) will be obtained at day 5 to determine drug steady state. 
X10 Decitabine will be given from day 1 to day 5 (or day 3, depending on dose level) of each cycle as described in section 5.2.3 
X11 Pembrolizumab will be administered every 3 weeks (Q3W). In Arm B, pembrolizumab administration will be started on day 8 of cycle 1 as 
described in section 5.2.1. 
X12 For cycle 1 day 1, laboratory screening tests can be considered valid for treatment on cycle 1 day 1 as long as they are performed within the 
screening laboratory test window (10 days). After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
X13 Pharmacokinetics (PKs) and correlative study blood draws at Days 8 and 15 in a cycle are only for Cycle 1 (not cycles 4, 7, etc.) 
X14 For subjects who have an allogeneic SCT within 24 months of last study treatment, transplant parameters will be collected and specific events 
will be collected for 18 months from the date of the allogeneic transplant to include graft-versus-host-disease (acute and/or chronic), veno-
occlusive disease, febrile syndrome (a steroid-requiring febrile illness without an infectious cause), and encephalitis, for all grades, and regardless 
of relationship to study drug.   Additional medically important adverse events post-allogeneic SCT may be submitted at the Investigator’s 
discretion. 
X15 Thyroid blood tests are only required every other cycle (e.g. day 1 only for odd cycles) 
X16 After cycle 2, the day 22 CBC with differential is not required (e.g. not for cycles 5, 8, etc.) 
X17After 30 day safety visit, only new SAEs considered related to study intervention need to be collected and assessments (as applicable) may be 
by phone or videoconference. Active AEs at the time of 30 day safety visit should be followed through resolution or stability.  
X18See table in section 9.1.7 for list of tests to include (not just the comprehensive metabolic panel) 
X19CBC with differential at Day 22 is for cycle 1 only (e.g. not for cycles 4, 7, etc) 
 

 
45 
 
 
 
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45 
 
 
STUDY FLOW CHART – ARM 
C 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1&4 
 
 
2&5 
3 &6 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 
D8 
D15 
 
 
D22 
D1 
 
 
D22 
D1 
D15 
At time of 
discon 
30 days post 
discon 
Every 8 weeks 
post discon 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
x 
 
x----------------------------------------------------x 
x 
x 
x 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
x 
x14 
Review Adverse Events 
 
 
x----------------------------------------------------x 
x 
x 
x17 
Physical Examination 
x 
x2 
x2 
 
 
x 
 
X 
 
x 
x 
 
Vital Signs and Weight 
x 
 
x-on all days with physical exam or infusion-x  
x 
x 
 
ECOG Performance Status 
x 
x3 
x 
 
 
x 
 
X 
 
x 
x 
 
Pregnancy Test – Urine or Serum β-
HCG 
x 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
x 
x12 
 
 
 
x 
 
X 
 
 
 
 
CBC with Differential 
x 
x12 
x 
X13 
x19 
x 
x15 
x 
X 
x 
x 
 
Chemistry18  
x 
x12 
x 
X13 
 
x 
X 
x 
X 
x 
x 
 
EBV PCR 
x 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
46 
 
STUDY FLOW CHART – ARM 
C 
 
Treatment Cycles1 
Post-treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1&4 
 
 
2&5 
3 &6 
Discon 
Safety 
Follow-up 
 
Follow Up 
Visits 
 
Scheduling Window (Days) ± 2 : 
 
D1 
D8 
D15 
 
 
D22 
D1 
 
 
D22 
D1 
D15 
At time of 
discon 
30 days post 
discon 
Every 8 weeks 
post discon 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
x12, 16 
 
 
 
x16 
 
x16 
 
x 
x 
 
Tumor Imaging4 
x4 
 
 
 
 
x4 
 
x4 
 
 
 
 
mSWAT and Photograph of skin 
involvement5 
x5 
x5 
 
 
 
x5 
 
x5 
 
 
 
 
Archival/Newly Obtained Tissue 
Collection 
x6 
 
 
 
 
 
 
x7 
 
 
 
 
Correlative Studies Blood 
Collection 
 
x 
x13 
 x13 
 
x 
 
X 
 
x 
 
 
Pharmacokinetics (PKs)8 
 
x9 
 
 
 
 
 
 
 
 
 
 
Decitabine 
 
x10 
 
 
 
x10 
 
x10 
 
 
 
 
Pembrolizumab 
 
 
x11 
 
 
x11 
x11 
 
x11 
 
 
 
X1 After cycle 6, cycle 7 will follow the calendar for cycle 1&4, cycle 8 will follow the calendar for cycle 2&5, cycle 9 will follow the calendar for 
cycle 3&6 etcetera 
X2 Physical exam should be performed ONLY at D1 of each cycle beyond cycle 4 
X3 ECOG should be only performed at D1 of each cycle beyond cycle 4 
X4 CT/PET or CT will be performed at screening within 4 weeks from treatment start date and after cycle 2; then it will be repeated every 3 to 4 
cycles at the discretion of the treating physician. 

 
47 
 
 
 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
47 
 
X5 mSWAT and standardized photographs of skin involvement are strongly recommended at screening or cycle 1 day 1 not at both timepoints. 
mSWAT is required to be performed after cycle 2 and then it will be repeated every 3 to 4 cycles at the discretion of the treating physician. 
mSWAT will be performed along with CT/PET or CT evaluation. 
X6 Blood samples and tissue collection should be obtained in the screening phase of the study. 
X7 Tissue collection of the tumor lesion (including possible FNA or ultrasound when indicated per standard care) should be obtained, if possible, 
at screening or within Cycle 1 (please refer to section 6.1.1: Subject Inclusion Criteria number 7).  An optional biopsy may be performed post 
Cycle 3 or 4.   
X8 The pharmacokinetics (PKs) blood draw are only for patients at UVA. See section 9.1.7.3 for details.  X9 Cycle 1 only. Additional 
pharmacokinetics sample (only for patients at UVA) will be obtained on the final day (in Cycle 1) of scheduled treatment for the participant to 
determine drug steady state. See section 9.1.7.3 for details. 
X10 Decitabine will be given from day 1 to day 5 (or day 3, depending on dose level) of each cycle as described in section 5.2.3 
X11 Pembrolizumab will be administered every 3 weeks (Q3W). In Arm C, pembrolizumab administration will be started on day 8 of cycle 1 as 
described in section 5.2.1. 
X12 For cycle 1 day 1, laboratory screening tests can be considered valid for treatment on cycle 1 day 1 as long as they are performed within the 
screening laboratory test window (10 days). After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
X13 Correlative study blood draws at Days 8 and 15 in a cycle are only for Cycle 1 (not cycles 4, 7, etc.). Labs (CBC with differential and 
Chemistry) on day 15 are for cycle 1 only.  
X14 For subjects who have an allogeneic SCT within 24 months of last study treatment, transplant parameters will be collected and specific events 
will be collected for 18 months from the date of the allogeneic transplant to include graft-versus-host-disease (acute and/or chronic), veno-
occlusive disease, febrile syndrome (a steroid-requiring febrile illness without an infectious cause), and encephalitis, for all grades, and regardless 
of relationship to study drug.   Additional medically important adverse events post-allogeneic SCT may be submitted at the Investigator’s 
discretion. 
X15 After cycle 2, the day 22 CBC with differential is not required (e.g. not for cycles 5, 8, etc.) 
X16Thyroid blood tests are only required every other cycle (e.g. day 1 only for odd cycles) 
X17After 30 day safety visit, only new SAEs considered related to study intervention need to be collected and assessments (as applicable) may be 
by phone or videoconference. Active AEs at the time of 30 day safety visit should be followed through resolution or stability.  
X18See table in section 9.1.7 for list of tests to include (not just the comprehensive metabolic panel) 
X19CBC with differential at Day 22 is for cycle 1 only (e.g. not for cycles 4, 7, etc) 
 

 
 
 
 
 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
48 
 
9.0 TRIAL PROCEDURES 
9.1 
Trial Procedures 
The Trial Flow Chart - Section 8.0 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below. Study treatment is expected up to two years.  
It may be necessary to perform these procedures at unscheduled time points if deemed clinically 
necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional 
informed consent be obtained from the subject.  In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into Forte EDC, a password-protected data 
capture system provided by the UVA Coordinating Center / GTcLC. Clinical data will be entered 
directly from the source documents. 
9.1.1 Administrative Procedures 
9.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating in 
a clinical trial. 
9.1.1.2 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion 
in advance of use.  The subject or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s willingness 
to continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures the 
subject’s dated signature or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.  
 
 
 
 
 
 
 
 
 

 
 
 
 
 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
49 
 
9.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
9.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.  Details regarding the disease for which the 
subject has enrolled in this study will be recorded separately and not listed as medical history.   
9.1.4 Prior and Concomitant Medications Review 
9.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study will 
be recorded separately and not listed as a prior medication.  
9.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the 
trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in Section 
9.2. 
9.1.5 Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
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.  
9.1.6 Clinical Procedures/Assessments 
9.1.6.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 5.0 (see Section 11.3).  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  

 
 
 
 
 
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50 
 
Please refer to section 9.2 for detailed information regarding the assessment and recording of AEs.   
9.1.6.2 Physical Exam 
The investigator or qualified designee will perform a physical exams according to standard clinical 
care during the study period.  Clinically significant abnormal findings at screening/baseline should be 
recorded as medical history.   
9.1.6.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart 
(Section 8.0).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
9.1.6.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status as outlined in the study flow chart (see 
Section 8.0).  
9.1.6.5 Tumor Imaging and Assessment of Disease 
The primary objectives are to evaluate the safety, tolerability, and efficacy of the study drugs.  All 
patients will be assessed by standard criteria for clinical response. Patients with measurable disease 
will be assessed by standard criteria.  For patients with PTCL, response will be evaluated with 
physical exam, computerized tomography (CT) and tissue biopsies as defined by the lymphoma 
response to immunomodulatory therapy criteria or LYRIC (Cheson et al., 2016)24.  Positron emission 
tomography / computerized tomography (PET/CT) will be utilized if available (optional).  
 
