A Phase 1/2 Study of Pembrolizumab Plus Pralatrexate for Treatment of Relapsed or Refractory Peripheral T-Cell Lymphomas
Phase: PHASE1
Conditions: Anaplastic Large Cell Lymphoma, Nodal Peripheral T-Cell Lymphoma With TFH Phenotype, Recurrent Anaplastic Large Cell Lymphoma, Recurrent Angioimmunoblastic T-Cell Lymphoma, Recurrent Enteropathy-Associated T-Cell Lymphoma, Recurrent Follicular Lymphoma, Recurrent Hepatosplenic T-Cell Lymphoma, Recurrent Mature T- Cell and NK-Cell Non-Hodgkin Lymphoma, Recurrent Monomorphic Epitheliotropic Intestinal T-cell Lymphoma, Recurrent Mycosis Fungoides, Recurrent Peripheral T-Cell Lymphoma, Not Otherwise Specified, Refractory Anaplastic Large Cell Lymphoma, Refractory Angioimmunoblastic T-Cell Lymphoma, Refractory Enteropathy-Associated T-Cell Lymphoma, Refractory Follicular Lymphoma, Refractory Hepatosplenic T-Cell Lymphoma, Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Refractory Mycosis Fungoides, Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified, Subcutaneous Panniculitis-Like T-Cell Lymphoma
Sponsor: City of Hope Medical Center

 
IRB #17501 
 
05/25/2021 
Packet: 08 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION 
 
 
TITLE:  A Phase 1/2 Study of Pembrolizumab plus Pralatrexate for Treatment of Relapsed or Refractory 
Peripheral T-cell Lymphomas 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 17501                      PROTOCOL DATE: 05/25/21 
 
COH Initial Submission  
 
 
(Protocol dated 07/12/2018)  
 
 
Version: 00 
COH Amendment 01  
 
 
(Protocol V1 dated 08/22/2018) 
 
 
Version :01 
 
COH Amendment 02  
 
 
(Title Page Dated 01/23/2019) 
 
 
Version: 02 
COH Amendment 03  
 
 
(Protocol dated 01/23/2019)  
 
 
Version: 03 
COH Amendment 04  
 
 
(Protocol dated 09/09/2019)  
 
 
Version: 04 
COH Amendment 05  
 
 
(Title page dated 04/24/2020) 
 
 
Version: 05 
COH Amendment 06  
 
 
Protocol Dated 05/25/2021 
 
 
 
Packet: 06 
COH Amendment 07  
 
 
Protocol Dated 05/25/2021(TP) 
             
Packet: 07 
COH Amendment 08                                     Protocol Dated 05/25/2021(TP)                                 Packet: 08 
 
 
DISEASE SITE: 
 
 
 
 
Peripheral T-cell Lymphoma 
 
STAGE: 
 
 
 
 
 
Relapsed/Refractory 
 
MODALITY(IES): 
 
 
 
 
 
 
TYPE:  
 
 
 
 
 
Phase 1/2 
 
PRINCIPAL INVESTIGATOR: 
 
 
Alex Herrera, MD 
 
CO INVESTIGATOR:  
 
 
 
Jasmine Zain, M.D. 
 
PARTICIPATING CLINICIANS: 
 
 
L. Elizabeth Budde, M.D., Stephen Forman, M.D., Larry 
Kwak, M.D., Matthew Mei, M.D., Liana Nikolaenko, M.D., 
Leslie Popplewell, M.D., Steven Rosen M.D., Tanya Siddiqi, 
M.D., Christiane Querfeld, M.D., Swetha Kambhampati, 
M.D., John Baird, M.D., James Godfrey, M.D. 
 
 BIOSTATISTICIAN:   
 
 
 
Lu Chen, Ph.D.  
 
 
 
PARTICIPATING SITES: 
 
 
 
City of Hope, Duarte 
 
 
 
 
 
 
 
Emory University 
 
University of Nebraska 

CONFIDENTIAL 
 
Page 1 of 101 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 1/2 Study of Pembrolizumab plus Pralatrexate for Treatment of 
Relapsed or Refractory Peripheral T-cell Lymphomas 
  
 
Version Date: 05/25/2021 
Protocol Version: 05 
 
City of Hope #: 17501 
Agents: Pembrolizumab, Pralatrexate 
IND Number: 140389 
Sponsor/ IND Holder: City of Hope 
Funding Support: Merck, Acrotech Biopharma, LLC 
Industry Partner: Merck, Acrotech Biopharma, LLC 
NCT Number: NCT03598998 
Participating Sites: City of Hope (Duarte), University of 
Nebraska, Emory University 
 
Principal Investigator 
Alex F. Herrera, M.D. 
City of Hope National Medical Center 
Dept. of  Hematology 
T: 626-256-4673 x 62405 
F: 626-301-8256 
Email: aherrera@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
E-mail: DCC@coh.org  
 
 
 
 

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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD 
City of Hope National Medical 
Center 
Dept. of Information Sciences 
T: 626-256-4673 x 86626 
Email: lchen@coh.org 
 
Co-Investigator 
Jasmine Zain, MD 
City of Hope National Medical 
Center 
Dept. of Hematology 
T: 626-256-4673 x 82405 
Email: jazain@coh.org 
 
 
 
Protocol Development Scientist 
Sandrine Puverel, PhD 
City of Hope National Medical 
Center 
Dept. of Hematology 
T: 626-256-4673 x 84220 
Email: spuverel@coh.org 
 
 
 
 
Participating non-COH sites 
Site PI 
Matthew Lunning, MD 
University of Nebraska 
601 S Saddle Creek Rd 
Omaha, NE 68198 
T: 402-559-3848 
Email: mlunning@unmc.edu 
 
 
Site PI 
Pamela Allen 
Winship Cancer Institute of 
Emory University 
1365-C Clifton Road NE 
Atlanta, GA 30322 
T: 404-778-1900 
Email: 
pamela.b.allen@emory.edu 
 
 
 
 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
  
 
Each cycle = 21 days. Maximum duration of protocol therapy is 24 months. 
Folic acid and Vitamin B12 supplementation is standard of care for pralatrexate therapy. 
Folic acid is given daily during the course of therapy. Vitamin B12 is given every 3 cycles.  
 
1 Disease staging is performed at screening and every 4 cycles until disease progression or off study therapy. Disease staging 
will be by either PET/CT (preferred) or CT scan, but, if disease is FDG-avid, will be PET/CT at baseline, Cycle 4 and every 8 cycles 
thereafter. Refer to Study calendar and Section 11.1 for details. 
2 Peripheral blood for correlative studies will be collected on C1D1, C2D1, C4D1, C5D1, and at EOT (refer to Table 9.3.1 for 
additional details). 
3 End of treatment visit. 
4 Follow-up Phase for patients who have completed treatment without disease progression will include staging every 12 weeks 
for the first year and every 18 weeks thereafter, until disease progression or off study. 
 
 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 1/2 Study of Pembrolizumab plus Pralatrexate for Treatment of Relapsed or Refractory Peripheral T-cell 
Lymphomas 
Study Detail 
Population/Indication(s): 
Relapsed/Refractory Peripheral T-cell Lymphomas 
Phase: 
1/2 
Sample Size: 
Expected: 30 evaluable (Phase 1: 12 evaluable, Phase 2: 24 
evaluable (including up to 6 patients from Phase 1 at RP2D) 
Maximum: 40 
Estimated Accrual Duration: 
48 months 
Estimated Study Duration 
6 years  
Participant Duration: 
Until progression, unacceptable toxicity, or withdrawal 
Participating Sites: 
 City of Hope Duarte, CA 
 University of Nebraska, NE 
 Emory University, GA 
Study Agents: 
Pembrolizumab, Pralatrexate 
Sponsor: 
City of Hope 
Industry Partner:  Merck, Acrotech Biopharma, LLC 
Rationale for this Study 
Outcomes of patients with relapsed or refractory PTCL are dismal. Current therapies available for relapsed or 
refractory PTCL, including novel agents, are associated with poor response rates and short median progression-
free survival, and few patients are salvaged by stem cell transplantation.1-5 Novel therapies for relapsed or 
refractory PTCL are urgently needed. Because of inadequate response rates using novel therapies as single agents 
in PTCL, we anticipate that novel therapeutic combinations will be necessary to impact these aggressive and 
difficult-to-treat diseases. 
In early studies evaluating PD-1/PD-L1 pathway inhibitors in PTCL and MF/CTCL, response rates of 15-40% have 
been observed. Therefore, these well-tolerated immunotherapy agents with a different mechanism of action 
compared to all other available drugs for treating T-cell lymphomas are a potential backbone on which to build a 
novel therapy combination. One logical combination partner for a PD-1/PD-L1 inhibitor in PTCL is the antifolate 
drug, pralatrexate. Antifolate agents, like pemetrexed, have immunologic effects which may result in synergy with 
PD-1 blockade, including activation of IFNγ-producing NK cells and, potentially, activation of CD8+ T-cells.6,7 There 
is already clinical evidence of potential synergy between PD-1 inhibitors and anti-folate drugs. In a randomized 
phase II trial of patients with metastatic non-small cell lung cancer (NSCLC), patients treated with a PD-1 inhibitor, 
pembrolizumab, plus with carboplatin and an antifolate chemotherapy, pemetrexed, had a higher ORR (71%) than 
patients treated with pembrolizumab combined with carboplatin and paclitaxel (ORR 50%). (Gadgeel, ASCO 2015; 
Papadimitrakopoulou, ASCO 2014). We propose a phase 1/2 study to evaluate the safety and efficacy of combining 
pralatrexate with pembrolizumab for the treatment of relapsed or refractory aggressive PTCL. 
Objectives 
Primary Objective 
o 
Evaluate the safety and tolerability of a regimen combining pembrolizumab and pralatrexate in patients 
with relapsed or refractory PTCL. 
o 
Establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combined 
pralatrexate and pembrolizumab regimen. 
o 
Estimate the overall response rate (ORR) according to the Lugano Classification8 in patients treated with 

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pembrolizumab plus pralatrexate at the RP2D. 
Secondary Objective 
o 
Estimate the complete response (CR) rate according to the Lugano Classification,8 duration of response 
(DOR), overall survival (OS) and progression-free survival (PFS) in patients treated with pembrolizumab 
plus pralatrexate. 
o 
Estimate the ORR and CR rate according to the International Harmonization Project response criteria 
(Cheson 2007).9 
o 
Evaluate responses and disease progression according to the Lymphoma Response to 
Immunomodulatory therapy Criteria (LYRIC).10 
Exploratory Objective 
o 
Explore immunologic and genomic biomarkers of response to pembrolizumab plus pralatrexate therapy. 
Study Design 
This is a prospective, single-arm, multi-center, open-label phase 1/2 study of pembrolizumab (MK-3475) plus 
pralatrexate in subjects with relapsed or refractory peripheral T-cell lymphomas (PTCL) that have failed at least 
one prior line of therapy. 
The phase 1 dose-escalation portion of the study, with 2 dose levels and 1 possible de-escalation dose level, will 
determine the MTD and RP2D of the combination therapy. The starting dose will be 20 mg/m2 of pralatrexate on 
days 1 and 8 and 200 mg IV of pembrolizumab every 21 days, administered in 21-day cycles. The planned dose 
levels in the Phase 1 portion of the study are outlined in the table below. The phase 1 portion will use a modified 
rolling 6 design allowing 3 patients to be treated and evaluated for dose-limiting toxicity simultaneously, with up 
to 6 patients per dose level.  
Dosing regimen and schedule 
Dose level 
Pembrolizumab (Day 1) 
Pralatrexate (Days 1 and 8) 
-1 
200 mg IV 
15 mg/m2 IV 
1 
200 mg IV 
20 mg/m2 IV 
2 
200 mg IV 
30 mg/m2 IV 
In the phase 2 portion, pembrolizumab will be administered at a dose of 200 mg IV and pralatrexate at the RP2D 
selected in the phase 1 portion following the same schedule. The phase 2 portion will use a Gehan two-stage 
design with advancement to the second stage based on ORR in the first stage. 
In both phases, patients will receive up to 24 months of combined pembrolizumab and pralatrexate therapy. In 
both phases, Vitamin B12, Folic acid and Leucovorin will be administered as indicated in the study calendar and 
Section 5.13.2. 
 
Evaluation Criteria and Endpoints 
Response/progression 
Disease response/progression will be evaluated using 2014 Lugano Classification8,11. Participants who meet the 
definition of progressive disease per Lugano Classification8 should be evaluated using the LYRIC criteria10. The ORR 
and CR rate will also be estimated according to the International Harmonization Project response criteria (Cheson 
2007).9 

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Primary Endpoints 
 Dose limiting toxicity (DLT) (defined in Section 5.5). The DLT observation period will be 2 cycles. Toxicities will 
be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE, Version 5.0).  
 Overall response rate (ORR), per the Lugano classification.8 
Secondary Endpoints 
 Complete Response (CR) rate per the Lugano classification.8 
 ORR and CR rate according to the International Harmonization Project response criteria (Cheson 2007).9 
 Duration of Response (DOR). 
 Overall Survival (OS). 
 Progression-Free Survival (PFS). 
 Toxicity: Toxicity and adverse events will be recorded using the NCI CTCAE 5.0 scale. Observed toxicities will 
be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), 
severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), date of onset, duration, 
reversibility, and attribution.  
 Unacceptable Toxicity (defined in Section 11.2) 
Statistical Considerations 
Phase 1 portion 
During the Phase 1 portion of the study, a modified, more conservative version of the Rolling 6 design of Skolnik 
et al will be employed. In this design, at most, 3 patients will be under observation for DLT on the current test 
dose level at any time. DLT observation period is 2 cycles. Patients who did not receive the doses of 
pembrolizumab during DLT period (not due to DLT), or those who missed any doses of pralatrexate during DLT 
period (not due to DLT) will be replaced. Once 3 patients are evaluable with no patient at that dose level 
experiencing a DLT, the dose can be escalated, or up to 3 additional patients may be treated at the current dose 
level. No more than 6 evaluable patients will be accrued to any dose level. Escalation will terminate as soon as ≥ 
2 patients experience DLT at a given dose level. If 1/6 patients experience DLT at the current dose level, the dose 
will be escalated to the next higher level. If more than 1/6 patients experience DLT, then the next lower dose will 
be expanded. MTD will be declared the highest dose level at which 6 evaluable patients have been treated and, 
at most, 1/6 patients experiences DLT. The MTD will be considered the RP2D, unless the PI chooses a lower dose 
level, based on toxicity in subsequent cycles. 
 
Phase 2 portion 
In the phase 2 portion, patients will be treated at the RP2D. The phase 2 portion of this study will implement a 
Gehan two-stage design to estimate the ORR and to evaluate the activity of the combined regimen. Patients 
treated during the Phase 1 portion at the RP2D will be included in the Phase 2 evaluations if they are evaluable 
for response, defined as patients who received at least 1 dose of pembrolizumab and at least 1 dose of 
pralatrexate and had at least 1 disease assessment. The sample size is based on the desire to estimate the 
response rate with approximately 10% standard error, and early stopping if the combination is unexpectedly 
ineffective. In the pivotal PROPEL trial, the overall response rate (ORR) in 109 evaluable patients who received 
pralatrexate as a single agent was 29%, including 12 (11%) complete responses (CR) and 20 (18%) partial responses 
(PR).5  

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The phase 2 portion of the study is expected to evaluate a minimum of 7 and a maximum of 24 patients evaluable 
for response, including the patients treated at RP2D during the Phase 1 portion. At stage 1, if 0 responses are seen 
in the first 7 patients (including up to 6 patients enrolled during the Phase 1 portion that are evaluable for 
response), the study will be terminated and the true ORR will be declared ≤35%. If at least 1 patient responds, the 
trial will continue to the second stage. At stage 2, a total of 24 patients will be evaluated (including up to 6 patients 
enrolled during the Phase 1 portion that are evaluable for response).  
This design provides for estimation of the response rate with approximately 10% standard error. The standard 
error will be 9.4%-10.2% after 24 patients if the ORR rate is 30%-70%. Under this design if the ORR is >35%, there 
would be ≥95% chance of at least one response among the first 7 patients. 
Safety Analysis and Stopping Rules for Excessive Toxicity or Rapid Disease Progression 
Because of the unique immune-related adverse events (IrAEs) observed with checkpoint inhibitors, we will 
monitor for “Unacceptable toxicity” (defined in Section 11.2) and treatment-related mortality at any time during 
study treatment with this new combination of drugs. This monitoring will include all patients treated on the study 
regardless of the dose levels they were on. The expected rate of “unacceptable toxicity” should not be >33%. If 
the rate of “unacceptable toxicity” is >33% after at least 6 patients are treated on study at any bi-annual safety 
review, or if a 2nd death that is at least possibly related to study treatment occurs regardless of the number of 
patients on study, accrual will be halted and a full review of these events will be performed by the City of Hope 
Data Safety Monitoring Committee (DSMC). Patient accrual will not resume until approved by the DSMC to do so. 
These rules are in addition to the bi-annual review of all toxicities submitted to the City of Hope Data Safety 
Monitoring Committee (DSMC). Patients with ongoing toxicity will be followed until resolution or stability. 
In addition, because of the evidence that PD-1 may act as a tumor suppressor in preclinical T-cell lymphoma 
models and the recent reports of rapid disease progression in patients with ATLL, a subtype of PTCL, we will also 
monitor for rapid progression of disease. If at any bi-annual safety review during the conduct of the study, and 
after at least 3 patients are treated on study, > 33% of patients who received at least one dose each of 
pembrolizumab and pralatrexate experience rapid progression, the study accrual will be halted and a full review 
of these events will be performed by the City of Hope Data Safety Monitoring Committee (DSMC). Patient accrual 
will not resume until approved by the DSMC to do so. 
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
- Age 18 or older 
- ECOG performance status of 0 or 1. 
- Patients must have a histologically confirmed diagnosis of mature peripheral T-cell or NK-cell 
lymphoma according to the WHO classification, including transformed mycosis fungoides, with 
hematopathology review at the participating institution. Refer to Section 3.1 for a full list of eligible 
histologies. 
- Patients must have failed at least one prior regimen. 
- Patient must have measurable disease by CT or PET scan, with one or more sites of disease ≥ 1.5cm 
in longest dimension.   
- Be willing to provide tissue from a fresh core or excisional biopsy (performed as standard of care) of 
a tumor lesion prior to starting study therapy or from archival tissue of a biopsy that was performed 
after the most recent systemic therapy. Exception can be granted by the PI if a biopsy is not feasible 
and/or safe. 
- Patients must have received one dose of Vitamin B12 (1 mg IM) within 10 weeks prior to first dose of 

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pralatrexate, and must have begun folic acid supplementation (1 mg orally, once daily) within 10 days 
of first dose of pralatrexate. Note: if folic acid was not started but MMA and HCY levels were checked 
and are in normal range at screening, the investigator can decide to start study therapy immediately. 
Vitamin B12 and folic acid supplementation is standard of care for pralatrexate therapy. 
- Adequate hematological, renal, and hepatic function. 
- Female of childbearing potential: negative urine or serum pregnancy test within 72 hours prior to 
receiving the first dose of study medication. 
- Agreement to use effective methods of contraception for both women of childbearing potential and 
male patients during the study and through 6 months post-last dose of pralatrexate for women and 3 
months post-last dose of pralatrexate for man, and 120 days post-last dose of pembrolizumab for both 
women and men. 
Main Exclusion Criteria 
- Patients with adult T-cell leukemia/lymphoma. 
Prior Therapy and Concomitant Therapy 
- Prior allogeneic hematopoietic stem cell transplantation within the last 5 years. 
- Prior autologous hematopoietic stem cell transplant within the last 60 days. 
- Patients who received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
without having had evidence of objective response. 
- Patients who received prior therapy with pralatrexate without having had evidence of 
objective response. 
- Investigational agent or anti-cancer monoclonal antibody (mAb) within 21 days prior to Day 
1 of therapy or who has not recovered (i.e. ≤1 or at baseline) from adverse events due to 
agents administered more than 21 days earlier.  
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days 
prior to Day 1 of therapy or who has not recovered (i.e. ≤1 or at baseline) from adverse events 
due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an 
exception and may qualify for the study. 
- Antineoplastic biologic therapy or major surgery within 21 days of the first dose of trial 
medication. If subjects received major surgery more than 21 days ago, they must have 
recovered adequately from the toxicity and/or complications from the intervention prior to 
starting therapy. 
- Received live vaccine or live-attenuated vaccine within 30 days prior to Day 1 of protocol 
therapy. Administration of killed vaccines is allowed. 
- Systemic steroid therapy or on any other form of immunosuppressive therapy within 7 days 
prior to the first dose of trial treatment. 
Other Illnesses and Conditions 
- Diagnosis of immunodeficiency. 
- 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. 

