Pilot Study of Pembrolizumab in Untreated Extranodal, NK/T Cell Lymphoma, Nasal Type
Phase: PHASE2
Conditions: NK/T-Cell Lymphoma of Nasal Cavity (Diagnosis), NK/T-Cell Lymphoma of Nasopharynx (Diagnosis)
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 1 of 50 
 
 
 
MSK PROTOCOL COVER SHEET 
 
 
 
Pilot study of pembrolizumab in untreated extranodal, NK/T cell lymphoma, nasal type 
Principal Investigator/Department: Alison Moskowitz / Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 2 of 50 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
3.0 
BACKGROUND AND RATIONALE .................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................. 6 
4.1 
Design ............................................................................................................................. 6 
4.2 
Intervention ...................................................................................................................... 6 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................ 7 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................ 9 
6.1 
Subject Inclusion Criteria ................................................................................................. 9 
6.2 
Subject Exclusion Criteria .............................................................................................. 11 
7.0 
RECRUITMENT PLAN ..................................................................................................... 12 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 12 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 13 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................................. 16 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................ 26 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...................... 37 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 41 
14.0 BIOSTATISTICS ............................................................................................................... 41 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES43 
15.1 Research Participant Registration .................................................................................. 43 
15.2 Randomization............................................................................................................... 43 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 43 
16.1 Quality Assurance ......................................................................................................... 43 
16.2 Data and Safety Monitoring ........................................................................................... 44 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 44 
17.1 Privacy .......................................................................................................................... 45 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................ 45 
17.2.1 
 46 
18.0 INFORMED CONSENT PROCEDURES ........................................................................... 48 
19.0 REFERENCES ................................................................................................................. 49 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 3 of 50 
 
 
ISRT 
CR** 
Pembro 
cycles 3-4 
≤CR 
Disease progression*** 
 
 
ISRT 
 
 
SMILE x2 
PET* 
PET 
 
Pembro 
cycles 1-2 
 
 
Stage I, II 
20.0 
APPENDICES ................................................................................................................... 50 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a pilot study evaluating front-line treatment with pembrolizumab in extranodal NK (“natural 
killer”)/T-cell lymphoma (ENKTL). The primary endpoint is to assess the complete response rate 
after 4 cycles of pembrolizumab in untreated ENKTL. Treatment will differ for early stage (stage I or 
II) and advanced stage (stage III or IV) patients as outlined below. This study will enroll a total of 19 
patients (regardless of stage). 
Stage I, II: 
 
 
 
 
*PET-positive patients will undergo biopsy to evaluate for persistent disease 
**Or biopsy showing no evidence of lymphoma 
***Patients with an “indeterminant response” by the LYRIC criteria (evidence of disease progression 
on PET but with clinical improvement) can be considered for another 2 cycles of pembrolizumab 
after discussion with the MSK PI.1 See section 9.1 for details. 
Abbreviations: ISRT (involved site radiation therapy), SMILE (steroids, methotrexate, ifosfoamide, 
asparaginase, etoposide) 
 
Stage III, IV: 
 
Pembro x8 
(cycles 5-12) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 4 of 50 
 
 
 
 
 
 
 
*Patients with PET showing less than partial metabolic response may undergo biopsy to evaluate for 
persistent disease after discussion with PI. 
**Or biopsy showing no evidence of lymphoma 
***Patients with an “indeterminant response” by the LYRIC criteria (evidence of disease progression 
on PET but with clinical improvement) can be considered for another 2 cycles of pembrolizumab 
after discussion with the MSK PI.1 See section 9.2 for details. 
Abbreviations: ISRT (involved site radiation therapy), SMILE (steroids, methotrexate, ifosfoamide, 
asparaginase, etoposide), PMR (partial metabolic response) 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objectives: 
 
• 
Assess the complete response rate of pembrolizumab in untreated ENKTL. 
 