For patients with CTCL and PTCL with skin involvement, we recommend skin assessments using 
mSWAT, preferably by the same investigator at all times (to limit inter-observer variability) during 
the screening period and during the treatment period as defined in Study Flow Chart23. Please find 
mSWAT worksheet in section 11.2. Additional assessments will be performed as clinically indicated 
at investigator discretion.  
In particular, we strongly recommend standardized photographs of the skin involvement to document 
the appearance of skin lesions at baseline (screening or Cycle 1 day 1) and as defined in Study Flow 
Chart. Blood involvement assessments will be performed for only CTCL patients at the same time as 
the skin assessments. 
Evaluable for objective response.  Patients who have received at least one cycle of therapy will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  Patients who exhibit objective disease progression prior to the end of cycle 
1 will also be considered. 
The following disease parameters will be assessed. 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in two 
dimensions (longest diameter to be recorded) as >20 mm with conventional techniques (PET/CT, 
MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements will be recorded in 
millimeters (or decimal fractions of centimeters).  Tumor volume will be recorded as the sum of the 
product of the diameters (SPD) of the largest predominant target lesions. FDG avidity is based on 
comparison with background tissues.  There is no specific SUV value that is considered a cut-off. 
Non-measurable disease (evaluable disease). All other lesions (or sites of disease), including small 
lesions (<10 mm using spiral CT scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, 

 
 
 
 
 
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
51 
 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are 
all non-measurable. 
Target lesions. All measurable lesions up to a maximum of 6 lesions total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  Target 
lesions should be selected on the basis of their SUV avidity (High SUV lesions will be prioritized, 
even if not the largest lesions) and size (lesions with the largest SPD diameter) and their suitability for 
accurate repeated measurements (either by imaging techniques or clinically).  An SPD for all target 
lesions will be calculated and reported as the baseline sum SPD.  The baseline sum SPD will be used 
as reference by which to characterize the objective tumor response based on CT criteria. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and 
above the 6 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up.  
The guidelines to assess response will be based on the Olsen (Olsen et al., 2011)23 and the Lymphoma 
Response to Immunomodulatory Therapy Criteria or LYRIC (Cheson et al., 2016)24. 
9.1.7 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below. Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 15.   

 
 
 
 
 
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Table 15: 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) Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bio carbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
EBV PCR 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
Creatinine 
† 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. 
 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
53 
 
Laboratory test before every day 1 of treatment, except cycle 1 day 1, should be performed within 72 hours prior to 
study treatment.  
For cycle 1 day 1 laboratory screening tests can be considered valid for treatment on cycle 1 day 1 as long as they are 
performed within the screening laboratory test window (10 days). After Cycle 1, pre-dose laboratory procedures can 
be conducted up to 72 hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment.  
9.1.7.1 Tumor Tissue Collection and Correlative Studies Blood Sampling 
The following exploratory parameters will be assessed: 
9.1.7.2 Biomarkers from tumor tissue and peripheral blood 
1. Standard flow cytometry to assess CD3, CD4, CD8, CD25, CD80, PD1, PD-L1, PD-L2 and Foxp3 in peripheral 
blood mononuclear cells and in addition we will analyze peripheral blood T lymphocytes by flow cytometry for CD45 
RA, CCR7, CD62L to understand changes in the T cell repertoire. Correlation in between changes and response to 
treatment will be made. 
 
2. Paraffin embedded primary tumor samples will be obtained pre- and post-treatment as defined below and 
OpalMultiplexing “MANTRA” will be performed. MANTRA is a tissue evaluation technique, which uses a 
fluorescent signal amplification probe to permit serial immunohistochemistry and compared to conventional 
immunohistochemistry permits multiplex detection. We will use Opal Multiplexing MANTRA to determine changes 
in the microenvironment (TILs, NK-cell and antigen-presenting cells) as a function of treatment.  The following set of 
6 markers will be analyzed on each tissue biopsy: CD3, CD7, CD4, CD8, PGM1, IDO; CD3, CD7, CD4, CD8, CD20, 
FOXP3; CD3, CD7, CD4, CD8, PD-1, PD-L1; CD3, CD7, CD4, CD8, CD56, Granzyme B. 
3. Gene expression profiling (GEP) analysis will be obtained on primary tumor samples pre- and post-treatment. 
Changes of gene expression profiling as a function of treatment with pralatrexate and decitabine will be analyzed. 
Specific attention will be placed on defined gene-signature already described and predictive of response to 
pembrolizumab (e.g. interferon-γ-related genes including CXCL9, CXCL10, IDO1, IFNG, HLA-DRA, STAT1). 
Additional signature associated with clinical outcome will be investigated.   
4. Genome wide methylation analysis will be performed to identify and quantify changes in methylation pre- and 
post-treatment. Specific attention will be placed on decitabine contribution in de-repressing and inducing transcription 
of multiple DNA hypermethylated human endogenous retrovirus (HERV) genes triggering a type I interferon-
response. 
5. GEP and methylation wide methylation profiling will be analyzed, and correlation will be made to identify 
biomarkers of response. The data gathered from the GEP and genome wide methylation will be used to create an 
algorithm of regulatory networks within PTCLs. The analysis of these data will provide information on etiology of 
PTCLs and will suggest possible targetable oncogenic pathways.  
9.1.7.3 Pharmacokinetic/Pharmacodynamic Evaluations 
Pharmacokinetic evaluation will be performed at UVA ONLY.  
The pharmacokinetics (PKs) blood draw for most timepoints can be performed with a +/- 30 minutes window. 
Exceptions include:  
1. 
The 24 hour after end of administration timepoint may be performed with  a +/- 90 minute window.  
2. 
End of infusion (EOI) draw should be within 10 minutes following completion of infusion 
3. 
30 minutes post completion of infusion draw should be +/- 5 minutes 
Pharmacokinetic evaluation will be performed only during cycle 1.  
• 
Pharmacokinetics will be assessed as followed in Arm A: 
On day 1 of cycle 1, blood samples will be obtained from patients at fixed time intervals after administration of 
pralatrexate to determine the plasma level of both pralatrexate and pembrolizumab. This will be compared to the 
known pharmacokinetic data for the individual agents in order to identify any possible effect of the combination. 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
54 
 
Specifically, blood samples will be obtained at day 1 pre-administration, end of administration (EOA), 30 minutes, 1 
hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after the end of administration. On day 8 and day 15 of cycle 1, 
blood samples will be obtained pre-administration, EOA, 2 hours and 4 hours after the end of administration.  
 
• 
Pharmacokinetics will be assessed as followed in Arm B: 
On day 1 of cycle 1, blood samples will be obtained from patients at fixed time intervals after administration of 
decitabine and pralatrexate to determine the plasma level of pralatrexate, decitabine and pembrolizumab. This will be 
compared to the known pharmacokinetic data for the individual agents in order to identify any possible effect of the 
combination. Specifically, blood samples will be obtained at day 1 and day 5 (day 3 if dose level is for decitabine on 
days 1-3) of cycle 1 pre-administration, end of administration (EOA), 30 minutes, 1 hour, 2, 4, 6, 8, and 24 hours after 
EOA. On day 8 and day 15 of cycle 1 blood sample will be obtained pre-administration, EOA, 2 and 4 hours after 
EOA.  
 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
55 
 
 
 
 
 
• 
Pharmacokinetics will be assessed as followed in Arm C: 
On day 1 of cycle 1, blood samples will be obtained from patients at fixed time intervals after administration of 
decitabine to determine the plasma level of decitabine. This will be compared to the known pharmacokinetic data for 
the individual agents in order to identify any possible effect of the combination. Specifically, blood samples will be 
obtained at day 1 of cycle 1 pre-infusion, end of infusion (EOI), 30 minutes, 1 hour, 2, 4, 6, 8 and 24 hours after EOI. 
On day 5 of cycle 1 (day 3 if dose level is for decitabine on days 1-3), blood samples will be obtained pre-infusion, 
end of infusion (EOI), 30 minutes after EOI, 1 hour after EOI, 2 hours after EOI, 4 hours after EOI, 6 hours after EOI 
and 8 hours after EOI.  

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
56 
 
 
 
Pharmacodynamics evaluation will be performed as described in detail in the laboratory manual. 
 
9.1.8 Other Procedures 
9.1.8.1 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 9.2.   
9.1.9 Visit Requirements 
Visit requirements are outlined in Section 8.0- Trial Flow Chart.   Specific procedure-related details are provided 
above in Section 9.1- Trial Procedures. 
9.1.9.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial 
treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All AEs that occur prior to 
the Safety Follow-Up Visit should be recorded.  Subjects with an AE of Grade > 1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should also 
be followed and recorded.   

 
  
  
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For subjects who have an allogeneic SCT within 24 months of last study treatment, transplant parameters will be 
collected and specific events will be collected for 18 months from the date of the allogeneic transplant to include 
graft-versus-host-disease (acute and/or chronic), veno-occlusive disease, febrile syndrome (a steroid-requiring febrile 
illness without an infectious cause), and encephalitis, for all grades, and regardless of relationship to study drug.   
Additional medically important adverse events post-allogeneic SCT may be submitted at the Investigator’s discretion.  
If available and relevant to an event post-allogeneic SCT, concomitant medications and/or laboratory results may also 
be reported. 
9.1.10 Subject Registration and Randomization  
All participants must sign the consent form prior to determination of eligibility for this study.    
When a site is ready to enroll a patient, the following documentation must be scanned and emailed to the UVA 
Coordinating Center:  
• 
Patient and staff signed signature page of the current informed consent form (ICF)  
• 
Completed Inclusion/Exclusion checklist demonstrating subject eligibility  
• 
Supporting documentation needed to confirm eligibility (lab results, scan results etc.)  
Consult the Study Reference Manual for instructions on sending this information. The Coordinating Center will 
consult with the Overall Study PI if questions arise in confirming eligibility. The UVA Coordinating Center will 
communicate the subject number and treatment dose assignment to the enrolling site. 
 
Registration will occur following verification of eligibility by the treating physician. 
 
Participants who are consented and accrued to the study should be registered in OnCore in accordance with the 
Clinical Trial Management System Policy via the UVa OnCore Resources link in Oncore. General guidelines are 
available in the OnCore User Manual and Data Entry Guide.  
Participants should receive their first study treatment within 2 weeks of registration. 
 
Treatment allocation will be discussed with participants during the process of informed consent and will occur after 
registration.  Treatment allocation will be based upon the study design until a safety bound has been triggered or 
target accrual has been met. Arm allocation slots are generated by the coordinating center. Treatment allocation will 
occur after registration and within 2 weeks of the start of treatment. 
This study does not involve any blinding or masking procedures.  Subjects will be told which treatment they are 
receiving. 
9.2 
DATA REPORTING / REGULATORY REQUIREMENTS 
The Global T-cell Lymphoma Consortium (GTcLC) consist of centers across the globe whose specialty is conducting 
clinical research studies in T-cell Lymphoma. The data and safety monitoring plan will adhere to the Data Safety 
Monitoring Board of the UVA Cancer Center for investigator-initiated studies. When a UVA faculty member holds an 
IND for a study UVA will be the coordinating center. All other sites under the GTcLC will be participating centers.    
When an industry study is being conducted under the auspices of the consortium the industry sponsor will be 
responsible for monitoring the study. UVA will continue to report any needed SAE, deviations, or toxicities as 
required by the institution and FDA.  For any investigator-initiated study within the consortium where the IND is held 
at another institution that institution will be the coordinating center and all other sites will be the participating centers. 
Each member site within the consortium will follow the guidelines of each individual institutional or FDA guidelines 
as well as local ethical standards. 
 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality of AE and 
SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety event reports can be 
found in section 11.5.   
 