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- Congestive heart failure Class III/IV according to the New York Heart Association (NYHA) 
Functional Classification. 
- Known severe hypersensitivity reaction to pembrolizumab, pralatrexate, leucovorin or any 
excipients. 
- Active autoimmune disease that has required systemic treatment in the past 2 years 
(replacement therapies for hormone deficiencies are allowed). Hemolytic anemia associated 
with the lymphoma does not exclude a patient from the study. 
- Known history of HIV (HIV ½ antibodies). 
- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
- History of active TB infection (Bacillus Tuberculosis). 
- Active central nervous system (CNS) involvement by lymphoma, including parenchymal 
and/or lymphomatous meningitis.  
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids 
or current pneumonitis/interstitial lung disease 
- Active, uncontrolled infection requiring systemic therapy.   
- Female: Pregnant or breastfeeding 
- 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 
Investigational Product Dosage and Administration 
 
Pembrolizumab 200 mg IV on Day 1 of each cycle. 
 
Pralatrexate 15, 20, or 30 mg/m2 (according to dose level) on Days 1 and 8 of each cycle. 
 
1 cycle = 21 Days. 
Clinical Observations and Tests to be Performed 
 Medical history and physical exam 
 Safety assessments (CBCs with differential, comprehensive chemistry panel, thyroid function and 
coagulation) 
 PET-CT 
 CT/ MRI scans  
 Correlative tumor tissue and blood samples. 
 
 
 

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TABLE OF CONTENTS 
SECTION                                                                                                                                                                       PAGE 
Protocol Team ................................................................................................................................................ 2 
Experimental Design Schema ......................................................................................................................... 3 
Protocol Synopsis............................................................................................................................................ 4 
Table of Contents ......................................................................................................................................... 10 
List of Tables and Figures .............................................................................................................................. 12 
Abbreviations ................................................................................................................................................ 13 
1.0 
Objectives ....................................................................................................................................... 14 
1.1 
Primary Objectives .................................................................................................................... 14 
1.2 
Secondary Objectives ............................................................................................................... 14 
1.3 
Exploratory Objectives .............................................................................................................. 14 
2.0 
Background..................................................................................................................................... 14 
2.1 
Introduction/Rationale for Development ................................................................................. 14 
2.2 
Pembrolizumab ......................................................................................................................... 16 
2.3 
Pralatrexate .............................................................................................................................. 17 
2.4 
Leucovorin ................................................................................................................................ 18 
2.5 
Overview and Rationale of Study Design .................................................................................. 18 
3.0 
Eligibility Criteria ............................................................................................................................ 20 
3.1 
Inclusion Criteria ....................................................................................................................... 20 
3.2 
Exclusion Criteria ...................................................................................................................... 22 
4.0 
Participant Enrollment ................................................................................................................... 25 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ................................................. 25 
4.2 
Participant Enrollment .............................................................................................................. 25 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment .................. 26 
4.4 
Dose Level Assignment ............................................................................................................. 26 
5.0 
Treatment Program ........................................................................................................................ 26 
5.1 
Study Overview ......................................................................................................................... 26 
5.2 
Treatment Cycle Definition ....................................................................................................... 27 
5.3 
Treatment Plan ......................................................................................................................... 27 
5.4 
Eligibility criteria for initiation of subsequent treatment cycles .............................................. 28 
5.5 
Definition of Dose-Limiting Toxicity .......................................................................................... 28 
5.6 
Definition of the MTD and Recommended Phase 2 Dose ........................................................ 29 
5.7 
Replacement of Subjects .......................................................................................................... 29 
5.8 
Agent Administration ................................................................................................................ 30 
5.9 
Assessments and Special Monitoring ....................................................................................... 30 
5.10 
Duration of Therapy and Criteria for Removal from Protocol Therapy .................................... 31 
5.11 
Follow-Up.................................................................................................................................. 32 
5.12 
Duration of Study Participation ................................................................................................ 32 
5.13 
Supportive Care, Prohibited Medications and Concomitant Therapy ...................................... 33 
6.0 
Anticipated Toxicities & Dose Modification/ Delay Guidelines ...................................................... 40 
6.1 
Anticipated Toxicities ................................................................................................................ 40 
6.2 
Dose Delay/ Modification - General instructions ..................................................................... 41 
6.3 
Dose Delay/ Modification Guidelines for Pembrolizumab-associated Adverse Events............ 42 
6.4 
Dose Delay/Modifications Guidelines for Pralatrexate-Associated Adverse Events ................ 46 
7.0 
Reporting OF Adverse Events, Unanticipated Problems & OTHER EVENTS OF INTEREST .............. 48 
7.1 
Assessment of Adverse Events ................................................................................................. 48 

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7.2 
Secondary Malignancy .............................................................................................................. 48 
7.3 
Adverse Events of Special Interest (AESI) Requiring Expedited Reporting ............................... 49 
7.4 
Pregnancies ............................................................................................................................... 49 
7.5 
Adverse Event (AE) collection guidelines .................................................................................. 50 
7.6 
Routine AE Collection and Reporting Guidelines ...................................................................... 50 
7.7 
Expedited Reporting ................................................................................................................. 50 
7.8 
Reporting to the FDA ................................................................................................................ 52 
7.9 
Reporting to Industry Partners ................................................................................................. 52 
8.0 
Agent Information .......................................................................................................................... 54 
8.1 
Pembrolizumab ......................................................................................................................... 54 
8.2 
Pralatrexate .............................................................................................................................. 56 
9.0 
Central Review & Correlative/ Special Studies ............................................................................... 58 
9.1 
Biomarker Research .................................................................................................................. 58 
9.2 
Tumor tissue ............................................................................................................................. 59 
9.3 
Correlative blood collection ...................................................................................................... 61 
10.0 
Study Calendar ............................................................................................................................... 66 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 71 
11.1 
Response/Progression .............................................................................................................. 71 
11.2 
Clinical Endpoint Definitions ..................................................................................................... 71 
12.0 
Statistical Considerations ............................................................................................................... 72 
12.1 
Study design overview .............................................................................................................. 72 
12.2 
Sample size accrual rate ........................................................................................................... 74 
12.3 
Statistical analysis plan ............................................................................................................. 74 
13.0 
Data Handling, Data Management, Record Keeping ...................................................................... 76 
13.1 
Source Documents .................................................................................................................... 76 
13.2 
Data Capture Methods and Management ................................................................................ 76 
13.3 
Case Report Forms/Data Submission Schedule ........................................................................ 76 
13.4 
Regulatory Records ................................................................................................................... 76 
14.0 
Adherence to the Protocol ............................................................................................................. 77 
15.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring ............................................. 77 
15.1 
All Investigator Responsibilities ................................................................................................ 77 
15.2 
Study Principal Investigator Responsibilities ............................................................................ 77 
15.3 
Protocol Management Team (PMT) ......................................................................................... 77 
15.4 
Quality Assurance ..................................................................................................................... 78 
15.5 
Risk Determination ................................................................................................................... 78 
15.6 
City of Hope Data and Safety Monitoring Committee .............................................................. 78 
16.0 
Ethical and Regulatory Considerations ........................................................................................... 78 
16.1 
Ethical Standard ........................................................................................................................ 78 
16.2 
Regulatory Compliance ............................................................................................................. 78 
16.3 
Institutional Review Board ....................................................................................................... 79 
16.4 
Informed Consent ..................................................................................................................... 79 
16.5 
Participant Withdrawal ............................................................................................................. 80 
16.6 
Special and Vulnerable Populations ......................................................................................... 80 
16.7 
Participant Confidentiality ........................................................................................................ 81 
16.8 
Use of Unused (Leftover) Specimens Collected for this Trial ................................................... 82 
16.9 
Conflict of Interest .................................................................................................................... 82 
16.10 
Financial Obligations, Compensation, and Reimbursement of Participants ............................ 82 
16.11 
Publication/ Data Sharing ......................................................................................................... 82 
References .................................................................................................................................................... 84 

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Appendix A: Performance Status .................................................................................................................. 89 
Appendix B: 2014 Lugano Response Criteria ................................................................................................ 90 
Appendix C: LYRIC CRiteria ........................................................................................................................... 94 
Appendix D: NYHA Cardiac Grading Criteria ................................................................................................. 95 
Appendix E: Contraception guidelines .......................................................................................................... 96 
Appendix F: Registration Coversheet ........................................................................................................... 97 
Appendix G: Correlative Tissue Form (For all sites) ...................................................................................... 98 
Appendix H: Tissue Shipping Guidelines to City of Hope Pathology Core .................................................... 99 
Appendix I: Correlative Blood Collection Form for Non-COH Sites Only .................................................... 100 
Appendix J: Blood shipping Guidelines to City of Hope APCF ..................................................................... 101 
 
LIST OF TABLES AND FIGURES 
Dosing regimen and schedule ................................................................................................................... 5 
Table 5.3 Dosing regimen and schedule ................................................................................................. 28 
Table 5.13.3 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines ............ 38 
Table 6.3 Dose Modification and toxicity management for irAEs typically associated with pembrolizumab 
42 
Table 6.4.1 Dose Modifications for Mucositis, based on NCI CTCAE Version 5.0 ................................... 46 
Table 6.4.2 Dose Modifications for Hematologic Toxicities .................................................................... 46 
Table 6.4.3 Dose Modifications for all Other Pralatrexate-Related Toxicities ........................................ 47 
Table 7.7 Criteria for Expedited Reporting ............................................................................................. 50 
Table 9.3.3. Blood sample collection and post-collection instructions. .................................................. 63 
Table 10 Study Activity Calendar ............................................................................................................ 66 
Table 12.1.1. Dose Escalation Rules ........................................................................................................ 73 
Table 13.3 Data Submission Schedule .................................................................................................... 76 
 
 
 

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ABBREVIATIONS 
Abbrevation 
 
 
Meaning 
AE 
ALT 
ANC 
AST 
C 
CFR 
COH 
CR 
CRA 
CRF 
CTCAE 
CTEP 
CTMS 
DSMC 
ECOG 
EOT 
FDA 
GCP 
HCY 
IB 
ICF 
IND 
IR 
irAE 
IRB 
IV 
LYRIC 
MMA 
PD 
PFS 
PI 
PMT 
PR 
PTCL 
SAE 
SD 
WHO 
Adverse Event 
Alanine Aminotransferase 
Absolute Neutrophil Count 
Aspartate Aminotransferase 
Cycle 
Code of Federal Regulations 
City of Hope 
Complete Response 
Clinical Research Associate 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
Clinical Trial Management System 
Data Safety Monitoring Committee 
Eastern Cooperative Oncology Group 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Homocysteine 
Investigator Brochure 
Informed Consent Form 
Investigational New Drug  
Indeterminate Response 
Immune-related adverse event 
Institutional Review Board 
Intravenous 
Lymphoma Response to Immunomodulatory Therapy Criteria 
Methylmalonic acid 
Progressive Disease 
Progression-Free Survival 
Principal Investigator 
Protocol Monitoring Team 
Partial Response 
Peripheral T-Cell Lymphoma 
Serious Adverse Event 
Stable Disease 
World Health Organization 
 

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1.0 OBJECTIVES 
1.1 Primary Objectives 
o Evaluate the safety and tolerability of a regimen combining pembrolizumab and pralatrexate in 
patients with relapsed or refractory PTCL. 
o Establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the 
combined pralatrexate and pembrolizumab regimen. 
o Estimate the overall response rate (ORR) according to the Lugano Classification8 in patients 
treated with pembrolizumab plus pralatrexate at the RP2D. 
1.2 Secondary Objectives 
o Estimate the complete response (CR) rate according to the Lugano Classification8, duration of 
response (DOR), overall survival (OS) and progression-free survival (PFS) in patients treated with 
pembrolizumab plus pralatrexate. 
o 
Estimate the ORR and CR rate according to the International Harmonization Project response 
criteria (Cheson 2007).9 
o Evaluate responses and disease progression according to the Lymphoma Response to 
Immunomodulatory therapy Criteria (LYRIC).10 
1.3 Exploratory Objectives 
o Explore immunologic and genomic biomarkers of response to pembrolizumab plus pralatrexate 
therapy. 
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
2.1.1 
Disease Under Study: Peripheral T-cell Lymphoma 
Peripheral T-cell lymphomas (PTCL) are an uncommon group of disorders, accounting for about 10% of all 
non-Hodgkin lymphomas (NHL). EBV-associated extranodal NK/T-cell lymphoma (NKTCL) is more common 
in parts of Asia and South America, while angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-
cell lymphoma, not otherwise specified (PTCL NOS) are more common in Western countries.12 TCLs are 
generally associated with poor outcomes after standard therapy, with variation in prognosis according to 
disease subtype.12 ALK-expressing anaplastic large cell lymphomas (ALCL) have a favorable prognosis with 
5-year survival exceeding 80%, though some studies suggest outcomes in ALCL are dependent on age 
rather than ALK status.12-14 Anthracycline-based induction combination chemotherapy is standard upfront 
treatment for patients with PTCL; however, with the exception of ALK-positive ALCL, relapse rates are 
high.15-17 Autologous hematopoietic stem cell transplantation (ASCT) is widely used as consolidation for 
PTCL patients in first remission to reduce the risk of relapse. Single-arm prospective and retrospective 
studies of consolidative ASCT for TCLs in 1st remission report improvements in survival compared to 
historical controls, but progression-free survival (PFS) remains low, ranging from 44-58% at 3-5 years.2,18-
21 Outcomes are poorer in patients who undergo ASCT with relapsed PTCL, with 3-5 year PFS ranging from 
32-41%.1,2  

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Current approved therapies available for relapsed or refractory TCLs include histone deacetylase 
inhibitors (romidepsin and belinostat), pralatrexate, and brentuximab vedotin (for ALCL). With the 
exception of brentuximab vedotin for ALCL, these agents are associated with low response rates and short 
median progression free survival.3-5  
In the pivotal PROPEL trial, 115 heavily pre-treated PTCL patients (median 3 prior systemic therapies) 
received pralatrexate as a single agent. The overall response rate (ORR) in 109 evaluable patients was 
29%, including 12 (11%) complete responses (CR) and 20 (18%) partial responses (PR), with a median 
remission duration of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most 
common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), 
and anemia (18%).5  
Romidepsin is a histone deacetylase (HDAC) inhibitor that has been approved for the treatment of PTCL 
and cutaneous T-cell lymphoma (CTCL). Of the 131 patients enrolled in the pivotal phase II trial, 130 had 
histologically confirmed PTCL by central review. The objective response rate was 25% (33 of 130), 
including 15% (19 of 130) with CR/CRu. The median duration of response was 17 months, with the longest 
response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced 
disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events 
were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).3 
Belinostat is a potent hydroxamic acid-derived pan-HDAC inhibitor. It was evaluated in an open-label 
phase II study. A total of 129 relapsed/refractory PTCL patients received 1000 mg/m2 belinostat infusion 
on days 1–5 of every 3-week cycle. Among 120 evaluable patients, the ORR was 26%, including 10% CR, 
and median response duration was 8.3 months. The most common grade 3–4 AEs were thrombocytopenia 
(13%), neutropenia (13%), and anemia (10%). This agent can be used even in patients who have a 
decreased platelet count.22  
Brentuximab vedotin is FDA-approved for relapsed CD30 expressing systemic anaplastic large cell 
lymphoma.23 Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 
patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. 
The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 
adverse events in 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral 
sensory neuropathy (12%). 
With high relapse rates after standard therapy including ASCT and inadequate second line treatment 
options, novel therapies are for relapsed or refractory PTCL are urgently needed. 
2.1.2 
PD-1/PD-L1 Pathway in Lymphoma 
The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally serves to 
dampen immune responses in tissues. PD-1 is expressed on activated T-cells and binds its ligands, PD-L1 
and PD-L2, on tissue cells or antigen presenting cells to decrease T-cell activation, proliferation, and 
survival.24 Tumor cells can co-opt this pathway to evade attack by the host immune system.24 A wide range 
of hematologic malignancies express PD-1 or PD-L1, including Hodgkin’s lymphoma (HL),25 diffuse large B-
cell lymphoma (DLBCL),26 primary mediastinal B-cell lymphoma (PMBCL),25,27 follicular lymphoma (FL),28 
chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),29 peripheral T-cell lymphomas 
(PTCL),30-34 multiple myeloma (MM),35 acute myelogenous leukemia (AML),36,37 and myelodysplastic 
syndrome (MDS).38,39 In addition, molecular analyses have demonstrated that genetic alterations involving 

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PD-L1 and its overexpression are critical in the pathogenesis of HL, PMBCL, and Epstein-Barr virus-
associated post-transplant lymphoproliferative disorders.25,40 
Inhibitors of PD-1 and PD-L1 have produced clinical responses in early-phase studies in patients with a 
range of lymphomas, including HL, DLBCL, and FL. Pidilizumab (CureTech, Yavne, Israel) produced 
responses as a single-agent in patients with rel/ref FL, CLL, and HL, in a phase I study,41 and yielded a 66% 
ORR when used in combination with rituximab in patients with relapsed or refractory FL in a phase II 
study.42 A phase Ib study of nivolumab demonstrated an 87% overall response rate (ORR) and 100% clinical 
benefit rate in 23 patients with relapsed or refractory HL.43 A subsequent phase II study of nivolumab in 
80 patients who failed ASCT as well as prior brentuximab vedotin confirmed a high ORR of 66%, with 9% 
of patients having a complete response per independent review. Notably, the majority of responders 
remained in remission at the time of censoring, thus a significant proportion of responses appear to be 
durable.44 A phase Ib study of pembrolizumab in 31 patients with rel/ref HL who failed prior brentuximab 
vedotin demonstrated a 65% ORR with 16% of patients achieving CR.45 A phase II study of pembrolizumab 
in patients with rel/ref HL is ongoing, but interim reports have demonstrated an ORR of 70%.46 Similarly, 
in a phase Ib study of nivolumab, a 36% ORR was observed in patients with rel/ref DLBCL, and a 40% ORR 
was observed in patients with rel/ref FL.47 In an early interim analysis, the PD-L1 inhibitor, atezolizumab, 
in combination with obinutuzumab produced a 15% ORR in patients with rel/ref DLBCL or FL. 23 patients 
with T-cell lymphoma were enrolled in the phase I study of nivolumab, including 13 patients with mycosis 
fungoides (MF)/CTCL and 5 patients with relapsed or refractory peripheral PTCL. The ORR was 40% in 
relapsed or refractory PTCL and 15% in CTCL. However, 69% of CTCL patients had stable disease, resulting 
in a clinical benefit rate of 84%. In addition, interim results from a phase 2 study of pembrolizumab in 
patients with MF/CTCL were presented at ASH 2016 by Khodadoust et al., and pembrolizumab produced 
a 38% ORR in patients with MF/CTCL. 
2.2 Pembrolizumab 
Pembrolizumab is a monoclonal antibody that binds PD-1 and inhibits the interaction between PD-1 and 
its ligands. The programmed death receptor-1 (PD-1) pathway is an immune checkpoint that normally 
serves to dampen immune responses in tissues. PD-1 is expressed on activated T-cells and binds its 
ligands, PD-L1 and PD-L2, on tissue cells or antigen presenting cells to decrease T-cell activation, 
proliferation, and survival24. Tumor cells can co-opt this pathway to evade attack by the host immune 
system24. Phase I studies of pembrolizumab in solid tumors and hematologic malignancies have 
demonstrated that the medication is safe, well-tolerated, and effective for treating classical Hodgkin 
lymphoma [Moskowitz, ASH 2014]. The ongoing KEYNOTE-013 study is evaluating pembrolizumab for 
treatment of other lymphoma subtypes, myelodysplastic syndrome, and multiple myeloma. 
 
The PD-1 pathway is an attractive therapeutic target in PTCLs: 
- 
PD-1 or PD-L1 are over-expressed in angioimmunoblastic T-cell lymphoma (AITL), peripheral T-cell 
lymphoma, not otherwise specified (PTCL-NOS), ALCL, extranodal NK/T-cell lymphoma, and HTLV-
associated adult T-cell lymphoma/leukemia30-34. 
- 
PD-1 inhibitors have produced clinical responses in early-phase studies in patients with a range of 
lymphomas, including PTCL 41-43,48-50. 
- 
Interim results from a phase 1 study of Nivolumab (Bristol-Myers Squibb, New York, NY) presented 
at the 2014 ASH annual meeting demonstrated a 40% ORR (2/5 patients) in relapsed or refractory 
PTCLs (Lesokhin, ASH 2014). 
 

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While responses to PD-1/PD-L1 inhibition have been observed in patients with NHL, there is room for 
improvement. The reported ORRs to single-agent PD-1/PD-L1 inhibition are ~35-40%, with a low CR rate 
(~0-10%). Given the responses to PD-1/PD-L1 inhibition observed across lymphoma subtypes, the addition 
of synergistic agents may result in deeper and more durable responses. 
However, it should be noted that a recent report described evidence of rapid progression of disease after 
treatment with an anti-PD-1 antibody in patients with adult T-cell leukemia-lymphoma (ATLL), which is a 
subtype of PTCL. All 3 patients with ATLL treated on a phase 2 clinical trial of nivolumab experienced rapid 
clinical progression of disease with leukocytosis, hypercalcemia, renal dysfunction, and elevated lactate 
dehydrogenase levels. Concurrently, HTLV-1 proviral loads were noted to be increased in 2 patients and 
2 patients also developed circulating atypical lymphocytes and hyperbilirubinemia.51 In a separate study, 
using a mouse model of human T-cell lymphoma, it was demonstrated that PD-1 can function as a tumor 
suppressor.52 Although, thus far, this phenomenon of rapid progression after anti-PD-1 therapy has only 
been described in ATLL, it is theoretically possible in other PTCL subtypes. 
 