Secondary objectives: 
 
• 
Assess safety of pembrolizumab as front line therapy for ENKTL. 
• 
Assess the partial response rate and overall response rate of pembrolizumab in 
untreated ENKTL. 
• 
Assess response after 2 cycles of pembrolizumab according to the LYRIC criteria1 
• 
Determine 2-year progression free survival and overall survival for newly diagnosed 
ENKTL treated with pembrolizumab-based therapy 
• 
Explore mechanism of action and markers of response and resistance through 
assessment of baseline and on-treatment biopsies 
• 
Evaluate plasma Epstein-Barr virus (EBV) PCR as a marker of response to therapy 
and/or early predictor of relapse. 
PMR** 
Pembro 
cycles 3-4 
Less than PMR 
Disease progression*** 
Off-study 
treatment 
PET* 
PET 
 
Pembro 
cycles 1-2 
 
Stage III, 
IV 
Pembrolizumab 
cycles 5-16 
SMILE x3 (with 
ISRT if indicated) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 5 of 50 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
Extranodal NK/T-cell lymphoma 
ENKTL is a rare, aggressive lymphoma characterized by extranodal presentation (commonly 
but not always the upper aerodigestive tract), association with Epstein-Barr virus (EBV), and 
higher prevalence in Asia, South America, and Central America.2 ENKTL has traditionally 
been associated with poor prognosis, with 5-year overall survival of 49%.3 Poor outcomes 
are largely due to resistance to conventional chemotherapy, such as CHOP, due to 
overexpression of P-glycoprotein leading to multidrug resistance (MDR). Modern ENKTL 
regimens, such as SMILE (steroids, methotrexate, L-asparaginase, and etoposide), were 
designed to overcome the MDR phenotype, and as a result produce higher response rates 
than previously observed with CHOP-like regimens.4 Building upon the high efficacy 
observed with SMILE, since 2009 our practice has been to treat with a modified version of 
SMILE in patients with untreated early stage and advanced stage ENKTL.5 Early stage 
patients are treated with 2 cycles of modified SMILE followed by consolidation with involved- 
field radiation therapy; advanced stage patients receive 3 to 4 cycles of SMILE following by 
consideration for autologous or allogeneic stem cell transplant. In a recent analysis of 
patients with ENKTL treated at our institution from 1996 through 2014, the 2-year 
progression free survival for early stage and advanced stage patients were 56% and 18% 
respectively.6 Among the 26 early stage patients, introduction of SMILE was associated with 
improved outcomes. Of the 11 early stage patients who received SMILE, 2-year progression 
free survival was 83%, significantly better than observed for patients who received CHOP 
(p=0.03). On the contrary, despite high response rates, the impact of SMILE was 
disappointing for advanced stage patients in our series. Among 17 advanced stage patients, 
9 received SMILE of whom only 1 remained progression-free at 1 year. While the outcomes 
for our early stage patients are excellent, SMILE chemotherapy is associated with 
considerable toxicity such as neutropenic fever, renal insufficiency related to methotrexate, 
ifosfamide induced encephalopathy, as well as significant nausea and vomiting; therefore, 
strategies to reduce toxicity while maintaining excellent outcomes for early stage patients are 
warranted. For advanced stage patients, outcomes are poor despite incorporation of SMILE 
and transplant. Strategies to improve treatment efficacy in the advanced stage setting are 
therefore greatly needed. 
Rationale for Pembrolizumab and ISRT in ENKTL 
Virus-associated lymphomas are known to up-regulate PD-L1 on tumor cells and/or tumor 
associated macrophages, likely imparting reduced immune surveillance in these diseases. 
Five out of 6 ENKTLs (83%) evaluated by immunohistochemical staining expressed PD-L1, 
indicating the potential for PD-1 blockade in this disease.7 Impressive results for 7 patients 
with relapsed or refractory ENKTL treated with pembroliuzmab was initially presented by Dr. 
Yok-Lam Kwong at the T-cell lymphoma Forum in January 2017 and recently published in 
Blood.8 All patients had failed prior L-asparaginase containing therapies and 2 patients 
previously underwent allogeneic stem cell transplant. Furthermore, 5 of the 7 patients had 
evidence of hemophagocytic syndrome at the time of treatment. All patients responded to 
therapy, with 5 patients achieving CR or near CR and 2 patients achieving PR. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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Based upon the observed efficacy of pembrolizumab in relapsed and refractory ENKTL, we 
believe that pembrolizumab has the potential to fundamentally alter the treatment paradigm 
for newly diagnosed ENKTL. Since this population will likely not have had prior radiation 
therapy, we propose here a pilot study incorporating pembrolizumab in untreated ENKTL for 
both early and advanced stage patients, followed by involved site radiation therapy (ISRT) 
when appropriate. Since radiation promotes anti-tumor immunity by causing increased 
antigen release from irradiated tumor tissue, the combination of pembrolizumab with ISRT 
can enhance pembrolizumab’s impact on ant-tumor immunity. We aim to establish 
pembrolizumab’s efficacy in untreated ENKTL, evaluate for markers of response and 
resistance, and explore its mechanism of action. 
 