 
  
  
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Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when appropriate, by 
a caregiver, surrogate, or the participant's legally authorized representative). 
 
The investigator and any designees are responsible for detecting, documenting, and reporting events that meet the 
definition of an AE or SAE as well as other reportable safety events. Investigators remain responsible for following 
up AEs, SAEs, and other reportable safety events for outcome. 
 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or SAE as well as 
other reportable safety events with respect to seriousness, intensity/toxicity and causality. 
 
9.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation/randomization must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the study, or 
is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of intervention allocation/randomization through 
90 days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer therapy must 
be reported by the investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to Merck if the event is considered drug-
related. 
 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in former 
study participants. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably related 
to the study intervention or study participation, the investigator must promptly notify Merck and the 
Sponsor/UVA CC/GTcLC. 
 
9.2.1.1 Reporting to Merck 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported to 
Merck within the time frames as indicated in  
 
Table 16. 
 
 

 
  
  
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Table 16  Reporting Time Periods and Time Frames for Adverse Events and Other Reportable Safety 
Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to 
Report Event and 
Follow-up 
Information to 
Merck: 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 business 
days but no longer 
than 3 calendar days 
of learning of event 
Pregnancy/Lactation 
Exposure 
Report if: 
- due to 
intervention 
- causes exclusion 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 business 
days but no longer 
than 3 calendar days 
of learning of event 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 business 
days but no longer 
than 3 calendar days 
of learning of event 
9.2.1.2 Adverse Event Reporting to Sponsor/UVA CC/GTcLC/DSMC 
The UVA Cancer Center Data Safety Monitoring Committee (DSMC) will oversee conduct of the study, patient 
safety and all interim analyses as specified in the data analysis plan.  Detailed guidelines regarding the structure, 
function and decision-making mechanisms for the Data Safety Monitoring Committee are provided in the DSMC 
charter. 
 
The Global T-cell Lymphoma Consortium (GTcLC) at UVA will be the coordinating center. All participating centers 
will report all serious adverse events to the UVA Cancer Center’s DSMC and to local ethics committees. 
 
AEs must be recorded into the study’s case report forms per the following guidelines. 
In the event of a DLT prior to initiation of cycle 2, site staff must report the occurrence to the UVA CC/GTcLC via 
the DLT CRF within 24 hours from the time the study team receives knowledge of the event. DLT’s that are deemed 
serious will also be submitted according to the reporting guidelines in section 9.2. DLTs occurring after the initiation 
of cycle 2 do not need to be submitted on the DLT CRF, but should be reported as AEs/SAEs accordingly. 

 
  
  
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Table 17 : High Risk Studies  
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade  
4 & 5 
Expected 
and 
unexpected 
 
Expected 
 
 
Unexpected 
Expected 
 
Unexpected 
Expected 
and 
Unexpected 
Without 
hospitalization 
With 
hospitalization 
Without 
hospitalization 
With 
hospitalization 
Unrelated 
Unlikely 
30 days 
30 days 
30 days 
30 days 
15 days 
30 days 
15 days 
7 days 
Possible 
Probable 
Definite 
30 days 
30 days 
15 days 
30 days 
15 days 
7 days 
7 days 
 (24-hrs)* 
7 days 
 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 
 
9.2.1.3 Serious Adverse Event Reporting to Sponsor/UVA CC/GTcLC /DSMC/IRB 
The study clinician will report to the sponsor (see Study Reference Manual for contact information and instructions) 
any serious adverse event, whether or not considered study intervention related, including those listed in the protocol, 
package insert or investigator brochure and must include an assessment of whether there is a reasonable possibility 
that the study intervention caused the event.  
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic or the participant is stable. Other supporting documentation of the event may be requested by the 
UVA Coordinating Center (UVA CC/GTcLC /Sponsor) and should be provided as soon as possible.  
 
Any event deemed serious   
 
• 
Report to the UVA CC/GTcLC within 24 hours from the time the study team received knowledge of the event 
according to UVA CC/GTcLC requirements.  
• 
Additional follow-up reports should be sent according to the Study Reference Manual 
• 
Report to your IRB in accordance with your IRB guidelines.   
 
Sponsor Reporting Requirements 
 
• 
The Sponsor  is responsible for notifying the UVA IRB-HSR of any event resulting in death that is deemed 
DEFINITELY related to (caused by) study within 24 hours from the time the study team received knowledge 
of the event.  Report using IRB Online and by telephone. 
 
• 
The Sponsor is responsible for notifying the Food and Drug Administration (FDA) of any unexpected fatal or 
life-threatening adverse event that is at least possibly related to study intervention as soon as possible, but in 
no case later than 7 calendar days after the sponsor's initial receipt of the information.  Report using the FDA 
Form 3500a. 
 
• 
The Sponsor is responsible for notifying the UVA IRB-HSR of any serious, unexpected, related adverse event 
within 7 calendar days from the time the study team receives knowledge of the event.  Timeline includes 
submission of signed hardcopy of AE form.  Report using IRB online.   
 

 
  
  
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61 
 
• 
The Sponsor is responsible for notifying the FDA and all participating investigators in an Investigational New 
Drug (IND) safety report of potential serious risks, from clinical trials or any other source, as soon as 
possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies 
for reporting (21 CFR 312.32 (c)(1)).  Other adverse event information should be sent to the FDA in the IND 
annual report. 
9.2.2 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy or infant 
exposure during breastfeeding in a participant (spontaneously reported to the investigator or their designee) that 
occurs during the study are reportable to Merck and to the UVA CC/GTcLC /Sponsor (see section 9.2. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues 
to term, the outcome (health of infant) must also be reported. 
9.2.3 Events of Clinical Interest 
Selected nonserious and SAEs are also known as ECIs and must be reported to Merck.  
Events of clinical interest for this study include:  
1. 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal laboratory results. 
For purposes of this study, 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. In the event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.  If an adverse event(s) is 
associated with (“results from”) the overdose of a Merck product, the adverse event(s) is reported as a 
serious adverse event, even if no other seriousness criteria are met. 
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 
9.2.4 Unanticipated Problems 
9.2.4.1 Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UPs)(may include a data 
breach) involving risks to participants or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in 
the protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 

 
  
  
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62 
 
9.2.4.2 Unanticipated Problem Reporting 
Site Reporting Requirements 
• 
UPs that are SAEs will be reported in accordance with the guidelines for SAE reporting. 
• 
UPs that are not adverse events, protocol deviations or data breaches (see section 9.2.5 for reporting for data 
breaches) should be reported as follows: 
o Report to the UVA CC/GTcLC within 2 calendar days from the time the study team receives 
knowledge of the event.  
o Report to your IRB of record in accordance with your IRB guidelines.   
 
Sponsor/UVA CC/GTcLC Reporting Requirements 
• 
Report UPs that are not adverse events, protocol deviations or data breaches to the UVA IRB-HSR within 7 
calendar days from the time the study team receives knowledge of the event.  Report using the Unanticipated 
Problem Report form. 
 
All UPs will be reported to appropriate institutional officials (as required by an institution’s written reporting 
procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) in 
accordance with institutional policies. 
9.2.5 Data Breaches 
9.2.5.1 Definition of a Data Breach 
An unauthorized acquisition, access, or use of protected health information (PHI) that compromises the 
security or privacy of such information. 
9.2.5.2 Reporting a Data Breach 
Site Reporting Requirements 
• 
Report to the Sponsor/UVA CC/GTcLC within 24 hours from the time the study team receives knowledge of 
the event.  
• 
Report to your IRB of record in accordance with your IRB guidelines.   
 
Sponsor/UVA CC/GTcLC Reporting Requirements 
• 
Report to the UVA Corporate Compliance and Privacy Office as soon as possible and no later than 24 hours 
from the time the incident is identified.  Report by telephone. 
 
• 
Report to ITC if the breach involves electronic data.  Report as soon as possible and no later than 24 hours 
from the time the incident is identified.  Refer to the following for details:  http://security.virginia.edu/report-
information-security-incident. 
 
• 
Report to UVA police if the breach includes such things as stolen computers.  Report by telephone. 
9.2.6 Protocol Violations or Deviations 
9.2.6.1 Definition of a Protocol Violation/Deviation 
A protocol deviation is defined as any change, deviation, or departure from the study design or procedures of a 
research project that is NOT approved by the institution’s IRB prior to its initiation or implementation, OR deviation 
from  standard operating procedures, Good Clinical Practices (GCPs), federal, state or local regulations. Protocol 
violations may or may not be under the control of the study team or UVa staff. These protocol violations may be 
major or minor violations. 

 
  
  
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9.2.6.2 Emergency Protocol Deviation/Violation 
When an emergency occurs that requires a violation of the protocol for a subject, this will be made only for that 
subject.  A decision will be made as soon as possible to determine whether or not the subject (for whom the violation 
of, the protocol was affected) is to remain on study. This decision will be made by Dr. Owen O’Connor the IND 
holder.  The subject’s medical records will completely describe the violation of, the protocol and state the reasons 
thereof. In addition, the Investigator will notify the IRB/EC and the FDA as applicable in writing of such violation of, 
the protocol.  
9.2.6.3 Non-Emergency Protocol Deviation/Violations 
Non-emergency minor violations of the protocol (i.e., deviations) will be permitted with approval of the PI.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations.  
9.2.6.4 Reporting of Protocol Deviations/Violations 
Site Reporting Requirements 
• 
Report major deviations to the UVA CC/GTcLC within 4 calendar days from the time the study team receives 
knowledge of the event. All deviations must be addressed in study source documents. Refer to the Study 
Reference Manual for instructions on recording minor deviations. 
• 
Report to your IRB of record in accordance with your IRB guidelines.   
 
Sponsor/UVA CC/GTcLC Reporting Requirements 
• 
Report to the UVA IRB-HSR major deviations within 7 calendar days from the time the study team received 
knowledge of the event.  Report using the Protocol Deviation and Protocol Exception Reporting Form. 
• 
Minor deviations do not need to be reported to the UVA IRB-HSR.   
9.2.7 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety events. 
Open-ended and nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.8 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be followed until 
resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-up.. In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in randomized 
participants for outcome. Further information on follow-up procedures is given in section 11.5. 
9.2.9 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable country specific regulatory requirements, global laws and regulations.  
 