2.3 Pralatrexate 
Pralatrexate is a potent antifolate that is FDA-approved for the treatment of relapsed or refractory PTCL. 
In the pivotal PROPEL trial, pralatrexate resulted in an ORR of 29% in heavily pre-treated PTCL patients, 
including 11% complete responses (CR) and 18% partial responses (PR), with a median remission duration 
of 10.1 months. 
Pralatrexate is a folate analogue metabolic inhibitor that competitively inhibits the enzyme dihydrofolate 
reductase (DHFR). The activity of DHFR is critical to catalyze the reduction of dihydrofolate (DHF) to 
tetrahydrofolate (THF), which in turn is required for deoxyribonucleic acid (DNA) synthesis. This 
mechanism of action results in a potential for broad spectrum cytotoxic activity against tumor cells and 
rapidly dividing nucleated cells. 
Treatment-limiting toxicity with pralatrexate: 
Mucositis is the most frequent and treatment-limiting adverse event (AE) associated with the 
administration of pralatrexate. In the pivotal PDX-008 study in the approved R/R PTCL indication (n=111), 
the ORR was 27%. Overall, mucositis was observed in approximately 70% of patients (Grade 1 or 2=50%, 
Grade 3 or 4=21%) and generally occurred early in the first cycle of treatment. Dose omissions and 
reductions due to mucositis occurred in 41% of patients with Grade 1 or 2 mucositis and in 23% of patients 
with Grade 3 or 4 mucositis.53 Mucositis was also observed at pralatrexate doses as low as 15 mg/m2 given 
3 weeks out of 4 weeks in Study PDX-010 (n=29), in which 59% of patients with cutaneous T-cell lymphoma 
(CTCL) developed mucositis (Grade 1 or 2=38%, Grade 3=21%). Study PDX-010 also tested a pralatrexate 
dose of 10 mg/m2, which was deemed to be a suboptimal starting dose. Among the 10 patients treated 
at this dose, 50% experienced Grade 1 or 2 mucositis, but no severe (Grade 3 or 4) mucositis was 
reported.54 Given these results, mucositis is considered a serious treatment-limiting toxicity observed with 
pralatrexate treatment at doses ≥15 mg/m2. 
No biomarker or other prognostic indicator has been identified to predict a patient’s likelihood of 
developing mucositis with pralatrexate treatment. Homocysteine (Hcy) and methylmalonic acid (MMA) 
levels at Baseline have been studied for correlation with subsequent development of mucositis. In one 
study, the investigators found that MMA levels were a predictor of the grade of mucositis that 

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developed,55 but results from other studies have been inconclusive.56 For additional information, see the 
current Investigator’s Brochure for pralatrexate.57 
Leucovorin, which is approved as an antidote for the toxicity from folic acid antagonists, including 
pralatrexate, will thus be administered. Vitamin B12 and Folic acid supplementation will be given as well. 
2.4 Leucovorin 
Leucovorin is the reduced form of a racemic mixture of diasterioisomers of folic acid, which is readily 
converted to other reduced folic acid derivatives (eg, tetrahydrofolate).58 Because leucovorin does not 
require reduction by DHFR as folic acid does, leucovorin is not affected by blockage of DHFR by folic acid 
antagonists, including pralatrexate. This allows purine and thymidine synthesis to take place in the 
presence of pralatrexate or other DHFR inhibitors (eg, MTX), and thus DNA, RNA, and protein synthesis 
can occur. Leucovorin may also limit pralatrexate action on normal cells by competing with pralatrexate 
for the same transport processes into the cell. Leucovorin is approved as an antidote for the toxicity from 
folic acid antagonists, including pralatrexate. Allergic sensitization, including anaphylactoid reactions and 
urticaria, has been reported following the administration of both oral and parenteral leucovorin.58 The 
use of leucovorin as a reactive rescue treatment for pralatrexate-induced mucositis has been evaluated 
in patients with PTCL.59 Patients with Grade 2+ mucositis received leucovorin 25 mg orally (PO) every 6 
hours for 5 days in the week of pralatrexate-induced mucositis and treatment was stopped at least 48 
hours prior to the administration of the next pralatrexate dose. All interventions (n=17) resulted in 
subjective improvement of mucositis by Day 4 following leucovorin treatment and 94% (16 of the 17) of 
interventions resulted in complete resolution of the mucositis by Day 7. None of these patients 
discontinued treatment with pralatrexate due to mucositis.59 In addition, there is evidence that 
proactively treating patients with leucovorin (50 mg IV) 24 hours after pralatrexate administration could 
prevent or reduce pralatrexate-induced oral mucositis. Three patients with CTCL, who were preemptively 
treated with single IV doses of leucovorin, 24 hours after pralatrexate administration, showed no 
mucositis.60 
2.5 Overview and Rationale of Study Design 
Rationale for study combination: 
Outcomes of patients with relapsed or refractory PTCL are dismal. Current therapies available for relapsed 
or refractory PTCL, including novel agents, are associated with poor response rates and short median 
progression-free survival, and few patients are salvaged by stem cell transplantation.1-5 Novel therapies 
for relapsed or refractory PTCL are urgently needed. Because of inadequate response rates using novel 
therapies as single agents in PTCL, we anticipate that novel therapeutic combinations will be necessary to 
impact these aggressive and difficult-to-treat diseases. 
In early studies evaluating PD-1/PD-L1 pathway inhibitors in PTCL and MF/CTCL, response rates of 15-40% 
have been observed. Therefore, these well-tolerated immunotherapy agents with a different mechanism 
of action compared to all other available drugs for treating T-cell lymphomas are a potential backbone on 
which to build a novel therapy combination. One logical combination partner for a PD-1/PD-L1 inhibitor 
in PTCL is the antifolate drug, pralatrexate. Antifolate agents, like pemetrexed, have immunologic effects 
which may result in synergy with PD-1 blockade, including activation of IFNγ-producing NK cells and, 
potentially, activation of CD8+ T-cells.6,7 There is already clinical evidence of potential synergy between 
PD-1 inhibitors and anti-folate drugs. In a randomized phase II trial of patients with metastatic non-small 
cell lung cancer (NSCLC), patients treated with a PD-1 inhibitor, pembrolizumab, plus with carboplatin and 

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an antifolate chemotherapy, pemetrexed, had a higher ORR (71%) than patients treated with 
pembrolizumab combined with carboplatin and paclitaxel (ORR 50%). (Gadgeel, ASCO 2015; 
Papadimitrakopoulou, ASCO 2014). We propose a phase 1/2 study to evaluate the safety and efficacy of 
combining pralatrexate with pembrolizumab for the treatment of relapsed or refractory aggressive PTCL. 

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3.0 ELIGIBILITY CRITERIA 
Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
Participants must meet all of the following criteria on screening examination to be eligible to participate 
in the study:  
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented willingness and ability to sign an informed consent of the participant and/or Legally 
Authorized Representative 
Age Criteria and Performance Status 
__2. Age 18 or older  
__3. ECOG performance status of 0 or 1. 
Nature of Illness and Disease Status Criteria 
__4. Patients must have a histologically confirmed diagnosis of mature peripheral T-cell or NK-cell 
lymphoma according to the WHO classification, with hematopathology review at the participating 
institution. Eligible histologies are: 
 
Peripheral T-cell lymphoma, not otherwise specified 
 
Anaplastic large cell lymphoma, ALK-negative 
 
Anaplastic large cell lymphoma, ALK-positive 
 
Angioimmunoblastic T-cell lymphoma 
 
Nodal peripheral T-cell lymphoma with TFH phenotype 
 
Follicular T-cell lymphoma 
 
Indolent T-cell lymphoproliferative disorder of the GI tract 
 
Extranodal NK-/T-cell lymphoma 
 
Enteropathy-associated T cell lymphoma 
 
Monomorphic epitheliotropic intestinal T-cell lymphoma 
 
Hepatosplenic T-cell lymphoma 
 
Subcutaneous panniculitis-like T-cell lymphoma 
 
Transformed mycosis fungoides  
__5. Patients must have failed at least one prior regimen, including: 
 
Recurrence of disease after a documented complete response (CR) 
 
Progression of disease after a partial response (PR) to the prior regimen 
 
Partial response, stable disease (SD) or progressive disease (PD) at the completion of the 
prior treatment regimen. If a patient has PR to prior regimen without PD, there must be 
biopsy-proven* residual disease that is measurable (see #6 below) 
* Exception can be granted by the PI if a biopsy is not feasible and/or safe. 
__6. Patient must have measurable disease by CT or PET scan, with one or more sites of disease ≥ 1.5cm 
in longest dimension.   
__7. Be willing to provide tissue from a fresh core or excisional biopsy (performed as standard of care) of 
a tumor lesion prior to starting study therapy or from archival tissue of a biopsy that was performed after 
the most recent systemic therapy. Exception can be granted by the PI if a biopsy is not feasible and/or 
safe. 

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Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
__8. Patients must have received one dose of Vitamin B12 (1 mg IM) within 10 weeks prior to first dose 
of pralatrexate, and must have begun folic acid supplementation (1 mg orally, once daily) within 10 days 
of first dose of pralatrexate. Note: if folic acid was not started but MMA and HCY levels were checked 
and are in normal range at screening, the investigator can decide to start study therapy immediately. 
Vitamin B12 and folic acid supplementation is standard of care for pralatrexate therapy. 
Clinical Laboratory Criteria 
__9. ANC ≥ 1,000/mm3. In Phase 2 portion of study, ANC < 1000/mm3 but ≥ 
500/mm3 is allowable if patients have demonstrated bone marrow 
involvement by lymphoma. 
NOTE: Growth factor is not permitted within 7 days of ANC 
assessment unless cytopenia is secondary to disease involvement. 
ANC: 
Date: 
__10. Platelets ≥ 75,000/mm3. In Phase 2 portion of study, Platelets < 
75,000/mm3 but ≥ 25,000/mm3 is allowable if patients have 
demonstrated bone marrow involvement by lymphoma. 
NOTE: Platelet transfusions are not permitted within 7 days of 
platelet assessment unless cytopenia is secondary to disease 
involvement. 
Plts: 
 
Date: 
__11. Total serum bilirubin ≤ 1.5X ULN OR Direct bilirubin ≤ ULN for 
subjects with total bilirubin levels > 1.5 ULN, unless has Gilbert’s 
disease or hepatic involvement by lymphoma  
ULN: 
Bil: 
Date: 
__12. AST ≤ 2.5 x ULN OR ≤ 5 X ULN for subjects with hepatic involvement 
by lymphoma as the etiology of transaminase elevation 
ULN: 
AST: 
Date: 
__13. ALT ≤ 2.5 x ULN OR ≤ 5 X ULN for subjects with hepatic involvement 
by lymphoma as the etiology of transaminase elevation 
ULN: 
ALT: 
Date: 
__14. Creatinine clearance of ≥ 60 mL/min per the Cockcroft-Gault formula. 
If CrCl is ≥ 60 mL/min as measured by 24 hour urine collection, this 
will be allowable. 
 
Cr Clearance: 
Date: 
__15. If not receiving anticoagulants: International Normalized Ratio (INR) 
OR Prothrombin (PT) ≤ 1.5 x ULN 
If on anticoagulant therapy:  PT must be within therapeutic range of 
intended use of anticoagulants 
ULN: 
INR: 
PT: 
Date: 
__16. If not receiving anticoagulants: Activated Partial Thromboplastin 
Time (aPTT) ≤ 1.5 x ULN 
If on anticoagulant therapy: aPTT must be within therapeutic range 
of intended use of anticoagulants 
ULN: 
 
aPTT: 
Date: 
 
 

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Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
 
__17. Female of childbearing potential: negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of 
study medication. If the urine test is positive or cannot be confirmed 
as negative, a serum pregnancy test will be required 
Urine: 
Serum: 
Date: 
 
 
 
 
 
 
Contraception 
__18. Woman of childbearing potential (WOCBP): use two effective methods of contraception (hormonal 
or barrier method) or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 6 months post last dose of pralatrexate and 120 days post last dose of pembrolizumab. 
WOCBP defined as not being surgically sterilized or have not been free from menses for >1 year. 
Male: use two effective methods of contraception (barrier method) or abstain from heterosexual activity 
with the first dose of study therapy through 3 months post last dose of pralatrexate and 120 days post 
last dose of pembrolizumab. 
Refer to Appendix E for Contraception Guidelines.  
3.2 Exclusion Criteria 
Nature of Illness and Disease Status Criteria 
__1.  Patients with adult T-cell leukemia/lymphoma 
Prior Therapy and Concomitant Therapy 
__2.  Prior allogeneic hematopoietic stem cell transplantation within the last 5 years. 
__3.  Prior autologous hematopoietic stem cell transplant within the last 60 days. 
__4.  Patients who received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
without having had evidence of objective response. 
__5.  Patients who received prior therapy with pralatrexate without having had evidence of 
objective response. 
__6.  Investigational agent or anti-cancer monoclonal antibody (mAb) within 21 days prior to 
Day 1 of therapy or who has not recovered (i.e. ≤1 or at baseline) from adverse events due to 
agents administered more than 21 days earlier.  
__7.  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days 
prior to Day 1 of therapy or who has not recovered (i.e. ≤1 or at baseline) from adverse events 
due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an 
exception and may qualify for the study. 
__8.  Antineoplastic biologic therapy or major surgery within 21 days of the first dose of trial 
medication. If subjects received major surgery more than 21 days ago, they must have 
recovered adequately from the toxicity and/or complications from the intervention prior to 
starting therapy. 
__9.  Received live vaccine or live-attenuated vaccine within 30 days prior to Day 1 of protocol 
therapy. Administration of killed vaccines is allowed. 
__10.  Systemic steroid therapy or on any other form of immunosuppressive therapy within 7 
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Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
Other Illnesses and Conditions 
__11.  Diagnosis of immunodeficiency. 
__12.  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. 
__13.  Congestive heart failure Class III/IV according to the New York Heart Association (NYHA) 
Functional Classification. 
__14.  Known severe hypersensitivity reaction to pembrolizumab, pralatrexate, leucovorin or 
any excipients. 
__15.  Active autoimmune disease that has required systemic treatment in the past 2 years 
(replacement therapies for hormone deficiencies are allowed). Hemolytic anemia associated 
with the lymphoma does not exclude a patient from the study. 
__16.  Known history of HIV (HIV ½ antibodies). 
__17.   Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
__18.  History of active TB infection (Bacillus Tuberculosis). 
__19.  Active central nervous system (CNS) involvement by lymphoma, including parenchymal 
and/or lymphomatous meningitis. Subjects with prior CNS involvement by lymphoma must 
have a baseline MRI and lumbar puncture at screening that demonstrate no active lymphoma 
in the CNS. 
__20.  Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease. 
__21.  Active, uncontrolled infection requiring systemic therapy.   
__22.  Female: Pregnant or breastfeeding 
__23.  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 
__24.  Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
__25.  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. 
__26.  Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns with clinical study 
procedures. 
 
 

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Participant MRN (COH Only):  
Participant Initials (F, M, L): 
Institution: 
Noncompliance 
__27.  Prospective participants who, in the opinion of the investigator, may not be able to 
comply with all study procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* 
by (Choose as 
applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
 

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4.0 PARTICIPANT ENROLLMENT  
NOTE: Sites must meet activation requirements prior to enrolling participants. 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after 
obtaining written informed consent.  Studies or procedures that are performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented (see Section 16.4), and the prospective participant must receive a copy 
of the signed informed consent document.  Screening procedures are listed in Section 10.0. 
4.2 Participant Enrollment 
Eligible participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City 
of Hope. DCC staff are available between the hours of 8:00 a.m. and 5:00 p.m. PST, Monday through 
Friday (except holidays). 
o E-mail: DCC@coh.org 
4.2.1 
Slot verification and reservation 
Issues that would cause treatment delays should be discussed with the Study PI. 
A designated study team member should email the DCC to verify current slot availability, and to reserve 
a slot for a specific prospective subject (provide DCC with subject initials), including a tentative treatment 
date. Slots can only be held for a limited time, at the discretion of the study PI.   
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible. 
4.2.2 
Registration Process 
Allow up to 24 hours for the DCC to review. To register a participant, the following procedure must be 
followed: 
1. The study team should contact the DCC via email to provide notification regarding the pending 
registration and communicate desired timeline of the registration, especially if it must be completed 
promptly to meet the registration window. 
2. The study team will email a Complete Registration Packet to the DCC,  which consists of a copy of the 
following documents:  
 Registration Cover Sheet (Appendix F) 
 Completed Eligibility Checklist (printed from Section 3.0 of the protocol) with required 
signature(s) 
 Signed informed consent 
 Signed HIPAA authorization form (if separate from informed consent) 
 Signed subject’s Bill of Rights (California only)  
  

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3. In some cases, the DCC may request additional documentation prior to registration. Please refer to 
the Work Instruction – Reviewing Packets and Registering Subjects for more information. A copy of 
this work instruction can be provided by the DCC, upon request. 
 
4. When all documents are received, the DCC will review and work with the study team to resolve any 
missing elements. Any missing documents may delay registration. A participant failing to meet all 
requirements will not be registered and the study team will be immediately notified. 
  
5. The DCC will send a Confirmation of Registration Form, including the subject study number and cohort 
assignment to:  
 The study team: Site Lead Investigator, treating physician/sub-investigator, protocol nurse, 
CRC and pharmacy (as needed) 
 The COH Study PI and COH study team designees (including but not limited to study monitor(s) 
and statistician(s)). 
6. Upon receipt of the Confirmation of Registration Form, COH study team will register the patient in 
OnCore. DCC will register non-COH patients in OnCore. 
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC immediately if the participant screen fails after registration or if the participant does not 
start treatment. 
For non-COH sites, the reason for screen failure will be documented in the registration coversheet (see 
Appendix F) and submitted to the DCC. 
Issues that would cause treatment delays should be discussed with the Study Principal Investigator. 
4.4 Dose Level Assignment 
During the Phase 1 portion, eligible participants will be assigned a dose level (Section 5.3). Once the 
recommended phase 2 dose (RP2D) is defined, participants will enroll at the RP2D dose (Section 5.6). 
5.0 TREATMENT PROGRAM 
5.1 Study Overview 
This is a prospective, single-arm, multi-center, open-label phase 1/2 study of pembrolizumab (MK-3475) 
plus pralatrexate in subjects with relapsed or refractory peripheral T-cell lymphomas (PTCL) that have 
failed at least one prior line of therapy. 
In the phase 1 portion, pembrolizumab will be administered at a constant dose of 200 mg IV and 
pralatrexate will be dose-escalated (range from 15-30 mg/m2 IV). The phase I portion will use a modified 
rolling 6 design allowing 3 patients to be treated and evaluated for dose-limiting toxicity simultaneously, 
with up to 6 patients per dose level. An MTD and RP2D will be selected based on toxicity and tolerability 
data. 
In the phase 2 portion, pembrolizumab will be administered at a dose of 200 mg IV and pralatrexate at 
the RP2D selected in the phase 1 portion following the same schedule. The phase 2 portion will use a 
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In both phases, patients will receive up to 24 months of combined pembrolizumab and pralatrexate 
therapy. In both phases, Vitamin B12, Folic acid and Leucovorin will be administered as indicated in the 
study calendar and Section 5.13. 
 
 
 
Each cycle = 21 days. Maximum duration of protocol therapy is 24 months. 
Folic acid and Vitamin B12 supplementation is standard of care for pralatrexate therapy. 
Folic acid is given daily during the course of therapy. Vitamin B12 is given every 3 cycles.  
 
1 Disease staging is performed at screening and every 4 cycles until disease progression or off study. Disease staging will be by 
either PET/CT (preferred) or CT scan, but, if disease is FDG-avid, will be PET/CT at baseline, Cycle 4 and every 8 cycles thereafter. 
Refer to Study calendar and Section 11.1 for details. 
2 Peripheral blood for correlative studies will be collected on C1D1, C2D1, C4D1, C5D1, and at EOT (refer to Table 9.3.1 for 
additional details). 
3 End of treatment visit. 
4 Follow-up Phase for patients who have completed treatment without disease progression will include staging every 12 weeks 
for the first year and every 18 weeks thereafter, until disease progression or off study. 
 