 
 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a pilot study evaluating front-line treatment with pembrolizumab in extranodal 
NK/T-cell lymphoma (ENKTL). The treatment will differ based upon stage as outlined 
below. 
4.2 
Intervention 
Early Stage (Stage I, II) ENKTL 
Newly diagnosed patients with early stage disease will initially receive 2 cycles of 
single-agent pembrolizumab, 200mg IVPB every 3 weeks followed by reassessment 
by PET. Patients with no evidence of disease progression will receive another 2 
cycles of pembrolizumab. In addition, patients with an “indeterminant response” by 
the LYRIC criteria (evidence of disease progression on PET but with clinical 
improvement) can be considered for another 2 cycles of pembrolizumab after 
discussion with the MSK PI.1 Patients who progress to stage III or IV ENKTL will 
come off treatment and receive subsequent standard of care treatment at the 
discretion of the treating physician. After 4 cycles of pembrolizumab, patients 
achieving complete response will receive involved site radiation (ISRT) and an 
additional 6 months of maintenance pembrolizumab. Patients who do not achieve 
complete response to pembrolizumab will undergo a biopsy. Those with pathologic 
complete response to treatment will receive the same treatment as those achieving 
complete response on PET (involved site radiation and an additional 6 months of 
maintenance pembrolizumab). Patients with less than complete response by PET or 
biopsy after 4 cycles of pembrolizumab will proceed to 2 cycles of SMILE 
chemotherapy and involved site radiation. 
(Refer to Stage I, II Schema in Section 1.0 Protocol Summary) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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Advanced Stage (Stage III, IV) ENKTL 
Newly diagnosed patients with advanced stage disease will initially receive 2 cycles 
of single-agent pembrolizumab, 200mg IVPB every 3 weeks followed by 
reassessment by PET. Patients with no evidence of disease progression will receive 
another 2 cycles of pembrolizumab. In addition, patients with an “indeterminant 
response” by the LYRIC criteria (evidence of disease progression on PET but with 
clinical improvement) can be considered for another 2 cycles of pembrolizumab after 
discussion with the MSK PI.1 After 4 cycles of pembrolizumab, those who achieve a 
partial metabolic response (PMR) to pembrolizumab will proceed to 3 cycles of 
SMILE chemotherapy, involved site radiation therapy (if indicated and according to 
institutional standards), followed by 10 months maintenance therapy with 
pembrolizumab. Patients who do not achieve partial metabolic response to 
pembrolizumab will undergo biopsy. Those with biopsy showing persistent lymphoma 
will come off study and receive treatment per discretion of treating physician. If the 
biopsy shows pathologic complete response to therapy, patients will receive the same 
treatment as those with PMR. 
(Refer to Stage III, IV Schema in Section 1.0 Protocol Summary) 
Hemophagocytic lymphohistiocytosis (HLH) 
Subjects with HLH may be considered for study regardless of the hematological 
criteria specified in Section 6.1. Cytopenias including hemoglobin <90 g/L, platelets 
<100 x 109/L, or neutrophils <1.0 x 109/L are characteristic of HLH per HLH-2004 
diagnostic criteria. For patients with HLH at baseline, dexamethasone is 
recommended with pembrolizumab administration. Patients with HLH should have 
enhanced blood count monitoring throughout the study. Patients with suspected HLH 
will receive dexamethasone 10mg/m2 daily for a minimum of 7 days followed by taper 
over 1-4 weeks as tolerated. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Pembrolizumab 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information. See Pharmacy Manual for detail information on handling and 
administration. 
5.1.1 Dispensing 
The study drug, pembrolizumab, will be supplied by Merck. Pembrolizumab will be 
shipped by Merck directly to each participating site. Receipt and dispensing of trial 
medication must be recorded by an authorized person at the trial site. The 
investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the 
subjects and the amount remaining at the conclusion of the trial. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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5.1.2 General Information: 
Generic Name: Pembrolizumab 
Commercial Name: Keytruda ® Solution for Infusion, 100mg/4mL vial 
Pembrolizumab (previously known as MK-3475 and SCH 9000475) is a potent and 
highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2 without ADCC or CDC activity. 
5.1.3 Formulation 
Pembrolizumab is a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for intravenous infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution 
contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
5.1.4 Clinical Pharmacology 
Mechanism of Action: 
PD-1 is an immune-checkpoint receptor that limits the activity of T lymphocytes in 
peripheral tissues. The PD-1 pathway is an immune control checkpoint that may be 
engaged by tumor cells to inhibit active T-cell immune surveillance. Pembrolizumab is 
a high affinity antibody against PD-1, which exerts dual ligand blockade of the PD-1 
pathway, including PD-L1 and PD-L2, on antigen presenting or tumor cells. By 
inhibiting the PD-1 receptor from binding to its ligands, Pembrolizumab reactivates 
tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and thereby 
also reactivates anti-tumor immunity. 
 