 
  
  
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9.3 
Other Regulatory, Monitoring and Quality Assurance/Quality Control Considerations 
9.3.1 Foreign Sites 
All studies conducted under an IND will obtain a waiver of Institutional Review Board (IRB) requirements under 
21CFRPart 56. The clinical parameters, data collection, data quality, and clinical trial conduct must adhere to U.S. 
regulations to be considered in the evaluation of a new drug application. 
 
Reference to: 
 
ICH guidance E5 Ethnic Factors in the Acceptability of Foreign Clinical Data: 
https://www.fda.gov/downloads/Drugs/Guidances/ucm073120.pdf 
Guidance for Industry and FDA staff: FDA Acceptance of Foreign Clinical Studies Not 
Conducted Under an IND Frequently Asked Questions. 
 
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM294729.pdf 
Guidance for Industry: Investigator Responsibilities – Protecting the Rights, Safety, and Welfare of Study Subjects. 
 
 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ 
UCM187772.pdf 
 
Office of Scientific Investigations. 
https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm090085.htm 
9.3.2 Compliance & Monitoring  
The Global T-cell Lymphoma Consortium consists of a network of physicians whose expertise in T-cell Lymphoma 
whose mission is to advance the standards of care for patients with these complex diseases.  
The consortium’s three Principal Investigators represent three geographic sectors; Asia, North America, and Europe. 
Columbia University Medical Center (CUMC) will be the central reporting administration for the consortium. In this 
capacity the consortium will function similar to that of a clinical research organization (CRO).  
Each global center will have a monitor at the site level who will follow the guidelines outlined in this document. A 
copy of monitoring reports will be made available to the Coordinating Center.  
Each individual site will continue to follow their individual institution’s guidelines for reporting purposes in addition 
to reporting these events to the centralized reporting administration of the consortium. The consortium central 
reporting administration will utilize the UVA Data Safety Monitoring Committee (DSMC) reporting templates for 
both serious adverse events and risk assessment. Reporting of SAEs will be in real time for each center using a 24 
hour fax & email system. All necessary documentation will be sent including any pertinent labs and clinic /hospital 
notes. The necessary reporting to the UVA DSMC, IRB, and FDA will be the responsibility of the IND holder. When 
a protocol is conducted under an IND, the holder of that IND will follow their institutional guidelines in addition to 
reporting to the central reporting administration of the consortium. Each site within the Consortium will utilize their 
Institutional DSMB (DSMC or DMB) committee within each geographical sector. This is intended to satisfy the 
policies and recommendations of the U.S. Food and Drug Administration (FDA) and local ethics boards.  
9.3.3   Study Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the 
reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and with applicable regulatory requirement(s).  

 
  
  
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• 
The UVA Coordinating Center will implement ongoing monitoring activities for this study to ensure 
that Participating Institutions are complying with regulatory and protocol requirements, data quality, 
and subject safety. Monitoring will occur before the clinical phase of the protocol begins, continue 
during protocol performance and through study completion. 
 
• 
Monitoring may be conducted either remotely or on-site.  For remote visits, each institution will be 
required to provide redacted source documents for review or appropriate access to the EMR. The 
UVA CC/GTcLC will provide the Participating Institution with a follow-up letter following 
completion of the monitoring  visit which should be maintained in the site regulatory files.  The 
schedule for monitoring may be adjusted according to subject accrual and data quality.  The 
Investigator will be notified in advance of each visit. 
 
• 
Independent audits may be conducted by each institution according to institutional guidelines. Results 
of these audits may be requested by the UVA Coordinating Center. 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US Code of 
Federal Regulations. 
 
The University of Virginia Cancer Center Data and Safety Monitoring Committee (CC DSMC) will provide oversight 
of the conduct of this study.  The CC DSMC will report to the UVA Protocol Review Committee (PRC). 
 
The UVA Cancer Center DSMC will review the following: 
• 
All adverse events  
• 
Audit results 
• 
Application of study designed stopping/decision rules 
• 
Whether the study accrual pattern warrants continuation/action 
• 
Protocol violations 
Whenever a PAM audit (described in the next paragraph) is conducted, the results will be provided to the DSMC 
Chair for review.  The UVA Cancer Center DSMC will meet every month for aggregate review of data.  Tracking 
reports of the meetings are available to the PI for review.  Issues deemed of immediate concern by the DSMC are 
brought to the attention of the sponsor (and if appropriate to the PRC and UVA IRB-HSR) and a formal response 
from the sponsor is requested.  Per the UVA Cancer Center NIH approved institutional plan, this study will be audited 
(post-approval monitoring) approximately every 6 months.  The audit may include direct access to source 
data/documents. 
Any study conducted at UVA and under the purview of the University of Virginia HSR-IRB is subject to review of 
UVA documents. Studies are chosen for Post-approval Monitoring (PAM) either a) at random or b) requested by a 
study team member or any member of the IRB-HSR.   
The purpose of Post-approval Monitoring audits is to ensure that documentation of clinical research studies is of the 
highest quality, verify protocol adherence, and ensure that all Federal and local rules concerning clinical research are 
being fulfilled.  Post-approval monitoring is done by staff within the office of the Vice President for Research (VPR) 
in accordance with their Standard Operating Procedures. The conduct of an on-site review may include but is not 
limited to: 
• 
requests for progress reports from investigators, 
• 
examinations of research records, including signed informed consent documents, protocol modifications, 
and unexpected, serious, and/or related adverse experience reports, 
• 
contacts with research subjects, or 

 
  
  
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• 
observation of the consent process and/or research procedures. Examples of when observation of the 
consent process could occur are: 
• 
Full board IRB determines during review of a project that a conflict of interest exists such that the 
informed consent process should be observed by a neutral party; 
• 
IRB is made aware of a complaint or concern with regard to the informed consent process; or 
IRB determines as a result of the monitoring process that the consent process is insufficient and education/training is 
required for conduct of consent. 
 
Investigators must enter study data onto CRFs or other data collection system.  The Investigator will permit study-
related audits by UVA Cancer Center or its representatives, IRB/EC review, and regulatory inspection(s) (e.g., FDA, 
EMEA, TPP), providing direct access to the facilities where the study took place, to source documents, to CRFs, and 
to all other study documents. 
9.3.3.1 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, 
documentation and completion according to institutional policies.] 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) 
for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted 
and data are generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the 
purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 
9.3.4 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing application in an 
International Conference on Harmonisation (ICH) region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the study intervention. These documents should be retained for a longer period, however, if required 
by local regulations. No records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be retained. Record 
retention will be in accord with drug 21 CFR 312.62 and HIPAA regulations. 
10.0 STATISTICAL CONSIDERATIONS 
10.1 
Study Design 
This is a Phase Ib study evaluating the safety and efficacy of pembrolizumab combined with pralatrexate (Arm A) or 
decitabine (Arm C) or decitabine and pralatrexate (Arm B) in patients with peripheral T-cell lymphoma (PTCL) and 
cutaneous T-cell lymphoma (CTCL). In all arms, toxicity will be assess according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0. Dose-limiting toxicity (DLT) is a binary outcome (yes/no) and 
will be determined by adverse events occurring during the first cycle of treatment (see Section 5.3 for DLT 
definition). In all arms, the maximum tolerated dose (MTD) is defined as the dose combination with a DLT rate 
closest to the target DLT rate of 25%. The study will accrue participants in cohorts of size 1 in all arms. After accrual 
of a participant to an arm, the accumulating DLT data will be used to update the model-based estimated DLT 

 
  
  
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67 
 
probabilities for each dose level. These estimates will then be used to update the recommended dose level for the next 
participant accrued to that arm of the study.  
 
Arms A and C: 
The primary objectives of Arms A and C is to determine the MTD, defined by acceptable toxicity, of decitabine (Arm 
C) or pralatrexate (Arm A) (plus a fixed dose of pembrolizumab) from among the 3 study dose levels in the following 
tables, and to evaluate efficacy, as determined by overall response rate, at the estimated MTD.  
 
Arm A 
Dose Level 
Pralatrexate 
Pembrolizumab* 
Level 1 (start) 
30 mg/m2 day 1, 8, 15 
200 mg day 1 
Level -1 
30 mg/m2 day 1, 15 
200 mg day 1 
Level - 2 
20 mg/m2 day 1, 15 
200 mg day 1 
 
Arm C 
Dose Level 
Decitabine 
Pembrolizumab* 
Level 1 (start) 
20 mg/m2 day 1->5 
200  mg day 8 
Level -1 
20 mg/m2 day 1->3 
200 mg day 8 
Level -2 
10 mg/m2 day 1->3 
200 mg day 8 
 
Based on the accumulated data from the previous 5 subjects (1 observed DLT) accrued to Arm A, the first eligible 
subject in Arm A will be entered onto Level 1. Based upon the accumulated data from the previous 4 subjects (2 
observed DLTs) accrued to Arm C, the first eligible subject in Arm C will be entered onto Level -1.  
 
Arm B: 
The primary objective of Arm B is to determine the MTD, defined by acceptable toxicity, of pembrolizumab 
combined with decitabine and pralatrexate from among the six study dose combinations in the following table, and to 
evaluate efficacy, as determined by overall response rate, at the estimated MTD. In a previous version of the protocol 
(dated 14 Dec 2022), fifteen dose combinations were considered for Part B. While the current protocol version 
reduces the number of dose combinations to six, we have maintained the original combination labels to maintain 
consistency with the original dose levels for each combination. 
 
Combination designation 
Pralatrexate 
20mg/m2 1,8,15 
Combination 6 
Combination 8 
20mg/m2 1,15 
Combination 3 
Combination 5 
15mg/m2 1,15 
Combination 1 
Combination 2 
  
10mg/m2 1-3 
10mg/m2 1-5 
Decitabine 
 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
68 
 
Based on the accumulated data from the first 4 subjects (1 observed DLT) accrued to Combination 8 in Arm B, the 
next eligible subject in Arm B will be entered onto Combination 8.  
10.2 
Dose allocation 
Arms A and C 
Dose allocation in Arms A and C will be based upon a continual reassessment method (CRM), which uses a model for 
the probability of DLT and the accumulated DLT data at each dose level to sequentially allocate each new patient 
cohort1. Toxicity assessment is based on the occurrence of DLTs, and the minimum follow-up for determination of 
escalation is one cycle of treatment. The DLT probabilities are modeled using a one-parameter working model 
, where 
 is the skeleton of the working model. The skeleton values 
are pre-specified constants and were chosen according to the algorithm of Lee and Cheung25, which yields a working 
model that results in well-performing operating characteristics in a broad range of scenarios. For this study, the 
skeleton values are 
. Based on the available DLT data 
, where 
where 
 is the number of DLT’s and 
 is the number of subjects treated on study dose level , the likelihood is given 
by 
. 
After accrual of each patient into the trial, the DLT probability estimates, 
, are updated via 
. 
These estimates are used to sequentially allocate patients to the dose indicated by the modeling to have the estimated 
DLT rate closest to 25%. The study will accrue participants in cohorts of size 1 and dose levels will not be skipped. 
The coherence principle will be used, where the next patient will not be treated at a dose level higher than the current 
dose level if the current patient experiences a DLT26. Additionally, the next patient will not be treated at a dose level 
lower than the current dose level if the current patient does not experience a DLT. The study will sequentially repeat 
the estimation procedure after the enrollment and follow-up of each cohort. The allocation procedure will be repeated 
until sufficient information about the MTD has been obtained according to the stopping rules described below.  
 