5.2 Treatment Cycle Definition 
In the absence of a delay due to toxicity, each treatment cycle lasts 21 days ± 3 days. Day 1 of a cycle is 
defined as the administration of pembrolizumab. 
5.3 Treatment Plan 
For a tabular view of the treatment, monitoring, and follow-up schedule, see study calendar in Section 10. 
This is a phase 1/2 study, including a phase 1 dose-escalation portion of the study with 2 dose levels and 
1 possible de-escalation dose level, for a total of 3 possible dose levels. The starting dose will be 20 mg/m2 
of pralatrexate on days 1 and 8 and 200 mg IV of pembrolizumab every 21 days, administered in 21-day 
cycles. The planned dose levels in the Phase 1 portion of the study are outlined in the table below. 

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Table 5.3 Dosing regimen and schedule 
Dose level 
Pembrolizumab (Day1) 
Pralatrexate (Days 1 and 8) 
-1 
200 mg IV 
15 mg/m2 IV 
1 
200 mg IV 
20 mg/m2 IV 
2 
200 mg IV 
30 mg/m2 IV 
In the phase 2 portion of the study, subjects will receive therapy at the RP2D. 
Intrapatient dose escalation is permitted in patients enrolled to dose level 1 if and only if the study 
proceeds to dose level 2 and dose level 2 is determined to be the RP2D. In that case, once dose level 2 is 
deemed safe and the study proceeds to the phase 2 portion of the study, patients who were enrolled to 
dose level 1 and are continuing to receive therapy can escalate to dose level 2 in their subsequent cycle 
of therapy. Patients must meet the criteria for initiation of subsequent cycles of therapy detailed in 
Section 5.4 of the protocol. 
5.4 
Eligibility criteria for initiation of subsequent treatment cycles 
Prior to initiation of Cycle 2 or any subsequent cycle, and based on the dose delay/modification guidelines 
provided in Section 6.3 and Section 6.4, patients will need to meet the following eligibility criteria: 
 
Mucositis ≤ grade 1 
 
Platelet count ≥ 25,000/µL 
 
ANC between 500-1,000/µL with no fever, or ANC ≥ 1000/µL 
 
AST and ALT ≤ 3 ULN OR ≤ 5 ULN for subjects with hepatic involvement by lymphoma as the 
etiology of transaminase elevation 
 
Total serum bilirubin ≤ 1.5 ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN, unless has Gilbert’s disease or hepatic involvement by lymphoma.  
 
No ongoing ≥ grade 3 pralatrexate-related toxicity 
 
No ≥ grade 2 pneumonitis, diarrhea/colitis, hypophysitis, nephritis/renal dysfunction, or 
intolerable/persistent immune-related AE 
 
No ≥ grade 3 hyperthyroidism 
 
No evidence of myocarditis or newly onset type I diabetes mellitus 
 
No ≥ grade 3 hyperglycemia associated with evidence of β-cell failure 
 
5.5 
Definition of Dose-Limiting Toxicity 
The dose-limiting toxicity (DLT) observation period will be 2 cycles of therapy, from the start of Cycle 1 
through the start of Cycle 3, including any delays (regardless of cause) to start of C3. It will be 42 days if 
there is no delay. If C3D1 is shorter than 42 days from C1D1, DLT will be evaluated through prior to 
administration of study therapy on C3D1. 
Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE, Version 5.0) accessible at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 

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DLT will be defined as one of the following AEs that is at least possibly related to study treatment: 
Hematologic 
• 
Grade 4 neutropenia lasting > 7 days (despite the use of growth factor support). 
• 
Grade 4 thrombocytopenia lasting > 7 days or requiring platelet transfusion. 
• 
Grade 3 or 4 thrombocytopenia associated with grade 2 or higher bleeding. 
• 
Grade 4 anemia not associated with lymphoma. 
• 
Any Grade 5 AE. 
Non-hematologic 
• 
Grade ≥ 3 pneumonitis without suspected infectious cause. 
• 
Any ≥ grade 3 AE that does not resolve to grade ≤ 1 within 7 days with the exception of: 
o 
Grade ≥ 3 asymptomatic laboratory abnormalities, including lipase or amylase, that do not require 
hospitalization or delay of treatment. 
o 
Grade 3 nausea or vomiting, that improves to grade ≤ 2 within 7 days with supportive measures. 
o 
Grade 3 fatigue that improves to grade ≤ 2 within 14 days with supportive measures. 
o 
Grade 3 asymptomatic endocrinopathy of any duration. 
o 
Grade 3 fatigue related to endocrinopathy that resolves within 7 days of hormone-replacement 
or corticosteroid therapy. 
o 
Grade 3 inflammatory response attributed to local antitumor response of any duration. 
o 
Vitiligo or alopecia of any grade and duration. 
• 
Any Grade 5 AE 
5.6 
Definition of the MTD and Recommended Phase 2 Dose 
Dose escalation will proceed according to the schema outlined in Table 5.3. The maximum tolerated dose 
(MTD) is defined as the highest dose level at which < 2 out of 6 evaluable subjects experienced DLT. The 
MTD will be considered the recommended phase 2 dose (RP2D), however the principal investigator may 
ultimately choose a lower dose level as the RP2D, depending on toxicity considerations, dose reduction 
on subsequent cycles, and other considerations. 
5.7 
Replacement of Subjects 
During the Phase 1 portion of the study, subjects will be replaced for any of the following: 
• 
Missed any doses of pralatrexate during the DLT period (not due to DLT). 
• 
Did not receive the doses of pembrolizumab during the DLT period (not due to DLT). 
Subjects who are replaced for missed doses may continue to receive study treatment if there is clear 
clinical benefit, but will not be included in DLT analysis. 

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During the Phase 2 portion of the study, subjects who did not receive at least 1 dose of pembrolizumab 
and 1 dose of pralatrexate, or who did not have a tumor response assessment (except due to progression 
of disease prior to the first tumor response assessment) will be replaced. If a patient discontinues study 
treatment prior to the first response assessment due to progressive disease, the treating physician is 
encouraged to obtain imaging to confirm progression.  
5.8 Agent Administration 
5.8.1 
Pembrolizumab  
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
Pembrolizumab (200 mg) will be administered as a 30-minute IV infusion on Day 1 of each 21-day cycle. 
The final concentration of the diluted solution should be 1 mg/mL - 10 mg/mL and administered IV over 
30 minutes, through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter. 
Every effort should be made to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion 
time is 30 minutes: -5 min/+10 min). 
The pembrolizumab dose is fixed at 200 mg. There are no dose reductions. Management and dose delays 
associated with pembrolizumab AEs are outlined in Section 6.3.  
Pembrolizumab will always be given first (before pralatrexate). 
5.8.2 
Pralatrexate 
Pralatrexate will be administered by intravenous (IV) push according to dose levels, over 3 to 5 minutes, 
via the side port of a free-flowing 0.9% sodium chloride injection on Days 1 and 8 of each cycle. 
Pralatrexate dosing should be based on baseline body surface area (BSA). Patients with a BSA>2m2 can be 
treated either at the actual BSA or at BSA=2m2, at the Investigator’s discretion. The patient will receive 
the same dose of pralatrexate (based on the BSA calculated at baseline) throughout treatment unless the 
patient’s actual weight changes by ≥10% (in that case the dose will be adjusted accordingly). 
5.9 Assessments and Special Monitoring 
Section 10 summarizes the trial procedures to be performed. Note: Protocol therapy should be 
administered on Day 1 of each cycle after all procedures/safety assessments have been completed. 
It may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator.  
5.9.1 
Special Monitoring for pembrolizumab. 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology. These adverse events may occur shortly after the first dose or several months 
after the last dose of pembrolizumab. 

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Diarrhea/colitis  
 Participants 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).  
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. 
Management of infusion reactions  
 Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.  
 Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
5.9.2 
Monitoring for pralatrexate. 
Oral mucositis is common and mucositis should be graded at each study visit. Oral mucositis will be graded 
according to the CTCAE v5.0 and pralatrexate dose delay/modification guidelines in section 6.4 should be 
adhered to. 
5.10 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Participants will receive protocol therapy until one of the below criteria are met: 
o Disease progression 
 
Note: Following consultation with the Study PI, participants who meet progression per 2014 
Lugano classification 8 but who meet the criteria of “indeterminate response” (IR) according 
to the provisional modification to the 2014 Lugano Classification, the LYRIC criteria 10 
(Appendix C), and are deriving clinical benefit may continue to receive protocol therapy 
beyond progression as long as they meet the following criteria: 
− 
Continue to meet treatment criteria 
− 
Investigator-assessed clinical benefit  
− 
Tolerance of study drug 
− 
Stable performance status 
− 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
 
If the patient has IR per LYRIC criteria and is receiving therapy beyond progression:  
− 
A confirmatory PET-CT should be performed within 12 weeks after initial 
progression to determine whether the patient meets PD criteria according to the 
LYRIC criteria 10. 
− 
Further progression is defined according to the LYRIC criteria  
− 
Protocol therapy should be discontinued permanently upon documentation of PD 
per the LYRIC criteria 
o Unacceptable toxicity despite dose delay/ modification  

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 
Note: If one agent is delayed due to toxicity, then participants many continue with 
monotherapy for the other agent. 
 
Completed protocol therapy. 
o General or specific changes in the participant's condition (including intercurrent illness)  
which render the participant unacceptable for further treatment in the judgment of the 
investigator 
o Withdrawal of consent for further protocol therapy by the participant (See Section 16.5) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to End of Protocol Therapy assessments and follow-up. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC and the Study PI should be promptly notified 
of the change in participant status. 
5.11 Follow-Up 
Following completion of protocol therapy, all participants will enter follow-up after ending protocol 
treatment.  This is comprised of: 
o Safety Follow-up- 30 days post-last dose of protocol therapy through to (a) 90 days post-
last dose of protocol therapy or (b) until initiation of a new anticancer therapy (whichever 
occurs sooner) 
 Note: the period for safety follow-up will be extended until stabilization or resolution for all 
reportable AEs (per the agreement of the Study PI) and accompanying follow-up safety 
report. 
o Response Follow-up- for those who have yet to have disease progression. 
o Survival Follow-up- for those who progressed or completed Response Follow-up. 
This follow-up will be performed typically via medical record review. It will entail (a) Disease 
status (for those who have yet to progress) (b) Vital status (all participants). 
Assessment time points and windows are detailed in Section 10.0. 
5.12 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities  
o Withdrawal of consent (See Section 16.5) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or 
administrative reasons 
Documentation of the reason for discontinuing study participation and the date effective should be made 
in the medical record and appropriate eCRF. The COH DCC should be promptly notified of the change in 
participant status. 

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5.13 Supportive Care, Prohibited Medications and Concomitant Therapy  
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. 
If concomitant therapy must be added or changed, including over-the-counter medications or alternative 
therapies, the reason and name of the agent/therapy should be recorded in the eCRF and the medical 
record. 
5.13.1 Prohibited concomitant medication and medications to use with caution 
The following are prohibited from Day 1 of protocol therapy until end of protocol therapy (last day of 
study agent or decision to end study agent(s) whichever occurs later): 
o Antineoplastic systemic chemotherapy or biological therapy  
o Immunotherapy not specified in this protocol 
o Chemotherapy not specified in this protocol 
o Other investigational agents other than pembrolizumab and pralatrexate 
o Live vaccines  
o Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the PI. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. 
The following medications should be used with caution: 
o “Sulfa” antibiotics 
o Non-steroidal anti-inflammatory drugs 
o   Probenecid 
When administering pralatrexate to patients receiving probenecid or other drugs that may affect 
relevant transporter systems (eg, NSAIDs), monitor patients closely for signs of systemic toxicity due 
to increased drug exposure. 

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5.13.2 Specific supportive care guidelines for pralatrexate 
5.13.2.1 Leucovorin 
Mucositis is the most frequent and treatment-limiting adverse event (AE) associated with the 
administration of pralatrexate. Leucovorin (d,l-folinic acid) is a reduced form of a racemic mixture of 
diasterioisomers of folic acid and is well-recognized and approved as rescue therapy for high-dose 
methotrexate (MTX) therapy, mitigating gastrointestinal lining and bone marrow cell toxicity [3]. It is also 
indicated to treat MTX or other folic acid antagonist overdose and is used in combination with fluorouracil 
to treat cancer of the colon. Leucovorin is approved as an antidote for the toxicity from folic acid 
antagonists, including pralatrexate. In the present study it is thus used to prevent or reduce mucositis 
resulting from pralatrexate treatment. 
Leucovorin (25 mg tablets) will be administered orally three times daily (every 8 hours) for 2 days for a 
total of 6 doses (150 mg cumulative weekly dose) beginning 24h (+/- 2h) after each dose of pralatrexate 
is administered. 
The patient will be instructed to take the first dose of leucovorin 24 hours (±2 hours) after the 
administration of pralatrexate, and to continue to take the leucovorin three times daily (every 8 hours)  
for 2 days. At each weekly treatment visit, the patient will be asked whether they have taken leucovorin 
as instructed and will be supplied with a prescription to obtain additional doses.  
5.13.2.2 Folic Acid supplementation/Premedication (Standard of care for pralatrexate therapy) 
Folic acid (1 mg orally, once daily) supplementation is to begin within 10 days (as early as possible) prior 
to the first dose of pralatrexate administration (per pralatrexate product insert). However, if folic acid was 
not taken but MMA (methylmalonic acid) and HCY (homocysteine) levels were checked and are in normal 
range at screening, the investigator can decide to start study therapy immediately. Administration should 
continue during the full course of pralatrexate therapy and for 30 days after the last dose of pralatrexate. 
5.13.2.3 Vitamin B12 supplementation/Premedication (Standard of care for pralatrexate therapy) 
Vitamin B12 (1 mg IM) will be administered anytime within 10 weeks prior to initiation of pralatrexate 
(per pralatrexate product insert) and can be administered during screening, and will be administered 
every 3 cycles. Administration should continue during the full course of pralatrexate therapy and for 30 
days after the last dose of pralatrexate. 
5.13.3 General Supportive Care Guidelines 
Participants 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 or pralatrexate administration.  

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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
Myocarditis 
 
For suspected immune-mediated myocarditis, ensure adequate evaluation to exclude 
other etiologies. 
 
Administer corticosteroids as appropriate. 
Pneumonitis  
 Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
Grade 2 
 Administer systemic corticosteroids. 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Grade 3 or 4 
 Immediately treat with IV steroids.  
 Administer additional anti-inflammatory measures, as needed. 
Diarrhea/colitis  
 All participants 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. 
Grade 2 diarrhea/colitis 
 Administer oral corticosteroids. 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Grade 3 or 4 diarrhea/colitis 
 IV steroids followed by high dose oral steroids 
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Type 1 diabetes mellitus* OR ≥ Grade 3 hyperglycemia**  
o *if new onset, including diabetic ketoacidosis [DKA])  
o **if associated with ketosis (ketonuria) or metabolic acidosis (DKA)  
For T1DM or Grade 3-4 hyperglycemia 
 Insulin replacement therapy is recommended.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
Hypophysitis  

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Grade 2 (i.e. symptomatic) 
 Treat with corticosteroids. 
 When symptoms improve to ≤ Grade 1, 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. 
Grade 3 or 4  
 Treat with an initial dose of IV corticosteroids followed by oral corticosteroids. 
 When symptoms improve to ≤ Grade 1, 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  
Grade 2 Hyperthyroidism  
 Non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. 
Grade 3 or 4 Hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  
 When symptoms improve to ≤ Grade 1, 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 
Grades 2-4 Hypothyroidism  
 Thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated 
per standard of care. 
Hepatic  
Grade 2 
 Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
 Treat with IV or oral corticosteroids 
Grade 3 or 4 
 Treat with intravenous corticosteroids for 24 to 48 hours.  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks 
Renal failure or nephritis  
Grade 2 
 Treat with corticosteroids 
Grade 3 or 4 
 Treat with systemic corticosteroids.  
 When symptoms improve to ≤ Grade 1, steroid taper should be started and continued 
over no less than 4 weeks 

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Management of infusion reactions  
 Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are 
provided in Table 5.13.3. 
 
 
 

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Table 5.13.3 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
 

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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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
5.13.4 Other Considerations 
Refer to Appendix E for contraception related guidance. 
 

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6.0 ANTICIPATED TOXICITIES & DOSE MODIFICATION/ DELAY GUIDELINES 
6.1 Anticipated Toxicities 
6.1.1 
Pembrolizumab 
Per the IB the expected toxicities for pembrolizumab are as follows (asterisk signifies ≥ 10%; no asterisk 
signifies 1-10%, † signifies < 1%, and ^ signifies unknown frequency): 
Blood and lymphatic system 
disorders (includes 
investigations) 
Anemia, neutropenia†, thrombocytopenia†, leukopenia†, 
lymphopenia†, eosinophilia†, hemolytic anemia†,immune 
thrombocytopenic purpura† 
Cardiac 
Myocarditis † 
Endocrine 
Hyperthyroidism, hypothyroidism, hypophysitis †, adrenal 
insufficiency †, thyroiditis † 
Eye 
Uveitis †, dry eye †, Vogt-Koyanagi-Harada disease ^ 
Gastrointestinal  
Diarrhea*, nausea *, abdominal pain, vomiting, colitis, 
constipation, dry mouth, pancreatitis †, small intestine perforation 
†  
General Disorders and 
Administration Site 
Fatigue *, asthenia, edema, pyrexia, influenza-like illness, chills 
Hepatobiliary 
Hepatitis †, sclerosing cholangitis ^ 
Immune system 
Infusion related reactions, severe infusion reactions †, sarcoidosis 
†, solid organ transplant rejection ^, GvHD (potential risk), 
haemophagocytic lymphohistiocytosis † 
Investigations (excluding 
hematologic) 
AST/ALT increased, blood alkaline phosphatase increased, blood 
creatinine increased, low sodium levels†, low potassium levels†, 
low calcium levels†, blood bilirubin increased†, amylase 
increased†, increased calcium † 
Metabolism and Nutrition 
Decreased appetite, type 1 diabetes mellitus † 
Musculoskeletal and Connective 
Tissue  
Arthralgia, back pain, myositis, musculoskeletal pain, arthritis, pain 
in extremity, tenosynovitis † 
Nervous system 
Headache, dizziness, dysgeusia, epilepsy †, lethargy †, Guillian-
Barré syndrome†, peripheral neuropathy†, myasthenic syndrome 
†, encephalitis †, myelitis† 
Psychiatric disorders 
Insomnia † 
Renal and urinary  
Nephritis † 
Respiratory, Thoracic and 
Mediastinal 
Cough, pneumonitis, dyspnoea 
Skin and Subcutaneous Tissue  
Pruritus*, rash*, vitiligo, dry skin, erythema, hair color change †, 
eczema †, alopecia †, severe skin reactions†, Steven-Johnson 
Syndrome†, toxic epidermal necrolysis† 
Vascular Disorders 
Hypertension †, vasculitis † 

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6.1.2 
Pralatrexate 
Per package insert: the most common adverse reactions (>35%) are mucositis, thrombocytopenia, 
nausea, and fatigue. Most common serious adverse reactions are pyrexia, mucositis, sepsis, febrile 
neutropenia, dehydration, dyspnea, and thrombocytopenia. 
Bone Marrow Suppression 
Pralatrexate can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and 
anemia. 
Mucositis 
Treatment with pralatrexate may cause mucositis.  
Dermatologic Reactions 
Pralatrexate has been associated with severe dermatologic reactions, which may result in death. 
Dermatologic reactions have been reported in clinical studies and post-marketing safety reports in 
patients treated with pralatrexate. Dermatologic reactions have included skin exfoliation, ulceration, and 
toxic epidermal necrolysis (TEN) (post-marketing reports). These reactions may be progressive and 
increase in severity with further treatment, and may involve skin and subcutaneous sites of known 
lymphoma.  
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported in patients with lymphoma receiving pralatrexate in post-
marketing reports.  
Hepatic Toxicity 
Hepatic toxicity and liver function test abnormalities have been observed after pralatrexate 
administration. Persistent liver function test abnormalities may be indicators of liver toxicity.  
Risk of Increased Toxicity in the Presence of Impaired Renal Function 
Patients with moderate to severe renal function impairment may be at greater risk for increased exposure 
and toxicity. Serious adverse drug reactions including TEN (post-marketing reports) and mucositis were 
reported in patients with end stage renal disease (ESRD) undergoing dialysis who were administered 
FOLOTYN therapy.  
Pregnancy and Breastfeeding 
Pralatrexate can cause fetal harm when administered to a pregnant woman. Pralatrexate was 
embryotoxic and fetotoxic in rats and rabbits.  
6.2 Dose Delay/ Modification - General instructions 
If pembrolizumab administration is held for toxicity, and the toxicity is most likely attributed to 
pembrolizumab and not attributed to pralatrexate, administration of pralatrexate may continue. 
If pralatrexate administration is held for toxicity, and the toxicity is most likely attributed to pralatrexate 
and not attributed to pembrolizumab, administration of pembrolizumab may continue. 
 