5.1.5 Pharmacokinetics and Drug Metabolism 
 
Absorption: Pembrolizumab is dosed via the IV route and therefore is immediately 
and completely bioavailable. 
 
Distribution: Consistent with a limited extravascular distribution, the volume of 
distribution of pembrolizumab at steady state is small (approximately 7.7 L; 
Coefficient of Variation (CV): 14%). As expected for an antibody, pembrolizumab 
does not bind to plasma proteins in a specific manner. 
 
Metabolism: Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its clearance. 
 
Excretion: The systemic clearance of pembrolizumab is - approximately 0.2 L/day 
(CV: 28%) and the terminal half-life (t½) is approximately 26 days (CV: 24%). 
 
Exposure to pembrolizumab as expressed by peak concentration (Cmax) or area 
under the plasma concentration time curve (AUC) increased dose proportionally 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 9 of 50 
 
 
within the dose range for efficacy. Upon repeated dosing, the clearance of 
pembrolizumab was found to be independent of time, and systemic accumulation was 
approximately 2.1-fold when administered every 3 weeks. Steady-state 
concentrations of pembrolizumab were reached by 18 weeks; the mean Cmin at 
steady-state was 23 mcg/mL during a regimen of 2 mg/kg every 3 weeks. 
 
5.2 
SMILE 
Refer to package insert for the drugs included in SMILE: methotrexate, leucovorin, 
ifosfamide, MESNA, etoposide, PEG-asparaginase, pegfilgrastim. 
5.3 
Involved Site Radiation Therapy (ISRT) Guidelines 
5.3.1 ISRT Volume 
ISRT will be employed according to the published ILROG guidelines for using ISRT 
for extranodal lymphomas.10 The pre-pembrolizumab gross tumor volume (pre- 
pembro GTV) will be determined using information from the initial PET/CT SIM. 
PET/CT SIM will be preferably performed with CT IV contrast with a 5-point mask and 
after a dental consultation. Body and arms position, immobilization, and use of Deep 
Inspiration Breath Hold will be determined by the attending Radiation Oncologist. 
Post-pembrolizumab/post-SMILE gross tumor volume (GTV) will be determined with 
information derived from the post-pembrolizumab/SMILE PET/CT SIM performed at 
the same conditions as the initial PETCT-SIM. Clinical treatment volume (CTV) and 
when relevant internal target volume (ITV) will always include the post- 
pembrolizumab/SMILE GTV and will account for pre-pembrolizumab GTV according 
to the quality of response to pembrolizumab (+/- SMILE), presence of organs at risk 
(OAR), and quality of imaging information. CTV will not include normal tissues like 
lung, heart, kidney, bowel, bone muscle or breast that are no longer involved after 
response to pembrolizumab (+/- SMILE). Planning treatment volume (PTV) will 
account for set-up variability and beam characteristics. Radiation treatment plan will 
be approved by an attending radiation oncologist. Intensity Modulated Radiation 
Therapy (IMRT) and 3-D conformal planning using photons and or electrons is 
allowed. 
 