Arm B 
Dose combination allocation in Arm B will be conducted using a DLT-adapted partial order continual reassessment 
method (POCRM) for dose-finding with combinations of agents2. The study will accrue eligible participants in 
cohorts of size 1 and will be based upon a modeling approach that uses (a) a selected set of five possible orderings for 
the DLT probabilities and (b) a skeleton for the DLT probabilities under each ordering. In drug combination studies, 
the toxicity relationship between some of the combinations being studied may be uncertain. If a combination involves 
increasing the dose of one agent while decreasing the dose of the other agent relative to another combination, then it 
may not be known which is more toxic. For example, combination 2 is an increase in the dose of decitabine and a 
decrease in the dose of pralatrexate relative to combination 3, which creates uncertainty in the ordering of DLT 
probabilities between combination 2 and combination 3. The specification of multiple possible orderings of DLT 
probabilities accounts for these types of uncertainty in the modeling approach. 
 
Possible 
orderings 
of 
DLT probabilities 
1)      1-2-3-5-6-8 
2)      1-2-3-6-5-8 
3)      1-3-2-5-6-8 
4)      1-3-2-6-5-8 
5)      1-3-6-2-5-8 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
69 
 
Skeleton of DLT probabilities under 
each ordering** 
  
Combination labels 
Order 
1 
2 
3 
5 
6 
8 
1 
0.012 
0.03 
0.062 
0.11 
0.174 
0.25 
2 
0.012 
0.03 
0.062 
0.174 
0.11 
0.25 
3 
0.012 
0.11 
0.03 
0.174 
0.062 
0.25 
4 
0.012 
0.062 
0.03 
0.174 
0.11 
0.25 
5 
0.012 
0.062 
0.03 
0.11 
0.174 
0.25 
**Skeleton values were chosen according to the algorithm of 
Lee and Cheung (Clin Trials, 2009)25  
Within each ordering, the CRM is fit to estimate DLT probabilities using that ordering’s working model and the 
accumulated 
data. 
For 
each 
possible 
ordering,   
 in the table above, the DLT probabilities are modeled via a one-parameter power model 
 where the 
 are the skeleton values for order 
 given in the 
table above. Uniform prior weights 
 are placed on each possible ordering so that each ordering/skeleton 
is considered equally likely a priori. After accrual of each patient into the trial, the parameter 
 is estimated for each 
ordering by maximum likelihood estimation where the likelihood is given by  
 
 
= 
the 
number 
of 
DLTs, 
and 
=the 
number 
of 
treated 
patients 
in 
combination  
. The ordering 
 with the largest likelihood is chosen and, within this ordering, DLT probability estimates are 
updated for each combination. If there is a tie between the likelihood values of two or more orderings, then the 
selected ordering  is randomly chosen from among the tied orderings. After accrual of each patient cohort into the 
trial, the DLT probability estimates, 
, are updated via 
. 
The DLT probability estimates are used to sequentially allocate participants according to the following rules: 
1. If the most recent participant accrued to the study does not experience a DLT, then the recommended 
combination for the next participant will be the combination indicated by the model to have an estimated DLT 
rate closest to 25%. Escalation of both agents simultaneously or escalation of more than one dose level of either 
agent is not allowed.  
2. If the most recent participant accrued to the study does experience a DLT: 
a. If the DLT is mucositis or thrombocytopenia or mucositis plus neutropenia and/or thrombocytopenia, 
then the recommended combination for the next participant will be restricted to either the current 
combination administered to the most recent participant or to de-escalation of one dose level of 
Pralatrexate, based on which combination has an estimated DLT rate closest to 25%.  
b. If the DLT is neutropenia or neutropenia and thrombocytopenia, then the recommended combination for 
the next participant will be restricted to either the current combination administered to the most recent 
participant or to de-escalation of one dose level of Decitabine, based on which combination has an 
estimated DLT rate closest to 25% 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
70 
 
The study will sequentially repeat the estimation procedure after the enrollment and follow-up of each cohort. The 
allocation procedure will be repeated until sufficient information about the MTD has been obtained according to the 
stopping rules described below.  
10.3 
Stopping rules and MTD definition  
Arms A and C 
Accrual to Arms A and C will be halted and trigger a review by the study investigators and the DSMC to determine if 
the study should be modified, or permanently closed to further accrual according to the following: 
1. Stop the study for safety if the observed DLT rate at the lowest study dose level (Level -2) ≥ the following 
number of DLTs out of the following number of patients treated at the lowest study dose level. These 
stopping guidelines are based on whether the lower limit of an Agresti-Coull27 binomial confidence interval 
(with 80% confidence) for the lowest study dose level exceeds the target DLT rate. The following bounds 
were generated using the web application at http://uvatrapps.uvadcos.io/crmb/]. Note that, given the accrual of 
previous participants to dose level 1 in Arms A and C, at most 4 participants can be accrued to Level -2 
before the maximum sample size is reached.  
 
 
 
 
 
 
2. If the recommendation is to assign the next patient to a dose level that already has 7 participants treated at the 
dose level, enrollment to the arm is stopped and the recommended dose level is declared the MTD. 
3. Otherwise, the MTD is defined as the dose level that is recommended after the maximum sample size of 10 
participants for the arm. 
Arm B 
Accrual to Arm B will be halted and trigger a review by the study investigators and the DSMC to determine if the 
study should be modified, or permanently closed to further accrual according to the following: 
1. Stop the study for safety if the observed DLT rate at the lowest combination (Combination 1) ≥ the following 
number of DLTs out of the following number of patients treated at the lowest combination. These stopping 
guidelines are based on whether the lower limit of an Agresti-Coull binomial confidence interval (with 80% 
confidence) for the lowest combination exceeds the target DLT rate27. The following bounds were generated 
using the web application at http://uvatrapps.uvadcos.io/pocrm/]. 
 
 
 
 
 
 
2. If the recommendation is to assign the next patient to a combination that already has 7 participants treated on 
the combination, the study is stopped and the recommended combination is declared the MTD.  
3. Otherwise, the MTD is defined as the combination that is recommended after the maximum target sample size 
of 30 participants are accrued to the study.  
10.4 
Sample size and accrual  
A maximum target accrual of 5 additional eligible participants is planned in Arm A (total accrual n=10) and 6 
additional eligible participants in Arm C (total accrual n=10).  A maximum target accrual of 26 additional eligible 
participants is planned in Arm B (total accrual n=30), but simulation results below indicate that the average estimated 
Stopping guidelines for DLTs at the lowest dose level 
Number of participants 
Boundary 
2-3 
≥ 2 
4 
≥ 3 
Stopping guidelines for DLTs at the lowest combination 
Number of participants 
Boundary 
2-3 
≥ 2 
4-6 
≥ 3 
7 
≥ 4 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
71 
 
sample size needed to complete accrual to Arm B is between 3.5 (total accrual n=7.5) and 11.3 (total accrual n=15.3) 
additional participants. Maximum total sample size for all arms is estimated to be approximately 23 additional 
participants (total accrual n=36). For estimation of ORR at the MTD, a sample size of 7 at the MTD produces a two-
sided 80% binomial confidence interval with a width equal to 0.556 when the sample proportion is 0.5. Additional 
subjects will be enrolled to replace any subjects who are enrolled, but do not receive treatment. Accrual is estimated at 
2 participants per month. Adjusting for an approximate 5% drop-out/ineligibility rate, maximum target accrual should 
not exceed 38 participants. 
10.5 
Operating characteristics  
Arms A and C 
Simulations were run to display the performance of the design characteristics in Arms A and C using the R statistical 
programming language. For each scenario, 5000 simulated trials were run using a random seed of 322348. The 
confidence level used to define the safety stopping guidelines was 80%. Each table reports the true DLT probability at 
each dose level, the percentage of trials in which each dose level was recommended as the MTD, the average number 
of participants  treated at each dose level, and the percentage of trials stopped early for safety. The results displayed in 
the following tables were based upon a maximum target accrual of 10 subjects.  
 
Operating characteristics in Arm A for the continual reassessment method with cohorts of size 1. Bold font indicates 
the level that is the MTD corresponding to a target DLT rate of 25%. Previously, there were 5 participants accrued (1 
observed DLT) on dose level 3. Sample size for each scenario is n=10 total (previous plus additional) participants. 
Scenario 
 
Dose 
level 1 
Dose 
level 2 
Dose 
Level 3 
% stopped 
for safety 
1 
 
True DLT prob:              
0.05 
0.15 
0.25 
0.0 
MTD selection % 
5.7 
22.6 
71.7 
Avg # of patients 
0.1 
0.6 
9.3 
 
 
2  
True DLT prob:              
0.15 
0.25 
0.40 
0.24 
MTD selection % 
18.9 
36.2 
44.7 
Avg # of patients 
0.3 
1.0 
8.7 
 
3 
True DLT prob:             
0.25 
0.40 
0.55 
1.24 
MTD selection % 
41.2 
34.0 
23.5 
Avg # of patients 
0.6 
1.4 
8.0 
 
 
Operating characteristics in Arm C for the continual reassessment method with cohorts of size 1. Bold font indicates 
the level that is the MTD corresponding to a target DLT rate of 25%. Previously, there were 4 participants accrued (1 
observed DLT) on dose level 3. Sample size for each scenario is n=10 total (previous plus additional) participants. 
Scenario 
 
Dose 
level 1 
Dose 
level 2 
Dose 
Level 3 
% stopped 
for safety 
1 
 
True DLT prob:              
0.05 
0.15 
0.25 
0.0 
MTD selection % 
6.9 
3.1 
62.1 
Avg # of patients 
0.3 
1.2 
8.5 
 
 
2  
True DLT prob:              
0.15 
0.25 
0.40 
0.52 
MTD selection % 
23.6 
43.7 
32.2 
Avg # of patients 
0.7 
1.8 
7.5 
 
3 
True DLT prob:             
0.25 
0.40 
0.55 
2.24 
MTD selection % 
50.1 
35.4 
12.2 

 
  
  
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72 
 
Avg # of patients 
1.5 
2.0 
6.5 
 
Arm B 
Simulations were run to display the performance of the design characteristics in Arm B using the R statistical 
programming language. For each scenario, 5000 simulated trials were run using a random seed of 322348. The 
confidence level used to define the safety stopping guidelines was 80%. Simulation results include the true DLT 
probability at each combination, the percentage of trials in which each combination was recommended as the MTD, 
the average number of participants treated at each combination, the average sample size, and the percentage of trials 
stopped early for safety. The results displayed in the following tables were based upon a maximum target accrual of 
30 participants where accrual was stopped when 7 participants were treated on the recommended combination.  
 