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In the event that attribution of a treatment-emergent toxicity is unclear, but is at least possibly related to 
both study medications, both drugs should be delayed/modified according to the most conservative dose 
delay criteria. The most conservative dose delay criteria should be observed for any particular AEs called 
out in the dose delay/modification tables (Tables 6.3, 6.4.1, 6.4.2, or 6.4.3) or according to the general “all 
other IrAE” guidelines in Table 6.3 for unspecified immune-related AEs or the “all other pralatrexate-
related” AE guidelines in Table 6.4.3 for non-immune related AEs. 
6.3 Dose Delay/ Modification Guidelines for Pembrolizumab-associated Adverse Events 
o Toxicities will be graded using the NCI CTCAE Version 5.0. 
o Baseline values are from the last values obtained prior to treatment. 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications.  Based on existing clinical study 
data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 6.3. 
 
 
 
 
Table 6.3 Dose Modification and toxicity management for irAEs typically associated with 
pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations represented in Table 6.3 where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE 
does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per 
day within 12 weeks.  
3. For situations represented in Table 6.3 where pralatrexate has been withheld, pralatrexate can be resumed at prior dose after 
AE improves to grade 1 or 0. If the investigator feels that the AE was related to pralatrexate, the pralatrexate dose can be 
reduced by one level after discussion with the overall study PI. 
Exceptions: 
- 
For patients who develop severe renal impairment (eGFR or CrCl 15 to < 30 mL/min/1.73m2) while on treatment with 
pralatrexate at the 30 mg/m2 dose level, the dose of pralatrexate upon recovery will be reduced to 15 mg/m2. 
- 
For patients who develop severe renal impairment (eGFR or CrCl 15 to < 30 mL/min/1.73m2) while on treatment with 
pralatrexate at the 20 mg/m2 dose level or lower, pralatrexate will be permanently discontinued. 
4. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 

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Immune-
related AEs 
Toxicity grade or 
conditions 
(CTCAE v5.0) 
Action taken to 
pembrolizumab 
and/or pralatrexate 
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and follow-up  
Pneumonitis  Grade 2 
• 
Withhold 
pembrolizumab 
• 
Consider holding 
pralatrexate 
• 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 
pembrolizumab 
• 
Hold pralatrexate 
Diarrhea / 
Colitis  
Grade 2 or 3 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• 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. 
Grade 4, or 
recurrent Grade 3 
• 
Permanently 
discontinue 
pembrolizumab 
• 
Hold pralatrexate 
 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed by 
taper 
• 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable 
Grade 3 or 4  
• 
Permanently 
discontinue 
pembrolizumab 
• 
Hold pralatrexate 
• Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper 

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Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
• 
Withhold 
pembrolizumab 
• Initiate insulin 
replacement therapy 
for participants with 
T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for hyperglycemia 
or other signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
• 
Withhold 
pembrolizumab 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)  
Grade 3 or 4  
• 
Withhold or 
permanently 
discontinue 
pembrolizumab1  
Hyperthyroi
dism  
Grade 2 
Continue 
pembrolizumab 
• Treat with non-
selective beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue 
pembrolizumab1 
Hypothyroid
ism 
Grade 2, 3, or 4 
Continue 
pembrolizumab  
• Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis 
and Renal 
dysfunction 
Grade 2 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper. 
• 
Monitor changes of renal function 
 
Grade 3 
• 
Permanently 
discontinue 
pembrolizumab 
• 
Hold pralatrexate 
Grade 4 
• 
Permanently 
discontinue 
pembrolizumab 
and pralatrexate 
Neurological 
Toxicities 
Grade 2 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• Based on severity of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
• 
Permanently 
discontinue 
pembrolizumab 
• 
Hold pralatrexate 

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If the neurological 
toxicity is felt to be 
due to pembrolizumab 
and not pralatrexate, 
resumption of 
pralatrexate may be 
considered in 
consultation with the 
study PI. 
Myocarditis 
Grade 1 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• 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 
pembrolizumab 
• 
Hold pralatrexate 
Exfoliative 
Dermatologi
c Conditions 
Suspected SJS, 
TEN, or DRESS 
• 
Withhold 
pembrolizumab 
• 
Hold pralatrexate 
• 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 
pembrolizumab 
and pralatrexate 
All other 
immune-
related AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
pembrolizumab 
• 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 
pembrolizumab based 
on the type of event.  
Events that require 
discontinuation 
include, but are not 
limited to: 
encephalitis and other 
clinically important 
irAEs 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
pembrolizumab 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic 
control (in case of T1DM).   

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6.4 Dose Delay/Modifications Guidelines for Pralatrexate-Associated Adverse Events 
Pralatrexate dose modifications will be allowed according to the criteria outlined in Table 6.4.1, Table 
6.4.2, and Table 6.4.3. 
Exceptions: 
- 
For patients who develop severe renal impairment (eGFR or CrCl 15 to < 30 mL/min/1.73m2) while 
on treatment with pralatrexate at the 30 mg/m2 dose level, the dose of pralatrexate upon 
recovery will be reduced to 15 mg/m2. 
- 
For patients who develop severe renal impairment (eGFR or CrCl 15 to < 30 mL/min/1.73m2) while 
on treatment with pralatrexate at the 20 mg/m2 dose level or lower, pralatrexate will be 
permanently discontinued. 
Treatment may be delayed to allow sufficient time for recovery. Patients whose treatment is delayed 
because of pralatrexate-related toxicity should be evaluated at weekly intervals (or less) until adequate 
recovery has occurred. A patient who has not received pralatrexate for more than 28 days since last study 
drug administration should be discontinued from further pralatrexate treatment. Any patient who 
requires a pralatrexate dose modification due to toxicity should continue to receive the modified regimen 
for the remainder of the study unless agreed otherwise with the overall study PI or their designee. For 
patients who require a pralatrexate dose reduction, for any reason, leucovorin should continue to be 
administered at the specified dose and schedule. For patients who require doses of pralatexate to be 
omitted due to mucositis (Table 6.4.1), leucovorin dosing should continue per protocol. For patients who 
require doses of pralatrexate be omitted for an adverse event other than mucositis or stomatitis (Table 
6.4.2 and Table 6.4.3), leucovorin treatment should be stopped until the patient resumes pralatrexate 
treatment. Safety assessment and routine clinical care should be followed at all times. 
Table 6.4.1 Dose Modifications for Mucositis, based on NCI CTCAE Version 5.0 
Mucositis Grade 
on Day of Treatment 
Action 
Dose Upon Recovery to ≤Grade 1 
Grade 2 
Omit pralatrexate dose  
Continue prior pralatrexate dose  
Grade 2 recurrence 
Omit pralatrexate dose 
Reduce pralatrexate by one dose 
level (e.g. should be lowered to 20 
mg/m2 if receiving 30 mg/m2, 15 
mg/m2 if receiving 20 mg/m2) 
Grade 3 
Omit pralatrexate dose 
Hold pembrolizumab 
Reduce pralatrexate by one dose 
level 
Resume pembrolizumab 
Grade 4 
Permanently discontinue pralatrexate 
Hold pembrolizumab 
If not probably or definitely related 
to pembrolizumab, pembrolizumab 
resumption can be considered in 
discussion with Study PI  
Table 6.4.2 Dose Modifications for Hematologic Toxicities 

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Blood Count 
on Day of Treatment 
Duration of 
Toxicity 
Action 
Dose Upon Restart 
Platelet ≤25,000/µL 
1 week 
Omit pralatrexate dose 
Hold pembrolizumab 
Continue prior pralatrexate dose 
Resume pembrolizumab 
2 weeks 
Omit pralatrexate dose 
Hold pembrolizumab 
reduce pralatrexate by one dose 
level 
Resume pembrolizumab 
3 weeks 
Permanently stop 
pralatrexate 
Hold pembrolizumab 
Pembrolizumab resumption can be 
considered in discussion with Study 
PI 
ANC 500-1,000/µL with 
fever 
OR 
ANC <500/µL 
1 week 
Omit pralatrexate dose, give 
GCSF support 
Hold pembrolizumab 
Continue prior pralatrexate dose 
with GCSF support 
Resume pembrolizumab 
2 weeks or 
recurrence 
Omit pralatrexate dose, give 
GCSF support 
Hold pembrolizumab 
reduce pralatrexate by one dose 
level with GCSF support 
Resume pembrolizumab 
3 weeks or 2nd 
recurrence 
Permanently stop 
pralatrexate  
Hold pembrolizumab 
Pembrolizumab resumption can be 
considered in discussion with Study 
PI 
ANC= absolute neutrophil count, GCSF=granulocyte colony stimulating factor, GMCSF= granulocyte macrophage colony 
stimulating factor. 
Table 6.4.3 Dose Modifications for all Other Pralatrexate-Related Toxicities 
Toxicity Grade  
On Day of Treatment 
Action 
Dose Upon Recovery to 
≤Grade 1 
Grade 3 
Omit pralatrexate dose 
reduce pralatrexate by one 
dose level 
Grade 4 
Permanently stop pralatrexate therapy 
--- 

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7.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST 
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) as 
defined in the relevant regulations and reporting to all applicable parties, including but not limited to the 
COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 
7.1 Assessment of Adverse Events 
The site Investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy (available from the DCC). Adverse events will 
be characterized using the descriptions and grading scales found in NCI CTCAE v5.0. A copy of the scale 
can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm.  
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
• 
Unrelated – The event is clearly NOT related to study treatment, and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
• 
Unlikely – The event is unlikely related to the study treatment, and is most likely related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
• 
Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration, but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
• 
Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.  
Definite – The event is clearly related to the study treatment, as it follows a reasonable temporal sequence 
from the time of drug administration and a known response pattern to the study drug, and is not 
reasonably explained by other factors such as the participant’s condition, therapeutic interventions, or 
concomitant drugs. 
7.2 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
The investigator must immediately notify the Study PI/ DCC via an expedited report. 

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7.3 Adverse Events of Special Interest (AESI) Requiring Expedited Reporting 
7.3.1 
Immune-related AEs 
An immune-related adverse event (irAE) is defined as an adverse event that is associated with drug 
exposure and is consistent with an immune-mediated mechanism of action and where there is no clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to 
support an irAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the irAE. 
7.3.2 
Overdose 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater 
(≥5 times the indicated dose). No specific information is available on the treatment of overdose of 
pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event 
of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
No specific information is available on the treatment of pralatrexate overdosage. If an overdose occurs, 
general supportive measures should be instituted as deemed necessary by the treating physician. 
Although there has been no formal or definitive evaluation of the effect of leucovorin following an 
overdose of pralatrexate, it has been established in clinical studies that leucovorin reduces pralatrexate 
toxicity, and based on the mechanism of action of pralatrexate, the prompt administration of leucovorin 
should be considered. 
7.3.3 
Abnormal Liver Function Tests 
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. 
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. 
7.4 Pregnancies 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported 
to them) that occurs during the trial. 
Efforts must be made by the investigator to follow the outcome of pregnancy outcome per institutional 
policies.  
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. If the newborn is healthy additional follow-up is not necessary.  
Any pregnancy related event described above must be reported to the Study PI/ DCC immediately 
within 24 hours of awareness. Protocol therapy is to be discontinued immediately. 

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7.5 Adverse Event (AE) collection guidelines 
o During Cycles 1 & 2, all grade toxicities with start and stop dates will be reported in the eCRFs. 
o After Cycle 2 until the end of the safety follow-up period (30-days post-last dose for AE or 90 days 
post-last dose for SAE), the highest grade AND all Grade 3+ toxicities (regardless of whether 
highest grade or not) per cycle and all SAEs with start/stop dates will be reported in the eCRFs. 
7.6 Routine AE Collection and Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation. Routine AE 
reporting will occur via data entry into the study eCRF. AEs will be monitored by the Protocol Management 
Team (PMT). AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must also be 
reported in routine study data submissions. 
AEs recorded in the CRF include: 
o All events considered unrelated, unlikely, possibly, probably or definitely related to protocol 
therapy. 
o Any Grade 1-5 during the DLT period (cycles 1 and 2), the highest grade AND all Grade 3+ toxicities 
(regardless of whether the highest grade or not) after cycle 2 during each cycle and during the 
safety follow-up period. 
o All SAEs. 
7.7 Expedited Reporting 
Table 7.7 indicates what events must be reported expeditiously. 
Table 7.7 Criteria for Expedited Reporting  
Time point 
What to report expeditiously 
From the signing of the consent to 
study completion 
All unanticipated problems 
 
From Screening until Day 1 of 
protocol therapy 
 
All SAEs related to protocol procedures 
 
Pregnancy and lactation 
 
Any reason for not starting Day 1 of protocol therapy 
 
For the time period beginning at 
treatment through 90 days following 
cessation of treatment, or 30 days 
following cessation of treatment if 
the subject initiates new anticancer 
therapy, whichever is earlier  
 
 
All SAEs regardless of relationship to protocol therapy, study 
procedure, underlying disease or concomitant treatment. 
 
Death due to any cause other than progression of the cancer under 
study. 
 
All AEs that meet the definition of an unanticipated problem. 
 
Overdose of either agent. 
 
Pregnancies and lactation. 
 
Abnormal liver function tests 
 
Discontinuation of protocol therapy due to unusual or unusually 
severe AE considered related to protocol therapy  
For participants yet to initiate anti-
cancer therapy: From Day 1 of 
therapy up to 120 days post-last 
pembrolizumab dose 
 
Pregnancies and lactation. 
Post Safety follow-up to removal 
from study 
 
All SAEs that are considered possibly, probably, or definitely related 
to pembrolizumab 
NOTE: All events reported expeditiously require follow-up reporting until the event is resolved, stabilized, or 

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determined to be irreversible by the investigator.  
The DCC should be consulted prior to ending the follow-up of events that have stabilized. 
7.7.1 
Expedited reporting guidelines (COH only) 
7.7.1.1 To the COH DSMC/IRB 
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
This includes all SAEs and UPs that meet COH DSMC/IRB expedited reporting criteria that occurred at COH 
and non-COH sites. For non-COH sites, the DCC will be responsible for reporting (see section 7.7.2) 
7.7.1.2 To Participating Investigators 
▪ Report all expedited reportable AEs to participating investigators as an IND Safety Report occurring 
within 30 calendar days of receipt of sponsor (lead site) notification, and indicate whether or not a 
protocol and/or consent form change is required. A cover letter will indicate the protocol title, the 
IND#, whether the FDA was informed (if applicable), and, for non-COH sites, a statement that the 
report should be submitted to their local IRB for review if applicable per local IRB policy. 
 
▪ Forward to participating sites all IND safety reports received from Merck and Acrotech Biopharma, LLC, 
indicating whether a consent form or protocol change is required within 30 days of notification to Study 
PI. 
7.7.2 
Expedited reporting guidelines (non-COH sites only) 
7.7.2.1 To the DCC/Study PI 
All events that meet the criteria specified in Table 7.7 will be reported to the DCC and Study PI within 
24 hours of notification that the event met the expedited reporting criteria. 
1. Sites are to report to their local IRB per their site’s specific institutional and IRB guidelines. As soon 
as possible, non-COH sites will provide to the COH DCC copies of the IRB submission and 
corresponding IRB response. 
2. Document/describe the AE/UP on each of the following: 
a. MedWatch 3500A or local IRB submission document* 
MedWatch 3500A is downloadable form at http://www.fda.gov/medwatch/getforms.htm 
*The local IRB submission document may be used if the document template is approved 
by the DCC 
b. Expedited Reporting Coversheet. A modifiable Microsoft Word document is available from 
the DCC. An electronic signature on the document will be accepted. 
3. Scan and email above documents to the Study PI (aherrera@coh.org) and DCC@coh.org with the 
subject title as “Herrera Pembro-PDX SAE COH IRB #17501”.  
a. If available, sites may include the local IRB submission for this event in the submission.  
4. If an email receipt from DCC personnel is not received within one working day, please email 
DCC@coh.org. 
 

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7.8 Reporting to the FDA 
The PI or designee will be responsible for contacting the Office of IND Development and Regulatory Affairs 
(OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will assist the PI with the 
preparation of the report and submit the report to the FDA in accordance with the approved City of Hope 
Clinical Research Adverse Event and Unanticipated Problem policy. 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, regardless of the site of occurrence, will be reported 
as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
- Any unexpected fatal or life threatening adverse experience associated with use of the drug must 
be reported to the FDA no later than 7 calendar days after initial receipt of the information [21 
CFR 312.32(c)(2)] 
- Any adverse experience associated with use of the drug that is both serious and unexpected must 
be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
- Any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 
The final IND report will be distributed to the Study PI and DCC. If it is determined that the IND safety 
report requires a change to the protocol or the consent form, the DCC will include instructions to 
participating sites for local IRB reporting.  
In addition, on behalf of the study PI, OIDRA will submit annually within 60 days of the anniversary date 
of when the IND went into effect, an annual report to the FDA which is to include a narrative summary 
and analysis of the information of all FDA reports within the reporting interval, a summary report of 
adverse drug experiences, and history of actions taken since the last report because of adverse drug 
experiences. 
7.9 Reporting to Industry Partners 
o Report to Merck using a MedWatch form, regardless of the site of occurrence, any expedited 
AEs within 2 working days of being aware of the event. The initial report will be as complete as 
possible and include an assessment of the causal relationship between the event and the study 
agent(s).  Information not available at the time of the initial report will be documented on a follow-
up report and submitted to Merck.  
The Merck protocol number will be included on expedited reports (or on the fax cover letter).  A 
copy of the fax transmission confirmation of the expedited report to Merck will be retained with 
the patient records. 
 
Merck Global Safety  
Attn: Worldwide Product Safety 
Fax: (215) 993-1220 
 
o Notify and forward information related to Serious Adverse Events (SAEs) to Acrotech 
Biopharma, LLC via facsimile or e-mail using the MedWatch form, whether the SAE is unexpected 
or not based on the product investigator’s brochure, and whether drug-related or not based on 

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clinical investigator’s assessment, within 24 hours of becoming aware of the event. Every effort 
should be made to provide complete and accurate information on the MedWatch form. 
Forms should be e-mailed to: 
E-mail:  DrugSafety@acrotechbiopharma.com   
Please cc: NKapoor@acrotechbiopharma.com for all correspondence 
 
o Report to Merck aggregate safety at time of COH PMT report. 
o Forward to Merck and Acrotech Biopharma, LLC copies of initial/annual/final FDA IND 
submissions. 

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8.0 AGENT INFORMATION 
8.1 Pembrolizumab 
Please refer to the IB for a detailed description. 
As of September 2017, pembrolizumab is FDA approved for advanced melanoma, metastatic non-small 
cell lung cancer, recurrent or metastatic head and neck cancer, relapsed/refractory classical Hodgkin 
lymphoma, advanced/metastatic urothelial carcinoma, unresectable or metastatic microsatellite 
instability-high cancer or mismatch repair deficient solid tumors, and advanced/metastatic gastric cancer. 
Refer to the package insert for a detailed description of the indications. Pembrolizumab is not approved 
for PTCL. 
8.1.1 
Other Names 
KEYTRUDA®, MK-3475. 
8.1.2 
Description and Molecular Weight 
Type IgG4 kappa monoclonal 
Source: Humanized (from mouse) 
Target: PD-1 receptor 
Molecular weight:  147 kDa 
8.1.3 
Mechanism of Action  
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell 
proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling 
through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. 
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with 
PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-
tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased 
tumor growth. 
8.1.4 
Pharmacokinetics 
Half-life elimination: 22 days (per package insert). 
8.1.5 
Human Toxicity 
See Section 6.1.1. 
8.1.6 
Formulation  
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in single-use 
Type I glass vial containing 100 mg/4 mL of pembrolizumab. The product is preservative-free, latex free 
solution which is essentially free of extraneous particulates.  
Pembrolizumab Solution for Infusion vials are filled to a target of 4.25mL (106.25mg) to ensure recovery 
of 4.0mL (100mg).  

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8.1.7 
Storage and Stability 
8.1.7.1 Non-diluted product 
Pembrolizumab Solution for Infusion, 100 mg/ 4 mL vial: pembrolizumab Solution for Infusion vials should 
be stored at refrigerated conditions 2 - 8 °C (36 - 46 °F) and protected from light. Do not shake and do not 
freeze. Vials should be stored in the original box to ensure the drug product is protected from light. 
8.1.7.2 Reconstituted and diluted solutions  
Pembrolizumab should not be mixed with other diluents. 
From a microbiological point of view, diluted solution should be used as soon as possible after 
preparation. 
Pembrolizumab solutions (which contain no preservative) may be stored at room temperature for a 
cumulative time of up to 6 hours. The 6-hour countdown begins when the vial is pierced and includes 
room temperature storage of  admixture solutions in the IV bags and the duration of infusion. (Please 
note this 6-hour timeframe is to provide a microbial control strategy. The microbial clock only starts when 
the product stopper is pierced and not when the vial is removed from the refrigerator).  
In addition, IV bags may be stored under refrigeration at 2°C to 8°C (36 °F to 46 °F), total cumulative 
storage time at room temperature and refrigeration should not exceed 24 hours.  
Temperature monitoring records are required when pembrolizumab admixture solution is refrigerated 
during storage or transfer. Only a period with recorded 2-8 °C can be accounted for refrigerated time. 
Time when temperature is above 8 °C and below 25°C should be deducted from a 6-hour room 
temperature storage time bucket.  
If refrigerated, allow the IV bags to come to room temperature prior to use. 
8.1.8 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the agent. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.1.9 
Preparation 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal 
saline) or regional equivalent or 5% Dextrose Injection, USP (5% dextrose) or regional equivalent and the 
final concentration of pembrolizumab in the infusion solutions should be between 1 mg/mL and 10 mg/ml. 
8.1.10 Administration 
Refer to Section 5.8.1. 
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to 
administration. Discard the drug product vial if visible particles are observed. In addition, the following 
precautions should be observed: 
•   Do not use pembrolizumab if discoloration is observed. 
•   Do not shake or freeze the vial(s). 