Operating characteristics summary for proposed design over five scenarios 
  
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
Scenario 5 
Observed % DLTs 
20.25% 
21.38% 
17.38% 
27.27% 
31.59% 
Average sample size 
8.42 
8.84 
7.51 
12.44 
15.32 
MTD selection % ±5% of 
target* 
92.50% 
90.38% 
98.70% 
22.34% 
37.28% 
Avg # of pts treated ±5% of 
target* 
6.93 
6.91 
6.99 
2.8 
4.4 
% of early stopping for safety 
0.00% 
0.02% 
0.00% 
0.52% 
1.84% 
* Includes combination with highest DLT rate if true DLT probability for all combinations is below 5% 
of the target 
 
 
Operating Characteristics 
  
  
True DLT 
probabilities 
MTD Selection 
Percentage 
Average Number 
of Patients Treated 
Scenario 1 
20mg/m2 1,8,15 
0.15 
0.20 
1.36 
92.50 
0.25 
6.93 
20mg/m2 1,15 
0.09 
0.14 
0.22 
5.60 
0.08 
1.00 
15mg/m2 1,15 
0.07 
0.07 
0.06 
0.26 
0.02 
0.15 
Scenario 2 
20mg/m2 1,8,15 
0.14 
0.25 
1.94 
90.38 
0.33 
6.91 
20mg/m2 1,15 
0.10 
0.14 
0.26 
6.64 
0.10 
1.28 
15mg/m2 1,15 
0.09 
0.10 
0.04 
0.72 
0.03 
0.20 
Scenario 3 
20mg/m2 1,8,15 
0.08 
0.10 
0.30 
98.70 
0.09 
6.99 
20mg/m2 1,15 
0.06 
0.07 
0.00 
0.98 
0.01 
0.39 
15mg/m2 1,15 
0.05 
0.05 
0.00 
0.02 
0.00 
0.03 
Scenario 4 
20mg/m2 1,8,15 
0.40 
0.47 
5.00 
57.16 
0.87 
6.52 
20mg/m2 1,15 
0.18 
0.25 
6.38 
22.34 
0.89 
2.77 
15mg/m2 1,15 
0.15 
0.18 
1.62 
6.98 
0.32 
1.07 
Scenario 5 
20mg/m2 1,8,15 
0.47 
0.55 
6.12 
34.72 
1.25 
6.09 
20mg/m2 1,15 
0.25 
0.47 
18.38 
13.10 
2.09 
2.53 
15mg/m2 1,15 
0.15 
0.25 
6.94 
18.90 
1.06 
2.31 
Pralatrexate 
10mg/m2 
1-3 
10mg/m2 
1-5 
10mg/m2 
1-3 
10mg/m2 
1-5 
10mg/m2 
1-3 
10mg/m2 
1-5 
  
  
Decitabine 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
73 
 
10.6 
Data Analysis Plan 
All subjects who are put on-study will be assessed for inclusion in the final report. All subjects who receive any 
protocol treatment will be monitored for adverse events. Adverse events will be described and coded based upon the 
NCI CTCAE v5.0. A DLT is defined in Section  5.3.  Occurrence of DLTs will contribute to escalation and stopping 
decisions.  Adverse events will be summarized by frequency and magnitude of event. Incidence of DLTs will be 
monitored against the safety bounds above. The bounds are non-binding, and provide a guideline that may result in 
study modification or closure. At study conclusion frequency, proportion and severity of adverse events, and DLTs by 
study dose level, as well as by arm, will be tabulated. Point estimates and 90% Agresti-Coull27 binomial confidence 
intervals will be calculated for dichotomous endpoints (AEs, DLTs, overall response). For longitudinal measurements 
(i.e., immunologic and pharmacodynamic markers; see Sections 3 and 5.6), graphical methods will be used to display 
the data and exploratory repeated measures models will be used to describe changes over time. For continuous 
variables (i.e., duration of response), means, medians, and variability measures will be summarized with point 
estimates and 95% confidence intervals. PFS and OS distributions will be estimated by the product limit method of 
Kaplan and Meier. 
11.0 APPENDICES 
11.1 
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. 
    
11.2 
Modified Severity Weighted Assessment Tool (mSWAT) Worksheet 
Subject Number: __________ 
Visit Name: ____________________________________ 
Date of Assessment: _____ / _____ / ________ 
 
Body Region 
% BSA in 
Body Region 
% BSA 
Patch* 
% BSA 
Plaque† 
% BSA Tumor‡ 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior trunk 
13 
 
 
 
Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
74 
 
Body Region 
% BSA in 
Body Region 
% BSA 
Patch* 
% BSA 
Plaque† 
% BSA Tumor‡ 
Posterior trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Thighs 
19 
 
 
 
Legs 
14 
 
 
 
Feet 
7 
 
 
 
Groin 
1 
 
 
 
% BSA by Involvement Category 
(Subtotal of each lesion type) 
100 
 
 
 
Weighting factor 
 
×1 
×2 
×4 
Subtotal lesion BSA × weighting factor 
(multiply % BSA by Involvement 
Category and weighting factor for each 
lesion type) 
 
 
 
 
*Any size lesion without induration or significant elevation above the surrounding uninvolved skin; poikiloderma 
may be present. 
†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may be present. 
‡Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth. 
 
Total Score of Target Lesions (sum of lesion BSA × weighting factor subtotals): __________ 
11.3 
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) 
11.4 
Response Evaluation Criteria in Lymphoid Malignancies and CTCL 
Overall response rates will be evaluated using clinical parameters, CT scan (PET/CT scan is allowable,  if available) 
and bone marrow biopsy, as outlined by the 2007 International Harmonization Project criteria and revised criteria 
(Lugano 2014)22,28 
11.5 
Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
11.5.1 Definition of AE 
AE definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use 
of study intervention, whether or not considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. 
• 
NOTE: For purposes of AE definition, study intervention (also referred to as Merck product) includes any 
pharmaceutical product, biological product, vaccine, diagnostic agent, or protocol specified procedure 
whether investigational or marketed (including placebo, active comparator product, or run-in intervention), 
manufactured by, licensed by, provided by, or distributed by Merck for human use in this study. 

 
  
  
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75 
 
Events meeting the AE definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• 
For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term should 
reflect the clinical symptoms or abnormal test result. An overdose without any associated clinical symptoms 
or abnormal laboratory results is reported using the terminology “accidental or intentional overdose without 
adverse effect.” 
     Events NOT meeting the AE definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen. 
• 
Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
11.5.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, 
if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
76 
 
• 
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is 
a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a 
pre-existing condition that has not worsened is not an SAE. A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a Merck product and is documented in the participant’s medical history. 
d. Results in persistent or significant disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
that may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
• 
In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
11.5.3 Additional Events Reported in the Same Manner as SAE 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH definition, are 
reportable to Merck in the same time frame as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose of pembrolizumab 
11.5.4 Recording AE and SAE 
AE and SAE recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, hospital 
progress notes, laboratory, and diagnostics reports) related to the event. 
• 
The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each examination. 
• 
There may be instances when copies of medical records for certain cases are requested by the Merck. In this 
case, all participant identifiers, with the exception of the participant number, will be blinded on the copies of the 
medical records before submission to the Merck. 

 
  
  
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• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
Assessment of intensity/toxicity 
• 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, not when it is rated as severe. 
1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable safety 
event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 5. Any AE that 
changes CTCAE grade over the course of a given episode will have each change of grade recorded on the 
AE CRFs/worksheets. 
• 
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 activities of daily living (ADL). 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• 
Grade 4: Life threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did Merck product cause the AE? 
2. 
The determination of the likelihood that Merck product caused the AE 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 product and the AE based upon the available information. 
3. 
The following components are to be used to assess the relationship between Merck’s product and the AE; 
the greater the correlation with the components and their respective elements (in number and/or intensity), 
the more likely Merck product caused the AE: 
• 
Exposure: Is there evidence that the participant was actually exposed to Merck product such as: reliable 
history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 
• 
Time Course: Did the AE follow in a reasonable temporal sequence from administration of Merck 
product? Is the time of onset of the AE compatible with a drug-induced effect (applies to studies with 
investigational medicinal product)? 
• 
Likely Cause: Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors. 

 
  
  
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• 
Dechallenge: Was Merck product discontinued or dose/exposure/frequency reduced? 
• 
If yes, did the AE resolve or improve? 
• 
If yes, this is a positive dechallenge. 
• 
If no, this is a negative dechallenge. 
• 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; (3) the study is a single-dose drug study; or 
(4) Merck product(s) is/are only used 1 time.) 
• 
Rechallenge: Was the participant re-exposed to Merck product in this study? 
• 
If yes, did the AE recur or worsen? 
• 
If yes, this is a positive rechallenge. 
• 
If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 
study is a single-dose drug study; or (3) Merck product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’S PRODUCT POSES ADDITIONAL 
POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INIRB/IEC. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the AE consistent 
with previous knowledge regarding Merck product or drug class pharmacology or toxicology? 
5. 
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. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck 
product relationship). 
• 
Yes, there is a reasonable possibility of Merck product relationship: 
• 
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to 
the administration of Merck product is reasonable. The AE is more likely explained by Merck product 
than by another cause. 
• 
No, there is not a reasonable possibility of Merck product relationship: 

 
  
  
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• 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR the AE is more likely explained by another 
cause than the Merck product. (Also entered for a participant with overdose without an associated AE.) 
7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal information to 
include in the initial report to the Merck. However, it is very important that the investigator always make an 
assessment of causality for every event before the initial transmission of the SAE data to Merck. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and send an SAE 
follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the investigator 
may attribute each AE causality to the combination regimen or to a single agent of the combination. In 
general, causality attribution should be assigned to the combination regimen (ie, to all agents in the 
regimen). However, causality attribution may be assigned to a single agent if in the investigator’s opinion, 
there is sufficient data to support full attribution of the AE to the single agent. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.  
• New or updated information will be recorded in the CRF.  
• The investigator will submit any updated SAE data to Merck within 2 business days but no longer than 3 
calendar days of receipt of the information. 
11.5.4.1 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety facsimile 
number:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), 
Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators will cross reference this 
submission according to local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the 
time of submission.  Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 

 
  
  
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12.0 SUMMARY OF CHANGES 
From 12/14/2022 to 04/12/2024 
  
Section(s) 
Change 
Justification 
1.0, 5.2.2, 5.2.3, 10.1, 10.2, 
10.3, 10.4, 10.5 
Multiple dose levels of both pralatrexate and 
decitabine were removed from the possibilities 
for Arm B. Starting dose level will still be 
Combination 8.  As a result of this revision, the 
maximum sample size (and estimated sample size 
for Arm B) were also decreased. 
Based on the safety data collected 
in Arms A and C, higher doses 
were removed from the possible 
combinations for Arm B 
Throughout 
Minor formatting changes 
To increase readability 
 
From 03/28/22 to 12/14/2022 
Section(s) 
Change 
Justification 
Title page 
The Mayo Clinic and Samsung University were 
removed from the list of participating sites 
Mayo 
Clinic 
and 
Samsung 
University 
will 
not 
be 
participating in the study going 
forward 
7.4 
Timing 
of 
drug 
administration 
Switch window for decitabine from 1 hour to 1 
hour + 60 minutes 
Commercial admin of decitabine 
usually ranges from 1-3 hours 
depending on dose, increases over 
an hour are not a safety issue, per 
IDS and infusion nurses 
5.1 Study Design 
7.6 
Randomization 
and 
Treatment Allocation 
Revised to allow investigator’s choice between 
Arms A and C until required accrual is reached 
Treatment arms are not being 
compared on this study, but for 
safety, participants should not be 
enrolled on Arm B until Arms and 
C are completed. The additional 
flexibility will allow participants 
(until an arm is closed) who have 
already received an included drug 
to try something different, which 
may be more effective for them. 
8.0 Trial Flowchart 
Updated footnotes related to pks to refer to 
section, 
which 
provides 
varying 
windows 
depending on timepoint 
Updated footnotes pertaining to decitabine 
administration and pk timing to refer to the final 
day for the cycle (since days of treatment/cycle 
will vary based on dose level) 
Removed physical exam requirement for Arm C, 
cycles 2&5, Day 22 
Corrected footnote reference on Arm C to refer to 
Arm C (not Arm B) 
Clarification and consistency 
9.1.7.3 
Pharmacokinetics/ 
Pharmacodynamics 
Evaluations 
For Arms B and C, added “(day 3 if dose level is 
for decitabine on days 1-3)” and updated graphic 
accordingly to accommodate all dose levels 
To accommodate all dose levels 
(consistency) 
10.2 Dose allocation 
Additional language was added to indicate that To prevent a drastic reduction in 

 
  
  
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dose levels will not be skipped (e.g. the dose will 
not decrease from dose level 2 to -1) and that the 
coherence principle will be used. 
dose level after some toxicity 
 
 
From 09/28/21 to 03/28/22 
SECTION(S) 
Change 
Justification 
Title page 
Beth Israel Medical Center was removed from the 
list of participating sites 
BIMC will not be participating in 
the study going forward 
3.1 Primary Objectives & 
Hypothesis 
Removed “de novo and” from the third primary 
objective in this section 
Internal consistency with initially 
stated objectives 
5.3 
Dose 
Limiting 
Toxicities 
Updated “during cycle 1” to “prior to initiation of 
cycle 2” 
Clarity with intended meaning 
6.1.2 
Subject 
Exclusion 
Criteria 
9.1.6.1 Adverse Event (AE) 
Monitoring 
11.3 Common Terminology 
Criteria for Adverse Events 
V5.0 (CTCAE) 
CTCAE “version 4.0” was updated to “version 
5.0”  
 
Internal consistency.  
6.2 Trial Treatments 
In the Arm C table (Table 9), updated decitabine 
dosing from 10 mg/m2 to 20 mg/m2 
Internal consistency 
7.3.2 Pralatrexate 
CTCAE “version 4.0” was updated to “version 
3.0”  
Correction, as version 3.0 is used 
in the pralatrexate package insert 
7.8.1 
Prophylactic 
Measurements 
and 
Supportive Care 
Removed restriction on G-CSF / GM-CSF during 
the first cycle of study treatment 
Internal consistency (section 5.3, 
Dose-Limiting 
Toxicities) 
indicates this use is acceptable 
8.0 Trial Flowchart 
9.1.7.3 
Pharmacokinetic/ 
Pharmacodynamic 
Evaluations 
In all footnotes related to a window for 
pharmacokinetics, the +/- 30 minute window was 
updated to refer to the pharmacokinetic section 
(9.1.7.3) 
Section 9.1.7.3 was revised to provide exceptions 
to the 30 minute window for the End of Infusion 
(EOI) draw and the 30 minutes following EOI 
draw 
Clarification 
on 
windows 
for 
pharmacokinetic blood collection 
8.0 Trial Flowchart 
A column for cycle 1 day 22 was added for Arms 
B and C to require a CBC with differential at this 
timepoint 
Footnote for cycle 1 day 22 CBC with differential 
lab was removed, as pembrolizumab is given at 
this timepoint, so CBC with differential should be 
collected at this timepoint consistently. 
Improved 
safety 
for 
earlier 
intervention as needed 
9.2.1 
Time 
Period 
and 
Frequency for Collecting 
AE, 
SAE, 
and 
Other 
Reportable 
Safety 
Event 
Information 
Removed some nonsense letters/numbers (a typo) 
from 
the 
section 
(EM5YT). 
These 
numbers/letters 
(the 
PI’s 
username) 
was 
accidentally added in a previous amendment. 
Language was added to limit DLT reporting: 
DLTs prior to cycle 2 need to be reported to the 
UVA CC within 24 hours of identification of the 
DLT. DLTs occurring during/after Cycle 2 only 
Correction and clarity on reporting 
expectations 

 
  
  
Protocol Type: Amended/Version Date: 12 Apr 2024 
 
 
 
 
 
 
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need to be reported as AEs. 
9.2.1.2 
Adverse 
Event 
Reporting to Sponsor/UVA 
CC/GTcLC/DSMC 
Renamed table from Table A to Table 17 
Removed “Oncore”, as AEs will be reported in 
Advarra 
Internal consistency 
10.1 Study Design, 10.5 
Operating Characteristics 
In Arm B, flat dosing was updated to be per m2 
throughout tables 
 
Internal consistency 
 
From 4/13/2021 to 09/28/2021 
Section(s) revised 
Change(s) 
Title page 
 Updated site PI information for Beth Israel Deaconess Medical Center 
Rationale: Update 
8.0 Trial Flow Chart 
Removed columns where there were no assessments 
Merged columns for AE assessment and concomitant medications 
Removed concomitant medication review from long term follow-up 
Limited AE assessment in long term follow-up 
Added footnote to refer to section to make sure that all chemistry assessments are 
included and renamed to “Chemistry” 
Simplified vital signs line to be collected on days when either a physical exam is 
completed or treatment is received 
Removed labs from days that do not have drug administration or a physical exam 
(except in Cycle 1) 
Rationale: AE assessment and reviews of concomitant medications is ongoing during study treatment, simplification 
and streamlining to collect all data that is needed for analysis (but not other data that aren’t needed for analysis 
 
 
 
 
From 11/23/2020 to 04/13/2021 
Section(s) revised 
Change(s) 
Title page 
Dr. John Lister’s information was updated 
Dr. O’Connor’s role was updated to Co-Principal Investigator  
Rationale: Corrections 
Statement of Compliance 
Added a signature page 
Rationale: To incorporate the signature page into the document 
6.1.2 
Subject 
Exclusion 
Criteria 
Exclusions #10 (pneumonitis/interstitial lung disease) and #18 (vaccines) were 
updated 
Rationale: To be consistent with current pembrolizumab risks and Merck template language 
6.2 Trial Treatments 
8.0 Trial Flowchart 
7.3Pharmacokinetic/ 
Pharmacodynamic 
Evaluations 
 
Updated to clarify that pralatrexate is administered by IV push (not infusion) 
 
Rationale: Clarification 
7.3.1 
Immune 
Related 
Adverse Events 
Section title was revised 
Section was considerably revised to clarify stopping/holding rules for immune related 
adverse events 
Rationale: To be consistent with risks associated with pembrolizumab and combinations including pembrolizumab 
according to the Merck template 

 
  
  
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9.1.7.3 
Pharmacokinetic/ 
Pharmacodynamic 
Evaluations 
“and 48 hours” was removed from the text regarding timepoints for Arm A 
A sentence was added to allow a 90 minute window for the 24 hour after end of 
administration timepoint. 
 
Rationale: Correction for consistency and a little more flexibility for the 24 hour timepoint 
 
From 11/03/2020 to 11/23/2020 
Section(s) revised 
Change(s) 
2.1 Trial Design 
3.1 Primary Objectives & 
Hypothesis 
5.5 Efficacy Endpoints 
9.1.6.5 Tumor Imaging and 
Assessment of Disease 
10.1 Study Design 
Efficacy, as assessed by ORR, has been moved to be a co-primary objective. 
10.1 Study Design 
Text has been added to clarify how participants will be assigned a dose level based on 
past DLTs and modeling 
The number of DLTs noted on Arm C so far was corrected and therefore the dose 
level that the next subject would be assigned was corrected  
Also, there were some changes to the table for clarity and to decrease confusion 
10.2 Dose allocation 
Additional text was added for clarification of the purpose of the table describing 
ordering of DLT probabilities 
10.5 Operating characteristics 
Tables have been reformatted for clarity 
 
From 09/23/2020 to 11/03/2020 (11/03/2020 version reviewed by IRB as part of version date 11/23/2020) 
Section(s) revised 
Change(s) 
1.0 Trial Summary 
Number of trial subjects was revised to indicate “Maximum of 45” 
2.1 Trial Design 
Updated to indicate model-based dose escalation study with arms A & C based and 
combination allocation in Arm B will be conducted using a DLT-adapted partial order 
continual reassessment method upon a continual reassessment method.  
Removed references to 3x3 design and expansion phase. 
2.2 Trial Diagram 
Updated to reflect removal of expansion phase. 
3 Objectives & Hypothesis 
Shifted primary objectives from the expansion phase to secondary objectives.  
Removed references to Phase I, Expansion Phase, and de novo. 
Added “the efficacy, as determined by” in the second secondary objective. 
5.1 Study Design 
Updated to indicate CRM design. 
Removed references to 3+3 design and phase 1. 
5.2.2 Pralatrexate 
Updated to refer to section 10 for pralatrexate dosing.  
5.2.3 Decitabine 
Updated to refer to section 10 for decitabine dosing.  
5.3 Dose Escalation and De-
escalation Schema and Rule 
Removed previous section in its entirety. 
5.5 Efficacy Endpoints 
Removed references phase 1 and expansion phase. 
6.1.1 
Subject 
Inclusion 
Criteria 
Removed references to Phase I, Expansion Phase, de novo PTCL and de novo CTCL. 
9.1.6.5 Tumor Imagin and 
Assessment of Disease 
Removed references phase 1. 
10 Statistical Considerations 
Replaced previous Statistical Analysis Plan Section in its entirety. 
Rationale: to reflect revised statistical analyses for a model-based phase I dose escalation study with no expansion 
phase. 