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•   Do not administer the product as an intravenous (iv) push or bolus. 
•   Do not combine, dilute or administer it as an infusion with other medicinal products.  
8.1.11 Supplier 
The agent will be supplied free of charge by Merck. 
8.1.12 Ordering 
Sites will be provided with an ordering form. 
8.1.13 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent (investigational or free of charge) using a drug accountability 
log. 
8.1.14 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to participants, and the amount remaining at the conclusion of the 
trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according 
to applicable federal, state, local and institutional guidelines and procedures. Destruction will be 
documented in a drug accountability log. 
8.2 Pralatrexate 
Please refer to the IB for a detailed description. Pralatrexate is indicated for the treatment of patients 
with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) with an Objective Response Rate (ORR) 
of 27%.57 
8.2.1 
Other Names 
FOLOTYN®, DIFOLTA. 
8.2.2 
Description and Molecular Weight 
Pralatrexate is a 10-deazaaminopterin analog of the DHFR inhibitor methotrexate, with a propargyl 
substitution at the carbon-10 (C-10) position. The molecular weight of pralatrexate is 477.5 g/mol. 
The structural formula of pralatrexate is shown below: 
 
Pralatrexate is a 1:1 racemic mixture of S- and R- diastereomers at the C10 position (indicated with *). 

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The molecular formula of pralatrexate is: C23H23N7O5 
8.2.3 
Mechanism of Action  
Pralatrexate is a folic acid analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. 
Similar to what has been reported for methotrexate, cellular uptake of pralatrexate is thought to occur 
via the RFC-1 protein. Inside the cell, pralatrexate is polyglutamated by folylpolyglutamyl synthase (FPGS), 
an enzyme involved in polyglutamation of reduced natural folates. Therefore, pralatrexate may also act 
as a competitive inhibitor for polyglutamation of natural folates. Further, it is believed that the addition 
of glutamate residues to pralatrexate leads to increased intracellular half-life (t1/2), thus allowing for 
prolonged drug action in malignant cells.56 
Treatment with pralatrexate leads to depletion of thymidine and other biological molecules, the synthesis 
of which depends on 1-carbon transfer. Depletion of thymidine results in inhibition of DNA replication and 
thus interference with cell proliferation. 
8.2.4 
Pharmacokinetics 
Refer to package insert.57 
8.2.5 
Human Toxicity 
See Section 6.1.2. 
8.2.6 
Formulation  
Refer to package insert. 
8.2.7 
Storage and Stability 
Pralatrexate Injection should be stored refrigerated (2-8ºC) and protected from light. Refer to package 
insert. 
8.2.8 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the agent. 
Appropriate mask, protective clothing, eye protection, gloves, and Class II vertical-laminar-airflow safety 
cabinets are recommended during preparation and handling. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
8.2.9 
Preparation 
Follow package label instructions. 
8.2.10 Administration 
Refer to Section 5.8.2. 
8.2.11 Supplier 
Pralatrexate is commercially available and will be sourced locally as per standard of care. 

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9.0 CENTRAL REVIEW & CORRELATIVE/ SPECIAL STUDIES 
9.1 Biomarker Research 
Immunologic and genomic biomarkers have been associated with tumor response to immunotherapy, 
including checkpoint inhibitors like pembrolizumab. We propose to evaluate a series of exploratory 
immunologic and genomic correlatives to explore the association between each biomarker and response 
or resistance to combined pembrolizumab and pralatrexate therapy. The correlative studies described 
below are exploratory in nature, and meant to be hypothesis-generating -they will not be powered for 
statistical significance. The below description is an anticipated rather than an exact list of studies that will 
be performed, as the investigators reserve the right to adjust the studies to be performed as techniques 
evolve and new data may become available that is relevant to the study agent and/or study population. 
Correlative studies will mainly be performed in the laboratories of Peter Lee, MD, Chair of the City of Hope 
Beckman Research Institute Division of Cancer Immunotherapeutics and Tumor Immunology, and John 
Chan, MD, Professor of Pathology at City of Hope Medical Center. 
 Immunologic Biomarkers: 
PD-L1 expression in tumor cells is a biomarker for response to anti-PD1 therapy in solid tumors.61 PD-L1 
expression has also been demonstrated in all HL patients tested who responded to PD-1 inhibition with 
pembrolizumab or nivolumab.43,62 Furthermore, the pattern and spatial relationship between PD-1 and 
PD-L1-expressing cells are associated with response in patients with melanoma treated with 
pembrolizumab.63  
The presence, abundance, and composition of tumor infiltrating lymphocyte (TIL) populations in various 
tumor types are associated with clinical outcome.64-66 In addition, the presence of certain TIL populations, 
particularly CD8+ T-cells, and their spatial orientation in tumors is associated with outcome after 
immunotherapy, including PD-1 blockade with pembrolizumab.63,67 Using high-resolution spectral analysis 
and automated scanning of tissue sections, the Lee laboratory at City of Hope has developed a technique 
for quantitative, spatial IHC analysis of TIL and other immune cell subsets in a tumor. The Lee lab has 
demonstrated that spatial grouping patterns of TILs and dendritic cells differ between tumor-draining 
lymph nodes and normal lymph nodes and are associated with outcome in patients with breast cancer.68,69 
We will evaluate the relationship between PD-1, PD-L1, and PD-L2 expression, and potentially other 
checkpoint receptors/ligands by immunohistochemistry (IHC) in pre-treatment tumor samples and 
response to study therapy. We will perform quantitative, spatial IHC analysis using the Vectra system in 
the Lee laboratory, including PD-1, PD-L1, PD-L2, other checkpoint receptors/ligands, dendritic cells, 
tumor associated macrophages,70 TILs including regulatory T-cells, and possibly other immune cell subsets 
and explore the association with response to study therapy. We will also analyze changes in immune cell 
subsets by flow cytometry on peripheral blood mononuclear cells (PBMCs) at baseline and during 
treatment and explore the association with response to study therapy. Cytokine analyses may be 
performed on the plasma portion of these samples. 
 Genomic Biomarkers: 
Genomic signatures define distinct subsets of T-cell lymphomas and are associated with outcome after 
standard therapy.71-73 Molecularly distinct subgroups exist even within PTCL histologic subtypes that are 
biomarkers of outcome and enhance prognostication over simple morphologic classification. Genomic 

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studies have elucidated tumor target-specific and microenvironmental characteristics that predict 
response to novel immunotherapies, including checkpoint inhibitors. One key target-specific genomic 
biomarker of response to immunotherapy is a tumor’s mutational burden. In clinical trials of melanoma 
patients treated with the anti-CTLA-4 antibody, ipilimumab, and non-small cell lung cancer (NSCLC) 
patients treated with pembrolizumab, patients with a higher mutational load in pre-treatment tumor 
samples have a higher rate of durable clinical benefit, objective response rate, and improved survival 
compared to patients with fewer mutations.74,75 Nonsynonymous genetic mutations result in the 
formation of neoantigens that improve recognition of the tumor by the host immune system, which 
appears to drive anti-tumor responses in the enhanced effector cell milieu created by checkpoint 
blockade. Similarly, in melanoma patients who have durable, complete responses after adoptive TIL 
therapy, specific neoantigens resulting from nonsynonymous mutations can be identified that are 
responsible for the robust anti-tumor responses observed.76,77 
In addition to a tumor’s mutational profile, tumor gene expression patterns impact response to novel 
immunotherapies. Increased expression of genes that encode for immune-related targets, such as T-cell 
surface markers, immune receptors, and cytokines/chemokines, in pre-treatment melanoma tumor 
samples are associated with response to ipilimumab.78 Similarly, overexpression of immune-related genes 
in pretreatment tumors of patients with melanoma and NSCLC is associated with outcome after treatment 
with an antigen-specific tumor vaccine and immunostimulant.79 
We will explore whether genomic signatures as determined for example by mutational or gene expression 
profiles in pre- and post-treatment tumor samples are associated with response and outcome after 
pralatrexate plus pembrolizumab therapy. 
 Circulating tumor DNA: 
The detection of circulating tumor DNA (ctDNA) has been studied in lymphoma. Next-generation 
sequencing (NGS)-based ctDNA detection performed by NGS of the immunoglobulin (Ig) or T-cell receptor 
(TCR) genes can identify ctDNA in the peripheral blood mononuclear cells (PBMC) and plasma (cell-free 
DNA) at diagnosis in a range of lymphomas, including classical Hodgkin lymphoma and diffuse large B-cell 
lymphoma (DLBCL).80-83 In addition, ctDNA levels correlate with treatment response in DLBCL, and the 
persistence or recurrence of ctDNA during and after upfront therapy is associated with subsequent DLBCL 
relapse.82,83 Ig/TCR-NGS assessment of can detect ctDNA in patients with PTCL prior to and after allogeneic 
stem cell transplantation.84 While the Ig-NGS method is powerful, the investigation of only Ig and TCR 
genes limits its sensitivity, resulting in a sizable minority of patients in whom the assay is not applicable. 
Meanwhile, ctDNA assessment using NGS for recurrent mutations and rearrangements has been explored 
in DLBCL, and the method appears feasible and highly sensitive.85,86. 
We will explore the performance of ctDNA assessment in the peripheral blood by capture-based NGS for 
recurrent somatic mutations in PTCL and explore the value of ctDNA as a biomarker of response to study 
therapy. 
9.2 Tumor tissue 
Each subject will have available archival tissue from a biopsy that was performed after the most recent 
systemic therapy or a fresh core or excisional biopsy of a tumor lesion (performed as standard of care) 
prior to starting study therapy. Exception can be granted by the PI if a biopsy is not feasible and/or safe. 
If feasible and safe, all subjects will also undergo biopsy of a tumor lesion at the time of disease 
progression (as part of standard of care). 

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9.2.1 
Tumor tissue handling guidelines 
9.2.1.1 Guidelines for paraffin-embedded specimens  
Using the formalin-fixed paraffin embedded (FFPE) tissue block, the following samples will be processed 
for correlative studies:  
o If tissue block is available submit (e.g. archived at participating study site): 
 
6 paraffin scrolls measuring 10 μm thick placed into a Nunc tube and frozen at -
80° C AND 
 
10 x 5 micron unstained slides 
o If tissue block is unavailable (e.g. archived at external site): 
o submit 20 x 5 μm unstained slides 
o 5 of these unstained slides will be processed according to the QualTek Sample 
Handling Manual. 
9.2.1.2 Guidelines for fresh tumor tissue processing  
Non-COH sites: 
After core biopsies are obtained for standard of care diagnostic purposes, 3 core biopsies (or fewer if it is 
not feasible to take 3 biopsies for research purposes) or 3 portions (1cm x 1cm) of excisional biopsy tumor 
specimens should be flash frozen and kept at -80oC until batch shipment. 
COH only: 
Three core biopsies OR 3 separate tissue sections from excisional biopsies should be submitted. If fewer 
than 3 core biopsies are available because of safety, then 1 or 2 cores may be submitted. 
Core biopsies:  
Three core biopsies will be obtained for diagnostic purposes and 3 (if feasible) similar additional cores will 
be obtained for research.  
The research portion of the specimen (banking): 
o One core biopsy will be snap frozen in OCT fixative, and an additional half of a core will be 
snap frozen without OCT fixative.  
o Half of a core will be finely minced in a 10cm petri dish and frozen at -80° C in a Nunc tube in 
1 ml of RPMI-1640 medium containing 20% fetal calf serum and 10% DMSO, then will be 
transferred to liquid nitrogen.  
o Half of a core will be processed for DNA and RNA extraction according to the manufacturer’s 
recommendation.  
o The final half of a core biopsy will be processed to dissociate the cells, with the cell suspension 
cryopreserved in liquid nitrogen. 
Excisional biopsies:   

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o An approximately 1cm x 1cm tumor sample will be divided into 5 equal portions and 
processed as described for core biopsies. 
The diagnostic portion of the specimen:  
o Process in a routine fashion by hematopathology. Using the formalin-fixed paraffin embedded 
(FFPE) tissue block, 15 x 5 micron unstained slides will be obtained 
 
5 of these unstained slides will be processed according to the QualTek Sample Handling 
Manual. 
9.2.1.3 Labeling of samples 
Samples will be labeled with the study number, institution, subject ID (issued by DCC), date, time point of 
collection (i.e. baseline or progression), and if applicable patient initials.  
9.2.1.4 Sample shipment and receiving lab 
Tissue specimens collected at the above indicated time points will either be taken to (COH only) or batch-
shipped (non-COH sites) to COH Pathology Core. For all sites, please include the Correlative Tissue form 
(Appendix G) with your shipment. 
Please note that samples should be batch shipped from non-COH sites on Monday to Wednesday in time 
for receipt Tuesday to Friday. Refer to Appendix H for tissue shipping details. 
 
9.3 
Correlative blood collection 
9.3.1 
Overview and Time points 
Peripheral blood (PB) will be collected prior to study treatment/procedures on C1D1, C2D1, C4D1, C5D1, 
and at EOT*. Refer to Table 9.3.1 for details.Table 9.3.1 Overview of correlative blood studies 
Time points of 
collection 
Total 
volume 
collected 
Tube type 
Receiving laboratory 
Type of 
analysis (non-
exhaustive) 
C1D1, C2D1, C4D1 
20 ml 
Green-top (sodium or lithium 
heparin) 
APCF 
FACS/Cytokine 
C1D1, C2D1, C5D1, 
and at EOT* 
20 ml 
Purple-top (K+EDTA) 
(For all COH patients) 
OR 
Cell-free DNA BCT® (Streck) 
(For all non-COH patients) 
APCF 
ctDNA/MRD 
*EOT time point: correlative blood will not be collected if a correlative blood sample for ctDNA/MRD 
(purple-top/cell-free DNA BCT® tube) was collected within the prior 8 weeks. 
APCF = Analytical Pharmacology Core Facility (COH). 
 

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9.3.2 
Labeling of blood samples 
Label tubes with COH protocol #, subject ID (issued by DCC), institution (for non-COH sites), date and 
actual timepoint of collection (e.g. D1C1 for Day1 of Cycle 1), and if applicable patient initials. 
 
9.3.3 
Blood collection 
9.3.3.1 Notifying the receiving laboratory 
Before a scheduled blood collection (at least one day in advance) e-mail Leslie Smith-Powell (LSmith-
Powell@coh.org) or Stephanie Lee (stlee@coh.org) at the Analytical Pharmacology Core Facility (APCF) to 
inform them of a pending collection. 
 
9.3.3.2 Order of draw for the research blood samples 
Please draw purple-top/ Cell-free DNA BCT® (Streck) tubes before the green-top tubes. 
Any heparin in the collection tube of the line used to draw the blood in a purple tube/ Cell-free DNA BCT® 
tube will make it unusable. 
If a purple tube/ Cell-Free DNA BCT tube immediately follows a heparin (green-top) tube in the draw order 
(for example if the last clinical/non-research sample was collected in a green-top tube), please collect a 
non-additive or EDTA tube as a waste tube prior to collection in the purple tube/ Cell-Free DNA BCT tube. 
If applicable, Cell-Free DNA BCT tubes can also be drawn after the EDTA tube and before the fluoride 
oxalate (glycolytic inhibitor) tube.  
 
9.3.3.3 Collection and post-collection guidelines 
 
Refer to Table 9.3.3 for collection and post-collection instructions. 
 
Refer to Appendix I and Appendix J for blood collection form and blood shipping guidelines, respectively. 

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Table 9.3.3. Blood sample collection and post-collection instructions. 
Tube Type 
Collection details 
Site of 
collection 
Post-collection instructions 
Green-top 
1- Blood samples will be collected 
from an indwelling venous catheter 
or by venipuncture. 
2- Invert tubes eight times after 
collection. 
3- Immediately place the tubes on 
ice. 
COH 
Promptly deliver the blood samples on ice to the APCF, 
Shapiro room 1042 for processing within 4 hours. 
Non-COH 
Ship overnight at ~+4oC to APCF laboratory. See Appendix J. 
Include with shipment: 
- Blood sample collection form (Appendix I). 
- Copy of latest CBC results (with differential) and date of test. 
Purple-
top 
Same as for green-top. 
COH 
Only 
Promptly deliver the blood samples on ice to the APCF, 
Shapiro room 1042 for processing within 4 hours. 
Cell-free 
DNA BCT® 
(Streck)* 
1- Blood samples will be collected 
from an indwelling venous catheter 
or by venipuncture. 
Prevention of backflow: 
(Because cell-free DNA BCT® contain 
chemical additives)  
a. Keep patient’s arm in the downward 
position 
during 
the 
collection 
procedure. 
b. Hold the tube with the stopper in the 
uppermost position so that the tube 
contents do not touch the stopper or 
the end of the needle during sample 
collection.  
c. Release tourniquet once blood starts 
to flow in the tube, or within 2 minutes 
of application. 
2- Fill tube completely. 
3- Remove tube from adapter and 
immediately mix by gentle 
inversion 8 to 10 times. 
4- Do not freeze samples. Store 
samples at 18-25oC until shipment. 
Non-COH 
Sites only 
Ship to APCF laboratory. See Appendix J. 
Include with shipment: 
- Blood sample collection form (Appendix I). 
- Copy of latest CBC results (with differential) and date of test. 
 
* Tubes are stable when stored at 2-300C through expiration date. Do not use expired tubes. If there is 
any indication of cloudiness or visible precipitate immediately contact the the COH Data Coordinating 
Center (DCC). Contact information: E-mail: DCC@coh.org.  

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9.3.4 
Sample Processing by APCF (COH) 
All blood samples will be processed at COH APCF. External (non-COH) sites will only be expected to collect 
and ship whole blood to COH APCF. 
Blood samples will be kept on a rocker set at low speed to mimic circulation and avoid clot formation until 
processing.  
 
Green-top tubes (PBMCs AND plasma), for FACS/Cytokine assays: 
(Process within 4h of collection for COH samples OR upon receipt of non-COH samples). 
 
 Centrifuge for 10 min at 1800g at 4oC. Both supernatant and pellet will be used. 
 Plasma: 
- 
The resulting upper plasma layer from each tube will be drawn up sequentially into a 
sterile 5 mL syringe and pushed through a sterile 0.2/0.8 micron disposable filter.  
- 
The filtered plasma will then be transferred in 500 µL aliquots into multiple appropriately-
labeled Starstedt microfuge tubes.  
- 
To one aliquot, add 0.5 mL glycerol/0.02% sodium azide solution to dilute the plasma 
50/50 v/v. Keep the diluted plasma sample at -20˚C and do not freeze.  
- 
All the remaining plasma aliquots will be stored frozen at -80˚C until ready for testing. 
 PBMCs: 
- 
Dilute the blood remaining in the green-top tubes used to prepare plasma above 1:1 with 
Hank’s Balanced Salt Solution (or equivalent) in a sterile conical centrifuge tube. 
- 
Isolate PBMCs by Ficoll-gradient separation per COH APCF procedures. 
- 
PBMCs samples will be stored in liquid nitrogen until use. 
 
 

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Purple-top and Cell-free BCT tubes (Plasma and PDWB), for sequencing assays: 
 
Purple-top 
(~20 mL) 
 
(Collected 
from COH 
patients 
only) 
Plasma and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
1. Centrifuge for 10 minutes at 1800 x g at 4°C.  
2. Remove the tubes from the centrifuge. Do not disturb the 
cellular layer.  
3. Extract plasma carefully. 
a. Do not disturb the buffy coat while pipetting plasma; leave 
~3-4mm of plasma behind to ensure the buffy coat is 
undisturbed. 
b. Save the PDWB portion (see below).  
4. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.   
5. Mix the remaining PDWB.  
6. Freeze at -80°C in 1-2mL aliquots.  
 
 
Cell-free 
DNA BCT  
(~20 mL) 
 
(Collected 
from non-
COH 
patients 
only) 
Plasma and 
Plasma 
depleted 
whole blood 
cells (PDWB) 
1. Centrifuge for 10 minutes at 1600 x g at room temperature. 
2. Remove the upper plasma layer and transfer to a new conical 
tube. Save the PDWB portion (see below). 
3. Centrifuge the plasma at 16000 x g for 10 minutes.  
4. Collect the plasma. 
5. Freeze plasma at -80°C in 1-2mL aliquots.  Do not fill tubes 
beyond 70% capacity.  
6. Mix the remaining PDWB.  
7. Freeze at -80°C in 1-2mL aliquots. 