 
  
  
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7.3 Resuming Administration 
of study drug 
Removed previous section in its entirety. 
Rationale: this section is redundant with section 7.2 bullet point two. 
Section 8.0 
Clarified footnote 7 for all calendars to indicate that pretreatment biopsy would be 
collected per standard care and that post treatment biopsy would be optional. 
Removed concomitant medication review on Arm B calendar D22 cycles 1 & 4 as 
there are no other study activities required at that time point. 
Added the superscript 16 to address footnote 16 for Arm B calendar D22 cycles 2 & 5. 
Section 13.0 
Replaced references section previously omitted. 
Section references, table references, and section headers were updated throughout the protocol document 
Rationale: Internal consistency 
 
From 08/25/2020 to 09/23/2020 (footer was also added to pages where it was missing) 
Section(s) revised 
Change(s) 
Title page 
Coordinating Center was updated to “Global T-cell Lymphoma Consortium (GTcLC) 
at the University of Virginia” 
“Participating Centers” was removed 
“Co-Investigator and Sponsor” was updated to “Co-Investigator and IND Holder” 
U.S. Subsites was updated to “Participating Sites” and UVA was added to this list 
The separate “Site Principal Investigators” section was removed and the Korea site 
was incorporated into the “Participating Sites” section. The Italian site was removed 
from the list. 
Rationale: Most of the changes were made for clarification of what sites will participate and Dr. O’Connor’s role as the 
IND Holder, since “Sponsor” can be interpreted to be the funding source. The Italian site will not be participating in 
the study after all. 
1.0 Trial Summary 
“to maximum of 21” was added to the expansion phase for number of trial subjects 
Rationale: At the request for this information by the UVA IRB-HSR 
8.0 Trial Flow Chart 
Study Flowchart-Arm C, footnote 12 was updated to a black font color 
Rationale: Readability 
9.2.1.3 
Serious 
Adverse 
Event 
Reporting 
to 
Sponsor/UVA 
CC/GTcLC/DSMC/IRB 
9.2.4.2 
Unanticipated 
Problem Reporting 
9.2.5.2 Reporting a Data 
Breach 
9.2.6.4 Reporting of Protocol 
Deviations/Violations 
Text relating to sites relying on UVA IRB-HSR was removed, as no outside sites will 
rely on UVA IRB-HSR 
Rationale: Clarification 
 
From 11/20/2019 to 08/25/2020 
Section(s) revised 
Change(s) 
Title Page 
8.0 Trial Flowchart 
9.1 Trial Procedures 
9.1.7.3 
Pharmacokinetic/ 
Pharmacodynamic 
Evaluations 
9.1.10 Subject Registration 
Site affiliation for Enrica Marchi, MD., Ph.D. and Owen O’Connor has been updated 
to UVA (University of Virginia) 
Enrica Marchi was updated to be the PI rather than Owen O’Connor. Owen O’Connor 
will remain as the IND Sponsor 
With Drs. Marchi and O’Connor at UVA, the Coordinating Center was transferred to 
UVA. Safety reporting requirements, data collection/entry and instructions for safety 
reporting were updated based on the UVA template 

 
  
  
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and Randomization 
9.2 
Data 
Reporting 
/ 
Regulatory Requirements 
9.3.2 
Compliance 
& 
Monitoring 
9.3.3 Study Monitoring (and 
subsection) 
9.3.4 
Study 
Records 
Retention 
Throughout 
As CUMC was previously the coordinating site and PKs were only collected for 
CUMC participants, now with UVA being the coordinating site, PKs are only 
collected for UVA participants (trial Flowchart and 9.1.7.3) 
CUMC was revised to UVA in multiple sections 
Rationale: The PI has changed and the new PI and Sponsor are now both affiliated with UVA. Accordingly, the 
coordinating center has also been moved to UVA so all safety reporting needed to be updated.  
9.1.8.1 
Withdrawal/ 
Discontinuation 
9.2 
Data 
Reporting 
/ 
Regulatory Requirements and 
subsections 
11.5 
Adverse 
Events: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, 
and 
Reporting 
(and subsections) 
Updated to current Merck template but removed option for retreatment and 
corresponding protocol section  
Rationale: Participants will not have the option for retreatment, so this was revised for accuracy, and the safety 
reporting sections of the new Merck template were used as they fit better with safety UVA reporting.  
2.2 Trial Diagram 
Statement was added to clarify that the days for pembrolizumab shown in the figure 
reflected cycle 1 only,  
Rationale: For clarification : Pembrolizumab is given every 3 weeks, though the study is based on 4 week cycles. 
3.3 Exploratory objective 
4.3.1 Pembrolizumab 
“pembrolizumab” was corrected to “pralatrexate” 
Minor corrections to language for clarity 
Rationale: Accuracy 
4.3.2 Pralatrexate 
5.2 Agents Administration 
 
Areas where “investigator’s brochure” or “package insert” are used were updated to 
include both terms where applicable. 
Rationale: Clarification, as both options are available for some of the drugs used in this study. 
5.3 Dose Escalation and De-
escalation Schema and Rule 
5.4 Dose Limiting Toxicities 
DLT definition was amended to remove the requirement for the DLT to occur in 
Cycle 1, though only cycle 1 DLTs will be used for the purposes of dose escalation 
and de-escalation 
Rationale: Revised for accuracy, as AEs that meet the definition of a DLT should cause a dose delay, regardless of 
when they occur during study treatment. 
5.4 Dose Limiting Toxicities 
5.5 
Required 
Blood 
Parameters 
and 
Other 
Investigations Prior to Each 
Treatment 
Revised for internal consistency and corrected based on AEs that may exist at the time 
of enrollment 
Rationale: Internal consistency and accuracy 
7.2 Dose Delays 
7.3 Resuming Administration 
of Study Drugs 
7.4 Dose Modification (and 
subsections) 
Revised for internal consistency: 2 week delay means study treatment discontinuation, 
so references to 3 and 12 weeks being cause for discontinuation of an individual drug 
were updated, “or baseline” was added to make these sections consistent with one 
another and the DLT definition, “or mucositis” was removed, as this exception is not 
true for pralatrexate, and febrile neutropenia specifics were added. 

 
  
  
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Rationale: Internal consistency 
7.8.2 Prohibited Concomitant 
Medications 
“or pralatrexate (for participants assigned to an arm including pralatrexate)” was 
added as an exception to the prohibition of investigational agents for participants 
assigned to an arm that includes pralatrexate 
Rationale: Correction for internal consistency  
7.10.3 Use in Pregnancy 
Some reporting information was added to this section and a reference to a different 
section for reporting to Merck was added 
Rationale: Updating to current Merck and UVA reporting templates 
7.11 
Subject 
Withdrawal/Discontinuation 
Criteria 
7.12 Clinical Criteria for 
Early Trial Termination 
Notes were added to clarify that participants that are off any study treatment for >2 
weeks for an adverse event are off all study treatment 
Corrected an incorrect section reference 
Corrected “study medication” to “pembrolizumab” as there are multiple study 
medications in this study. 
Rationale: Internal consistency 
7.11 
Subject 
Withdrawal/Discontinuation 
Criteria 
7.11.1 
Discontinuation 
of 
Study Therapy after CR 
Removed references to the option of re-starting study treatment after completion of 
initial round of study medications 
 
Rationale: Correction, as re-treatment following study treatment discontinuation is not an option for this study 
7.12 Clinical Criteria for 
Early Trial Termination 
“study drug” was updated to “pembrolizumab” as Merck is only providing 
pembrolizumab for this study 
Rationale: Accuracy 
8.0 Trial Flowchart 
Multiple revisions to be internally consistent and improve safety monitoring:  
1. Physical exam, vital signs and weight, CBC with differential, comprehensive 
serum chemistry panel, thyroid blood tests and ECOG status were added to 
the visit at discontinuation of treatment and 30-day safety follow-up  
2. ECOG was added to day 1 for cycles 3,6,9,12, etc. 
3. Thyroid testing was updated to occur at Day 1 of every other cycle (not every 
cycle).  
Footnotes were added/revised to  
1. Include that laboratory screening tests do not need to be repeated at C1D1 if 
they are performed in the 10 day window and at other cycles they may be 
completed in the 72 hours prior to treatment. (Previously only elsewhere in 
the protocol) 
2. Clarify that PKs are only required for UVA participants and that correlative 
blood draws on Day 8 and 15 only need to occur during cycle 1 
3. Include requirements for data collection for participants that have an 
allogeneic SCT following participation. (Previously only elsewhere in the 
protocol) 
4. Remove the need for CBC at Day 22 in later cycles (only where indicated for 
cycle 1 (or cycle 2 for Arms B and C) 
Rationale: For internal consistency and adequate safety monitoring 
9.1.6.2 
Physical 
Exam 
(previously “Full” Physical 
Exam) 
The section was renamed and revised --level of physical exams (full vs directed) 
should be consistent with standard clinical care  
Rationale: For consistency with standard clinical care. No designations for full vs. directed were included before this 
version either. 
9.3.2 
Compliance 
and 
Monitoring 
Some minor details were removed 

 
  
  
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Rationale: This level of detail may vary by site and these details will be available in a separate study reference manual 
10.0 Statistical Analysis Plan 
Minor revisions were made for accuracy 
Rationale: Accuracy 
Throughout document 
Minor grammatical corrections 
Formatting of headers was corrected 
Section numbers were made into cross references/links and were corrected as 
necessary 
Rationale: Internal consistency, readability and easier navigation 
 

 
  
  
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13.0 REFERENCES 
 
 
1. 
O'Quigley, J. & Shen, L.Z. Continual reassessment method: a likelihood approach. Biometrics 52, 
673-84 (1996). 
2. 
Wages, N.A., Conaway, M.R. & O'Quigley, J. Continual reassessment method for partial ordering. 
Biometrics 67, 1555-63 (2011). 
3. 
Campo, E. et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving 
concepts and practical applications. Blood 117, 5019-32 (2011). 
4. 
Swerdlow, S.H. et al. The 2016 revision of the World Health Organization classification of 
lymphoid neoplasms. 127, 2375-90 (2016). 
5. 
Vose, J., Armitage, J. & Weisenburger, D. International peripheral T-cell and natural killer/T-cell 
lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26, 4124-30 (2008). 
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