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10.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated.  
Table 10 Study Activity Calendar  
Protocol Activity 
Screening 
(Days 
-28 to D1) 
Protocol Therapy (Cycles)a, c, m 
 (± 3 Days for all time points except g) 
EOTp 
Follow-upw 
 
To be repeated (except e and l) 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Safety 
postb 
Responseq 
(Every 12 
weeks) 
Survivalz 
(Every 12 weeks) 
D1 
D8 D1 D8 D1 D8 D1 D8 D15g D1 
D8 
D1 D8 D1 D8 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Con. Med. review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Post-study anti-cancer ther. status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Pralatrexate 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Leucovorind 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vitamin B12e 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Folic acidn 
X 
X 
 
 
 
 
AE review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Exam. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy Test o 
Xk 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Xs 
 
 
PT/INR and aPPT 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, Plt 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistryu 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Protocol Activity 
Screening 
(Days 
-28 to D1) 
Protocol Therapy (Cycles)a, m 
 (± 3 Days for all time points except g) 
EOTp 
Follow-upw 
 
To be repeated (except e and l) 
 
 
1 
2 
3 
4 
5 
6 
7 
 
Safety 
postb 
Responseq 
(Every 12 
weeks) 
Survivalz 
(Every 12 weeks) 
D1 
D8 D1 D8 D1 D8 D1 D8 D15g D1 
D8 
D1 D8 D1 D8 
Urinalysisx 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid Testv 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PET-CT or CT N/C/A/Ph 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Xr 
 
X 
 
Archival or Newly Obtained Tumor 
Tissue Collection 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
 
 
Bone Marrow Aspirate and Biopsy j 
Xy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Blood Collection 
 
X 
 
X 
 
 
 
Xl 
 
 
Xl 
 
 
 
 
 
Xt 
 
 
 
* Tests to be performed within 28 days of treatment initiation.  
a. In the absence of a delay due to toxicity, each treatment cycle lasts 21 days ± 3 days. 
b. Safety visit to occur 30 (-2/+7) days post-last dose of protocol therapy. At the end of the treatment, each subject will 
be followed for 30 days for adverse event monitoring, and 90 days for severe adverse events and events of clinical 
interest. Safety follow up may be extended until resolution/stabilization of reportable AEs. 
c. 
Protocol therapy will continue for a maximum of 24 months until progressive disease, unacceptable toxicity, withdrawal 
of consent, pregnancy of the subject, non-compliance, or administrative reasons. 
d. Leucovorin will be administered orally three times daily (every 8 hours) for 2 days for a total of 6 doses beginning 24h 
(+/- 2h) after each dose of pralatrexate is administered. Refer to Section 5.13.2. 
e. Vitamin B12 (1 mg IM) will be administered anytime within 10 weeks prior to initiation of pralatrexate (per pralatrexate 
product insert) and can be administered during screening, and will be administered every 3 cycles. Administration 
should continue during the full course of pralatrexate therapy and for 30 days after the last dose of pralatrexate. Refer 
to Section 5.13.2. 
f. 
Vital signs: Weight, heart rate, blood pressure, respiration rate, and temperature.  Height required only at baseline. 
g. To be done between D15 and D21 (-3 days). 

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h. Disease staging is performed at screening and every 4 cycles until disease progression or off study therapy. Disease 
staging will be by either PET/CT (preferred) or CT scan, but, in patients with FDG-avid disease, it will be preferred (but 
not mandatory) to have PET/CT at baseline, Cycle 4 and every 8 cycles thereafter. Note: if there is no evidence of neck 
involvement by lymphoma at baseline, CT of chest, abdomen and pelvis (C/A/P) can be performed instead of N/C/A/P 
at subsequent re-staging. 
i. 
Tumor biopsy tissue will be obtained after routine diagnostic biopsy is done with the patient’s consent. Exception can 
be granted by the PI if a biopsy is not feasible and/or safe. For the EOT time point, tumor tissue will be collected from 
a standard of care tumor biopsy performed at the time of lymphoma relapse/progression (if such a biopsy is 
performed), unless the tumor is inaccessible or there is a safety concern. 
j. 
Following initial screening, and unless clinically indicated, bone marrow specimens will be collected only to confirm CR.  
k. 
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. 
l. 
Do not repeat this time point for correlative blood collection: peripheral blood is collected prior to study 
treatment/procedures on C1D1, C2D1, C4D1, C5D1, and at EOT (see also footnote t). 
m. Day 8 labs/visits are set up because of pralatrexate administration on these days. If a patient discontinues pralatrexate 
(and continues with pembrolizumab alone), these Day 8 labs/visits can be omitted. 
n. Folic acid supplementation is to begin within 10 days (as early as possible) prior to the first dose of pralatrexate 
administration (per pralatrexate product insert). However, if folic acid was not taken but MMA (methylmalonic acid) 
and HCY (homocysteine) levels were checked and are in normal range at screening, the investigator can decide to start 
study therapy immediately. Administration should continue during the full course of pralatrexate therapy and for 30 
days after the last dose of pralatrexate. Refer to Section 5.13.2. 
o. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancy 
testing will also be performed whenever an expected menstrual cycle is missed or when pregnancy is otherwise 
suspected. 
p. Assessments to be performed within 10 days of treatment discontinuation (except tumor imaging, see footnote r). 
Assessments performed after last dose of study agent and within 7 days of the decision to end treatment may serve as 
EOT assessments. 
q. For participants yet to progress. Follow-up will occur every 12 weeks (-/+ 7 days) starting from last on-treatment scan. 
After one year, the imaging time point will occur every 18 weeks (+/- 7 days). Response Follow-up will be performed 
until progression or off study, and for at least one year in each patient who did not progress yet. 
r. 
PET-CT (or CT) at time of discontinuation (EOT) will only be performed in patients who discontinue treatment for disease 
progression. Note: if a previous scan was obtained within 4 weeks prior to the date of discontinuation, then repeating 
the scan at treatment discontinuation is not mandatory. For patients who discontinue treatment for other reasons than 
disease progression (e.g. for toxicity, CR): PET-CT (or CT) will not be performed at EOT and will be performed 12 weeks 

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after their last scan, and according to the follow-up schedule thereafter (refer to footnote q for the frequency of scans 
during the follow-up period). 
s. 
Pregnancy test will be performed at the safety visit (30 days post last dose of protocol therapy). 
t. 
EOT time point: correlative blood will not be collected if a correlative blood sample for ctDNA/MRD (purple-top/cell-
free DNA BCT® tube) was collected within the prior 8 weeks. 
u. Serum chemistry panel to include: glucose, Blood Urea Nitrogen (BUN), creatinine, uric acid, total protein, albumin, 
magnesium, calcium, inorganic phosphorus, sodium, potassium, chloride, total CO2 or bicarbonate, total bilirubin, direct 
bilirubin (if total bilirubin is elevated above the upper limit of normal), alkaline phosphatase, ALT, AST, and LDH. 
v. 
Thyroid test includes TSH only. 
w. Please refer to Section 5.11 for details about the Follow-up period. 
x. 
Urinalysis to include blood, glucose, protein, specific gravity, and microscopic exam (if abnormal). 
y. 
Bone marrow biopsy at screening is not mandatory, and should only be performed if clinically indicated (e.g. for 
cytopenias). 
z. 
Participants who end Response Follow-up will enter Survival Follow-up. Survival assessment to occur bi-annually or as 
requested by the Study PI via medical record review, review of social security registry, or telephone call. 

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11.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
11.1 Response/Progression 
Disease response/progression will be evaluated using 2014 Lugano Classification (see Appendix B) 8,11. 
Participants who meet the definition of progressive disease per Lugano Classification should be evaluated 
using the LYRIC criteria10 (see Appendix C). The ORR and CR rate will also be estimated according to the 
International Harmonization Project response criteria (Cheson 2007).9  
PET-CT or diagnostic quality CT of the neck, chest, abdomen, and pelvis (N/C/A/P) with IV contrast will be 
performed at baseline (within the screening window, 28 days) prior to initiation of study therapy, and 
then after initiation of study therapy during cycle 4 and every 4 cycles thereafter until disease progression 
or off study therapy. Refer to study calendar (footnote r) for disease staging at EOT. Disease staging will 
be by either PET/CT (preferred) or CT scan, but, in patients with FDG-avid disease, it will be preferred (but 
not mandatory) to have PET/CT at baseline, Cycle 4 and at least every 8 cycles thereafter. In patients with 
FDG-avid disease, CR must be confirmed with PET/CT. Patients who enter CR with study therapy can be 
monitored with diagnostic quality CT scans thereafter until disease progression. MRI may be performed 
at the investigator’s discretion for lesions not well-visualized by CT, or if CT with intravenous contrast is 
contraindicated. PET-CT and CT results will be read by radiology at each study site and investigator 
response based on radiology reading will be performed. Lymphoma response assessment based on PET-
CT/CT will be based on the 2014 Lugano Classification (Appendix B).8,11 
Note: if there is no evidence of neck involvement by lymphoma at baseline, CT of chest, abdomen and 
pelvis (C/A/P) can be performed instead of N/C/A/P at subsequent re-staging. 
Following initial screening, and unless clinically indicated, bone marrow specimens will be collected only 
to confirm CR. 
For patients with progression of disease on imaging, it is strongly recommended that a confirmatory 
biopsy (performed as standard of care) be obtained whenever possible. Note that only an FDG-negative 
PET scan will be considered complete remission in patients whose tumor was FDG-avid at baseline. 
11.2 Clinical Endpoint Definitions 
Overall Response Rate (ORR): Defined as the proportion of patients that have a documented CR or PR at 
any time during study treatment. 
Complete Response (CR) rate: Defined as the proportion of patients that have a documented CR at any 
time during study treatment. 
Duration of Response (DOR): Defined as the time from the first achievement of PR or CR to time of PD. 
Patients who never achieve PR or CR are excluded. Patient who has not had disease progression/relapse 
at last follow-up is censored at the time of last follow-up.   
Overall Survival (OS): Defined as time from initiation of study therapy to death from any cause.  If a patient 
is alive at the last evaluation time period, survival time is censored at the time of last follow-up. 
Progression-Free Survival (PFS): Defined as the time from initiation of study therapy to the first 
observation of disease relapse/progression or death from any cause, whichever occurs first. If the patient 
has not progressed relapsed or died, the patient is censored at the time of last follow-up. 
Toxicity: Toxicity and adverse events will be recorded using the NCI CTCAE 5.0 scale. Observed toxicities 
will be summarized by type (organ affected or laboratory determination such as absolute neutrophil 

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count), severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), date of onset, 
duration, reversibility, and attribution.  
Unacceptable Toxicity: defined as one of the following AEs that is at least possibly related to study 
treatment: 
• 
Any ≥ grade 3 immune-related AE (IrAE) that does not resolve to grade ≤ 1 within 7 days with the 
exception of: 
o 
Grade 3 immune-related hepatitis if ALT or AST < 8 x ULN or total bilirubin < 5 x ULN. 
o 
Grade 3 asymptomatic endocrinopathy. 
o 
Inflammatory response attributed to local antitumor response. 
o 
Vitiligo or alopecia of any grade. 
 
• 
Any non-hematologic grade 4 AE that does not resolve to grade ≤ 1 within 7 days with the exception 
of: 
o 
Grade 4 asymptomatic lipase or amylase without evidence of pancreatitis 
o 
Grade 4 asymptomatic laboratory abnormalities including, but not limited to, hypo- or 
hyperglycemia, hypo- or hypernatremia, hypo- or hyperkalemia, hypo- or hypermagnesemia, 
hypo- or hyperphosphatemia, or hyperuricemia that do improve within 48 hours to Grade ≤ 2 with 
supportive measures. 
o 
Inflammatory response attributed to local antitumor response. 
 
• 
Any Grade 5 AE. 
12.0  STATISTICAL CONSIDERATIONS 
12.1  Study design overview 
This is a multi-center, single arm phase 1/2 study of pembrolizumab plus pralatrexate for patients with 
relapsed/refractory PTCL. Patients will receive 21-day cycles of the combination therapy up to 2 years 
until disease progression, unacceptable toxicity, or until the patient meets any criteria for removal from 
protocol therapy in Section 5.10, whichever is earlier. Response will be assessed every 4 cycles. The phase 
1 dose-escalation portion of the study, with 2 dose levels and 1 possible de-escalation dose level (Table 
5.3), will determine the MTD and the RP2D of the combination therapy. After the completion of the phase 
1 portion, additional patients will be enrolled and treated at the RP2D in the Phase 2 portion. Another 
primary endpoint is overall response rate per the Lugano classification.8 Secondary endpoints include CR 
rate, duration of response, overall survival, progression-free survival, ORR and CR rate per the 
International Harmonization Project response criteria (Cheson 2007)9 and response status based on LYRIC 
criteria10.  
12.1.1 Phase 1 design 
During the Phase 1 portion of the study, a modified, more conservative version of the Rolling 6 design of 
Skolnik et al will be employed.87 In this design, at most, 3 patients will be under observation for DLT on 
the current test dose level at any time. DLT observation period is 2 cycles (defined in Section 5.5). DLTs 
are defined in Section 5.5. Patients who are not evaluable for DLT (defined in Section 5.7), i.e., those who 
did not receive the doses of pembrolizumab during DLT period (not due to DLT) or those who missed any 
doses of pralatrexate during DLT period (not due to DLT), will be replaced. Once 3 patients are evaluable 

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with no patient at that dose level experiencing a DLT, the dose can be escalated, or up to 3 additional 
patients may be treated at the current dose level. No more than 6 evaluable patients will be accrued to 
any dose level. Escalation will terminate as soon as ≥ 2 patients experience DLT at a given dose level. If 
1/6 patients experience DLT at the current dose level, the dose will be escalated to the next higher level. 
If more than 1/6 patients experiences DLT, then the next lower dose will be expanded. MTD will be 
declared the highest dose level at which 6 evaluable patients have been treated and, at most, 1/6 patients 
experiences DLT. The MTD will be considered the RP2D, unless the PI chooses a lower dose level, based 
on toxicity in subsequent cycles. 
These rules are outlined in the Table below. 
 
Table 12.1.1. Dose Escalation Rules 
 
# Patients on Current Level 
Action 
With DLT^ 
Evaluable  
Evaluable + At Risk^ 
 
0 
0 
1-2 
Accrue next patient at this level* 
0 
0 
3 
Hold accrual 
0 
1 
1-3 
Accrue next patient at this level 
0 
1 
4 
Hold accrual 
0 
2 
2-4 
Accrue next patient at this level 
0 
2 
5 
Hold accrual 
0 
3-6 
3-6 
Accrue next patient at the next higher level*,+ 
1 
1 
1-2 
Accrue next patient at this level 
1 
1 
3 
Hold Accrual 
1 
2 
2 
Accrue next patient at this level 
1  
2 
3-4 
Hold accrual 
1 
3-5 
3-5 
Accrue next patient at this level 
1 
3-5  
6 
Hold accrual 
1 
6 
6 
Accrue next patient at the next higher level* 
2** 
any 
any 
Accrue next patient at next lower level (max 6) 
^: 
DLT: a patient with a documented DLT 
 
Evaluable: a patient who is either fully evaluable for toxicity for the purpose of dose escalations or has a DLT 
 
At Risk: a patient who is on treatment and has not yet passed the evaluation period nor had a DLT 
*:  During the dose-escalation portion, if higher dose level is already closed, the next lower dose will accrue to a 
total of 6 patients, with 2 or higher DLTs requiring further dose de-escalation. 
+: 
Although under this scenario escalating to the next higher dose level is suggested, additional patients can be 
accrued to the current level -up to n=6 patients. 
**:  Patients treated on a higher dose will have their treatment modified to the dose below the dose level with 2 
DLTs, if pending patients have DLT. 

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12.1.2 Phase 2 Design 
In the phase 2 portion, patients will be treated at the RP2D. The phase 2 portion of this study will 
implement a Gehan two-stage design88 to estimate the ORR and to evaluate the activity of the 
combination therapy. Patients treated during the Phase 1 portion at the RP2D will be included in the Phase 
2 evaluations if they are evaluable for response, defined as patients who received at least 1 dose of 
pembrolizumab and at least 1 dose of pralatrexate and had at least 1 disease assessment (Section 5.7). 
The sample size is based on the desire to estimate the response rate with approximately 10% standard 
error, and early stopping if the combination is unexpectedly ineffective. In the pivotal PROPEL trial, the 
overall response rate (ORR) in 109 evaluable patients who received pralatrexate as a single agent was 
29%, including 12 (11%) complete responses (CR) and 20 (18%) partial responses (PR).5  
The phase 2 portion of the study is expected to evaluate a minimum of 7 and a maximum of 24 patients, 
including the patients treated at RP2D during the Phase 1 portion that are evaluable for response. At stage 
1, if 0 responses are seen in the first 7 evaluable patients (including up to 6 patients enrolled during the 
Phase 1 portion that are evaluable for response), the study will be terminated and the true ORR will be 
declared ≤35%. If at least 1 patient responds, the trial will continue to the second stage. At stage 2, a total 
of 24 patients will be evaluated (including up to 6 patients enrolled during the Phase 1 portion that are 
evaluable for response).  
This design provides for estimation of the response rate with approximately 10% standard error. The 
standard error will be 9.4%-10.2% after 24 patients if the ORR rate is 30%-70%. The maximum width of 
the 95% exact binomial confidence interval for ORR will be 42% after 24 patients. Under this design if the 
ORR is >35%, there would be ≥95% chance of at least one response among the first 7 patients. 
12.2 Sample size accrual rate 
The expected sample size is 30 evaluable patients: 12 during the Phase 1, and 18 additional patients in 
the Phase 2, assuming 6 patients treated at RP2D during the Phase 1 are also evaluable for response. 
Between 3-4 high-volume PTCL centers, we expect to accrue 12 patients at COH and 30-36 total in 48 
months. The expected sample size may go up to 36 evaluable patients if the higher 2 dose levels are not 
safe and the lowest dose level is safe (18 in the Phase 1 and 18 in the Phase 2). Patients 
evaluable/inevaluable for Phase 1/2 portions are described in Section 5.7. Considering replacement of 
inevaluable patients, the maximum study accrual is set at 40 patients.   
12.3 Statistical analysis plan 
12.3.1 
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including age, gender, medical history, and prior 
therapy, will be summarized using descriptive statistics. For continuous variables, descriptive statistics 
(number [n], mean, standard deviation, standard error, median (range) will be provided. For categorical 
variables, patient counts and percentages will be provided. 
12.3.2 
Toxicity Analysis 
Observed toxicities will be summarized by type (organ affected or laboratory determination such as 
absolute neutrophil count), severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), 
date of onset, duration, reversibility, and attribution.  

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12.3.3 
Analysis of Anti-tumor Activity 
This study will aim to obtain an estimate of the anti-tumor activity of the study combination. ORR will be 
calculated as the proportion of evaluable patients that have confirmed CR or PR, as defined according to 
the 2014 Lugano Classification, exact 95% confidence intervals will be calculated for these estimates. 
Response rates will also be evaluated based on number and type of prior therapy(ies). Duration of 
response, as well as progression-free survival and overall survival will be estimated using the product-limit 
method of Kaplan and Meier. As secondary endpoints, the ORR and CR rate will also be estimated 
according to the International Harmonization Project response criteria (Cheson 2007).9 
Any patient treated at the RP2D, including those from the Phase 1 portion, will be included in efficacy 
analyses. Patients will be evaluable for efficacy assessment if they received at least one dose of 
pralatrexate and at least one dose of pembrolizumab and underwent at least one response assessment. 
As discussed in Section 5.7, patients will be evaluable for efficacy if they discontinued study therapy prior 
to the first response assessment because of progression of disease rather than solely because of 
unacceptable toxicity, withdrawal of consent, or investigator’s decision.  
12.3.4 Safety Analysis and Stopping Rules for Excessive Toxicity or for Rapid Disease Progression 
Because of the unique immune-related adverse events (IrAEs) observed with checkpoint inhibitors, we 
will monitor for “unacceptable toxicity” (defined in Section 11.2) and treatment-related mortality at any 
time during study treatment with this new combination of drugs. This monitoring will include all patients 
treated on the study regardless of the dose levels they were on. The expected rate of “unacceptable 
toxicity” should not be >33%. If the rate of “unacceptable toxicity” is >33% after at least 6 patients are 
treated on study at any bi-annual safety review, or if a 2nd death that is at least possibly related to study 
treatment occurs regardless of the number of patients on study, accrual will be halted and a full review 
of these events will be performed by the City of Hope Data Safety Monitoring Committee (DSMC). Patient 
accrual will not resume until approved by the DSMC to do so. These rules are in addition to the bi-annual 
review of all toxicities submitted to the City of Hope Data Safety Monitoring Committee (DSMC). Patients 
with ongoing toxicity will be followed until resolution or stability. 
 
In addition, because of the evidence that PD-1 may act as a tumor suppressor in preclinical T-cell 
lymphoma models and the recent reports of rapid disease progression in patients with ATLL, a subtype of 
PTCL, we will also monitor for rapid progression of disease. If at any bi-annual safety review during the 
conduct of the study, and after at least 3 patients are treated on study, > 33% of patients who received at 
least one dose each of pembrolizumab and pralatrexate (regardless of the dose level or if during the phase 
1 or phase 2 portion of the study) experience rapid progression (i.e. an acceleration of disease activity 
with disease progression according to the 2014 Lugano classification prior to completion of 3 cycles of 
study therapy), the study accrual will be halted and a full review of these events will be performed by the 
City of Hope Data Safety Monitoring Committee (DSMC). Patient accrual will not resume until approved 
by the DSMC to do so. 

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13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial.  
The investigator or their designee will prepare and maintain adequate and accurate source documents.  
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system (EDC) that is compliant 
with 21 CFR Part 11.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
13.3 Case Report Forms/Data Submission Schedule 
The investigator is responsible for all information collected on participants enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the investigator. All case report forms must be completed by designated study personnel.  The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 14 calendar days of treatment administration 
Adverse Event Report Forms 
Phase 1/ Safety Lead-in: Within 7 calendar days of the 
assessment/notification 
Phase 2: Within 10 calendar days of the assessment/notification 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms  
Within 10 calendar days of the assessment 
Off Treatment/Off Study 
Forms 
Within 10 calendar days of completing treatment or being taken off study 
for any reason 
Follow up/ Survival Forms 
Within 14 calendar days of the protocol defined follow up visit date or call 
13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 

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14.0 ADHERENCE TO THE PROTOCOL 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate hazard(s) 
for the protection, safety, and well-being of a research participant. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. All protocol deviations and 
planned protocol deviations will be reported in accordance with the City of Hope Clinical Research 
Protocol Deviation policy. 
Non-COH Sites: 
Deviations meeting the criteria specified in the City of Hope Clinical Research Protocol Deviation policy 
(available from the DCC) will be reported to the DCC and Study PI within 24 hours of notification that the 
event occurred.  
Procedure for reporting deviations to the COH DCC: 
1. Document the deviation on the Deviation Reporting Coversheet or submit your site-specific 
protocol deviation log if the log format has been approved for use by the DCC. This modifiable 
Microsoft Word document is available from the DCC. An electronic signature on this 
document will be accepted.  
2. Scan and email the Deviation Reporting Coversheet or protocol deviation log to the Study PI 
(aherrera@coh.org) and DCC@coh.org within 24 hours of notification of the deviation with 
the email subject title of “Herrera Pembro-PDX Deviation COH IRB #17501”. If an email receipt 
from the DCC is not received within one working day, please email DCC@coh.org.  
Sites are to report to their local IRB and DSMC per their site’s specific institutional and IRB guidelines. As 
soon as possible, non-COH sites will provide to the COH DCC copies of the IRB and/or DSMC submission 
and corresponding response(s). 
15.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
15.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
15.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing 
that sponsor responsibilities are executed in accordance with federal regulations.  
15.3 Protocol Management Team (PMT) 
The Protocol Management Team (PMT), minimally consisting of the study PI, collaborating investigators, 
site investigators, research nurse, clinical research associate/coordinator, and the study biostatistician, is 
responsible for ongoing monitoring of the data and safety of this study, including implementation of the 
stopping rules for safety/toxicity. 

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The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations, and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed.  
15.4 Quality Assurance  
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, that the 
study is implemented in accordance with the protocol and regulatory requirements, and that the quality 
and integrity of study data and data collection methods are maintained.  Monitoring for this study will be 
performed by the City of Hope Office of Clinical Trials Monitoring (OCTM), within City of Hope’s Office for 
Safety and Data Quality.  
Details of clinical site monitoring are documented in the OCTM SOP and the Risk Based Monitoring (RBM) 
plan. These documents specify the frequency of monitoring, monitoring procedures, the amount of 
subject data to be reviewed, and the distribution of monitoring reports to the study team and the COH 
DSMC.  
15.5 Risk Determination  
This is a high risk study, as defined in the City of Hope Institutional DSMP.  This determination was made 
because this study involves a COH IND. 
15.6 City of Hope Data and Safety Monitoring Committee 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor study progress, 
compliance, toxicity, safety, and accrual data from this trial via the PMT Progress Report (submitted by 
the Study Principal Investigator according to the frequency outlined in the City of Hope Institutional 
DSMP). The DSMC is composed of clinical specialists who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the Protocol 
Management Team.  
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
16.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  

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 
Title 21 Part 312 – Investigational New Drug Application  
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable institutional research policies and procedures 
16.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 
56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study. Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Each participating non-COH institution must provide for the review and approval of this protocol and the 
associated informed consent documents by an appropriate IRB holding a current US Federal wide 
Assurance issued by and registered with the Office for Human Research Protections (OHRP). The protocol 
and consent will be reviewed and approved by the COH IRB before submission to a participating site IRB. 
The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator, and, for external sites, the possession of the DCC, before the 
study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
All participating sites must follow the lead institution’s IRB-approved protocol. 
16.4 Informed Consent 
Each participating non-COH institution will be provided with a model informed consent form. Each 
institution may revise or add information to comply with local and/or institutional requirements, but may 
not remove procedural or risk content from the model consent form. Furthermore, prior to submission to 
the site’s IRB (initial submission and amendments), the consent and accompanying HIPAA form, if 
separate to the consent, must be reviewed and approved by the DCC. 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document. In addition, they will review the experimental subject’s bill of rights if 
applicable, and the HIPAA research authorization form. Prospective participants will be informed that they 
may withdraw from the study at any time and for any reason without prejudice, including as applicable, 
their current or future care or employment at City of Hope or participating institution or any relationship 

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they have with City of Hope or participating institution. Prospective participants will be afforded sufficient 
time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the site investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
16.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form.  Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
16.6 Special and Vulnerable Populations 
16.6.1 Inclusion of Women and Minorities 
The study is open anyone regardless of gender, race or ethnicity.  Efforts will be made to extend the 
accrual to a representative population. If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
Pregnant women are excluded because the effects of study agent(s) on embryogenesis, reproduction, and 
spermatogenesis in humans are unknown. 
16.6.2 Exclusion of Pediatric Population 
Pediatric participants (< 18 years old of age) are excluded from this study since safety and effectiveness 
of protocol therapy has not been defined for the study population.  
Participants with a history of HIV are excluded due to concerns about inadvertent augmentation of 
infectious and/or inflammatory activity. 

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16.6.3 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population.  In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and local IRB approval. 
16.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
Source documents provided to the DCC for the purpose of auditing or monitoring will be de-identified and 
labeled with the study number, subject ID, and if applicable patient initials. 
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant specimens will be de-identified (coded) prior to submission to research laboratories. The 
specimens will be labeled with the study number, subject (accession) ID, date and timepoint of collection. 
The key to the code will be maintained in the COH clinical trials management system which is a secure 
environment.  

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16.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will be either: (a) discarded or (b) placed in a COH IRB approved biorepository with clinical 
information and potentially PHI attached. 
With regard to which option will apply, each site IRB may choose to either: (a) leave the determination to 
the participant via a question in the informed consent document, which would communicated to the study 
registrar (DCC) at the time of participant registration, OR b) may choose to make a single determination 
on behalf of their respective participants, and communicate that determination to their respective 
participants via the informed consent. 
16.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
16.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Pembrolizumab will be provided free of charge to participants. 
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier.  The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope or at the non-COH site to the injured participant. There are no 
plans for City of Hope to provide financial compensation in the event of physical injury to a participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
16.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI. Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope, Merck, 
Acrotech Biopharma, LLC, and participating non-COH institutions.  The publication or presentation of any 
study results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996.  

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In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier. 
 
 

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Smith SM, Burns LJ, van Besien K, et al. Hematopoietic cell transplantation for systemic mature T-cell non-
Hodgkin lymphoma. J Clin Oncol. 2013;31(25):3100-3109. 
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Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed 
or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636. 
4. 
Foss F, Advani R, Duvic M, et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory 
peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2014. 
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O'Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-
cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29(9):1182-1189. 
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APPENDIX A: PERFORMANCE STATUS 
ECOG Performance Scale 89 
Grade 
Descriptions 
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. 
 
 
 

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APPENDIX B: 2014 LUGANO RESPONSE CRITERIA 
Response 
Site 
CT-Based Response 
PET-CT Based Response 
Complete 
Response 
 
Complete radiologic response 
(all of the following) 
Complete metabolic response (even 
with a persistent mass) 
Lymph nodes and 
extralymphatic 
sites 
Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter (LDi).  
No extralymphatic sites of 
disease. 
Score ≤ 3* with or without a residual 
mass on 5-point scale†. 
It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic uptake or with 
activation within spleen or 
marrow (e.g., with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response 
may be inferred if uptake at sites 
of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal by morphology; if 
indeterminate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes and 
extralymphatic 
sites 
≥ 50% decrease in SPD of up to 
6 target measurable nodes 
and extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 
mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 
mm 
For a node > 5 mm X 5 mm, but 
smaller than normal, use 
actual measurement for 
calculation 
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size 
At interim, these findings suggest 
responding disease 
At end of treatment, these findings 
indicate residual disease 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ enlargement 
Spleen must have regressed by 
> 50% in length beyond 
normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan 
No response 
or stable 
disease 
 
Stable disease 
No metabolic response 
Target nodes/nodal 
masses, 
extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria 
for progressive disease are 
met 
Score 4 or 5† with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires at 
least 1 of the following 
Progressive metabolic disease 
Individual target 
nodes/nodal 
masses 
PPD progression: 
Score 4 or 5† with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal lesions 
An individual node/lesion must 
be abnormal with: 
Longest diameter (LDi) > 1.5 cm 
and 
Increase by ≥ 50% from PPD 
nadir and 
New FDG-avid foci consistent with 
lymphoma at interim OR end-of-
treatment assessment 

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Response 
Site 
CT-Based Response 
PET-CT Based Response 
An increase in LDi or shortest 
diameter (SDi) from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, 
the splenic length must 
increase by > 50% of the 
extent of its prior increase 
beyond baseline (e.g., a 15-
cm spleen must increase to 
>16 cm). If no prior 
splenomegaly, must 
increase by at least 2 cm 
from baseline 
New or recurrent splenomegaly 
Nonmeasured 
lesion 
New or clear progression of 
preexisting nonmeasured 
lesions 
None 
New lesions 
Regrowth of previously 
resolved lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm 
in any axis; if < 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable 
to lymphoma 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation).  
If uncertain regarding etiology of 
new lesions, biopsy or interval 
scan may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 
Measured dominant lesions:  
Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable 
in two diameters. Nodes should preferably be from disparate regions of the body and should include, where 
applicable, mediastinal and retroperitoneal areas.  
Non-nodal lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation.  
Nonmeasured lesions:  
Any disease not selected as measured, dominant disease and truly assessable disease should be considered not 
measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or 
measurable or that do not meet the requirements for measurability but are still considered abnormal, as well 
as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in extranodal 
sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 

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metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow 
activation as a result of chemotherapy or myeloid growth factors). 
 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an 
interim scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a 
score of 3 as inadequate response (to avoid undertreatment).  
 
†PET 5-point scale:  
1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to 
be related to lymphoma. 
Abbreviations:   
CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product 
of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of 
the perpendicular diameters for multiple lesions. 
 
 

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APPENDIX C: LYRIC CRITERIA 
Lugano Classification was developed based on treatment with cytotoxic agents 8. Immunotherapeutic 
drugs, may produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest as clinical responses after initial increases in tumor 
burden or even the appearance of new lesions. Thus, the 2014 Lugano Classification may not provide an 
accurate assessment of response to immunotherapeutic agents. Provisional modification of the Lugano 
criteria (LYRIC Criteria) may be used to assess participants who meet progressive disease per Lugano 
Classification 8,10. 
Complete Response 
Partial Response 
Progressive Disease 
Same as Lugano  
Same as Lugano  
As with Lugano with the following exceptions: 
 
Indeterminate response (IR) 
 
IR1: ≥50% increase in SPD of up to 6 measurable lesions in 
first 12 weeks of therapy without clinical deterioration 
 
IR2: <50% increase in the overall SPD with 
a. Appearance of a new lesion(s), or 
b. ≥50% increase in PPD of a lesion or set of lesions at 
any time during treatment 
 
IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size or number  
 
Patients with IR should continue on therapy and have repeat 
imaging after an additional 12 weeks (or sooner if clinically 
indicated). 
Progressive disease criteria in these patients will be met if:  
 
IR1: An additional increase in the target SPD of ≥ 10% 
between the first IR1 timepoint and the SPD being 
assessed; or an increase in ≥ 5mm in either dimension of 
at least one lesion for lesions ≤ 2cm and 10mm for lesions 
> 2cm. 
 
IR2: the new or growing lesion(s) should be added to the 
target lesions (total of no more than 6) and there is PD if 
the SPD if the newly defined set of target lesions has 
increased ≥50% from their nadir value (which may 
precede the IR time point). 
 
IR3: There is evidence of PD by an increase in lesion size 
or the development of new lesions. 
Abbreviations: SPD, sum of the product of the diameters; PPD, product of the perpendicular diameters. 
 
 
 
 

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APPENDIX D: NYHA CARDIAC GRADING CRITERIA 
 
Modified from Dolgin et al., 1994 90 
 
New York Heart Association Classification of Heart Failure 
Class I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not cause fatigue 
or dyspnea. 
Class II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking uphill, walking 
or stair climbing after meals, in cold weather, in wind or when under emotional stress causes undue 
fatigue or dyspnea. 
Class III 
Symptoms with less than ordinary physical activity. Walking one to two blocks on the level and 
climbing more than one flight of stairs in normal conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 
 
 

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APPENDIX E: CONTRACEPTION GUIDELINES 
Pembrolizumab may have adverse effects on a fetus in uterus.  Furthermore, it is not known if pembrolizumab has 
transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether 
due to having had a vasectomy or due to an underlying medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are either:  
o 
(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  
o 
 have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening; OR  
o 
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.   
Single method (one of the following is 
acceptable): 
o 
intrauterine device (IUD) 
o 
vasectomy of a female subject’s 
male partner  
o 
contraceptive rod implanted 
into the skin 
Combination method (requires use of two of the following): 
o 
diaphragm with spermicide (cannot be used in 
conjunction with cervical cap/spermicide) 
o 
cervical cap with spermicide (nulliparous women 
only)   
o 
contraceptive sponge (nulliparous women only)  
o 
male condom or female condom (cannot be used 
together)  
o 
hormonal contraceptive: oral contraceptive pill 
(estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection  
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.   
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) 
if pregnancy were to occur during the study.  In order to participate in the study subjects of childbearing potential 
must adhere to the contraception requirement (described above) from the day of study medication initiation (or 14 
days prior to the initiation of study 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 

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APPENDIX F: REGISTRATION COVERSHEET  
COH IRB#: A Phase 1/2 Study of Pembrolizumab plus Pralatrexate for Treatment of Relapsed or Refractory 
Peripheral T-cell Lymphomas 
 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-218-7904  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 

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APPENDIX G: CORRELATIVE TISSUE FORM (FOR ALL SITES) 
 
A copy of this form should accompany the sample shipments to COH Pathology Core. 
Non-COH sites: refer to Appendix H for shipping instructions to COH Pathology Core. 
 
COH IRB number: 17501 
Shipping date (MM-DD-YYYY):   ________/________/________ 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
Date of collection/ biopsy (MM-DD-YYYY):    ________/________/________ 
Time point:     
  Baseline       
  Progression 
Diagnosis: 
Tissue type (FFPE scrolls, slides, biopsies): 
Number of scrolls: 
Number of slides: 
 
 
 
 
 
 
CRA/Study Coordinator/Nurse Printed Name:   
CRA/Study Coordinator/Nurse Signature:   
Contact Number: 
 
 
 

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APPENDIX H: TISSUE SHIPPING GUIDELINES TO CITY OF HOPE PATHOLOGY CORE  
 
These guidelines apply to non-COH sites only. 
All biological material must be shipped according to applicable government and International Air 
Transport Association (IATA) regulations.  
Shipping guidelines can also be found on the FedEx website. 
 
1. Aim to ship samples on a Monday through Wednesday. If this is not feasible, advance 
arrangements should be made with City of Hope Pathology Core (DL-PATHCORE-
BiospecimenSupport@COH.org).   
2. Notify City of Hope Pathology Core (DL-PATHCORE-BiospecimenSupport@COH.org) of impending 
shipment. To request a FedEx shipping label, email DCC@coh.org and indicate the planned 
shipment date. 
3. Slides/ Blocks: Batch ship at room temperature via FedEx. During extreme heat, include 
refrigerated (not frozen) gel packs or gel insulators. 
It is recommended to ship samples via FedEx overnight (for a delivery by 3 pm or earlier the next 
day) or FedEx 2-day (with a morning delivery). During extreme heat, ship via FedEx overnight (for 
a delivery ideally by 10.30 am, or 3 pm the next day). 
4. Frozen samples should be batch shipped on dry ice via FedEx overnight (for a delivery by 10.30 
am the next day). The shipment should contain enough dry ice to last at least 72 hours. 
5. On the day of shipment, email the sample shipment information to City of Hope Pathology Core 
(DL-PATHCORE-BiospecimenSupport@COH.org). 
6. Ship samples with a copy of the correlative tissue form (Appendix G) and a copy of the pathology 
report to: 
 
Karen Miller 
COH Pathology Core 
City of Hope National Medical Center 
1500 E. Duarte Road 
Familian Science (Building 084), Room 1207 
Duarte, CA 91010 
Telephone: 626-218-8408 
Email: DL-PATHCORE-BiospecimenSupport@COH.org 
 
 

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APPENDIX I: CORRELATIVE BLOOD COLLECTION FORM FOR NON-COH SITES ONLY 
Subject ID (issued by DCC):   
Participant Initials (F, M, L) (if applicable): 
Institution: 
 
To be used by non-COH sites for the following blood samples being sent to COH APCF: 
 
Sample # 
Timepoint of 
Collection * 
Expected 
Volume 
Tube Type Used 
(Select One) 
Collected 
Volume 
Time of Collection 
Date of 
Collection 
Indicate 
which sample 
was collected 
1. 
 
Cycle 1, Day 1 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
20 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
2. 
 
Cycle 2, Day 1 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
20 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
3. 
 
Cycle 4, Day 1 
20 mL 
Green-top 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
4. 
 
Cycle 5, Day 1 
20 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
5. 
 
EOT** 
20 mL 
Cell-free DNA BCT 
_____ mL 
____:____ AM/ PM 
____/____/____ 
 
 
* Peripheral blood is collected prior to study treatment on Day 1 of each indicated cycle. 
**EOT time point: correlative blood will not be collected if a correlative blood sample for ctDNA/MRD (purple-top/cell-free DNA 
BCT® tube) was collected within the prior 8 weeks. 
A copy of this form should accompany the sample shipments to COH APCF. Refer to the blood shipping guidelines 
for shipping instructions to COH APCF (Appendix J). 
CRA/Study Coordinator/ Nurse Printed Name:   
Contact Number: 
CRA/Study Coordinator/ Nurse Signature:   
Date: 
 
 
 

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APPENDIX J: BLOOD SHIPPING GUIDELINES TO CITY OF HOPE APCF 
These guidelines apply to non-COH sites only, for the shipping of all green-top tubes and cell-free DNA 
BCT® (Streck) tubes. 
Follow the requirements for the proper packaging and shipping of biomedical material found in 42 CFR 
Part 72 - Interstate Shipment of Etiologic Agents Centers for Disease Control and Prevention, Office of 
Health and Safety Biosafety Branch. 
 
1. Aim to ship samples on a Monday through Wednesday. If this is not feasible, advance 
arrangements should be made with Leslie Smith-Powell (LSmith-Powell@coh.org) or Stephanie 
Lee (stlee@coh.org) or their representative. 
1. Blood samples in green-top tubes will be sent overnight at around +4oC with a refrigerated cool 
pack in an appropriate container via FedEx. Cell-free BCT tubes will be shipped together with 
green tubes for the first 2 time points. For the C5D1 and EOT time points, cell-free BCT tubes 
should be shipped as soon as possible but no more than 3 days after being drawn via overnight 
courier at ambient temperature. 
2. On the day of shipment, email Leslie Smith-Powell (LSmith-Powell@coh.org) or Stephanie Lee 
(stlee@coh.org) or their representative the FedEx shipment #. 
3. Ship samples with a copy of the correlative blood collection form (Appendix I) and a copy of the 
latest CBC results (with differential) and the date of the test to: 
 
Dr. Tim Synold 
Analytical Pharmacology Core Facility  
Shapiro 1042 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010