 
5.3.2 ISRT Dose 
ISRT will be given once daily using fractions of 1.8 Gy. Total dose will be 45 Gy (25 
daily treatments) for patients who achieve a CR post-pembrolizumab (+/- SMILE). For 
patients who achieve less than CR, the dose may be increased to 50.4 Gy (28 daily 
treatments). 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 10 of 50 
 
 
• 
Histologic diagnosis of extranodal NK/T, nasal type cell lymphoma at the enrolling 
institution 
• 
18 years of age on day of signing informed consent. 
• 
Have a performance status of ≤ 1 on the ECOG Performance Scale. 
• 
Have measurable disease by PET/CT. 
• 
Demonstrate adequate organ function as defined in Table 2.0 below. 
 
Table 2.0 Adequate Organ Function 
System 
Laboratory Value 
Renal 
Serum creatinine OR 
Measured or calculated creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤ 1.5 X upper limit of normal (ULN) 
OR 
≥ 60 mL/min for subject with 
creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
≤ 3 X ULN for subjects with liver 
metastases 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver 
metastases 
Cardiac 
Ejection fraction 
≥ 50% 
Pulmonary 
Hemoglobin-adjusted diffusing 
capacity for carbon monoxide 
≥ 50% 
 
 
• 
Women of childbearing potential (WOCBP)* must have a negative urine or serum 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 
hours prior to receiving the first dose of study medication. 
o *A woman of childbearing potential is a sexually mature female who has 
not undergone a hysterectomy or bilateral oophorectomy; or has not been 
naturally postmenopausal for at least 24 consecutive months (i.e. has had 
menses at any time in the preceding 24 consecutive months) 
• 
Women of childbearing potential must be willing to use an adequate method of 
contraception 
o  Must agree to practice 2 effective methods of contraception from the time 
of signing the informed consent form through 120 days after the last dose 
of study therapy, or agree to completely abstain from heterosexual 
intercourse 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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• 
Male subjects of childbearing potential must agree to use an adequate method of 
contraception. 
o Male subjects, even if surgically sterilized (i.e. status post vasectomy) 
must agree to 1 of the following: 
▪ 
Practice effective barrier contraception during the entire study 
treatment period and through 120 days after the last dose of study 
therapy, or agree to completely abstain from heterosexual 
intercourse 
6.2 
Subject Exclusion Criteria 
• 
Received prior treatment for extranodal NK/T cell lymphoma 
• 
Medical illness unrelated to lymphoma, which, in the opinion of the treating 
physician and/or institutional principal investigator, makes participation in this 
study inappropriate. 
• 
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the 
first dose of study drug. Administration of killed vaccines is allowed. 
• 
Has a known additional malignancy that is progressing or has required active 
treatment within the past 2 years. Note: Participants with basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast 
carcinoma, cervical cancer in situ) that have undergone potentially curative 
therapy are not excluded. 
• 
Has known active CNS metastases and/or carcinomatous meningitis. 
• 
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients. 
• 
Has active autoimmune disease that has required systemic treatment in the past 
2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
• 
Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
• 
Has an active infection requiring systemic therapy. 
• 
Has a known history of Human Immunodeficiency Virus (HIV). 
• 
Has active Hepatitis B (defined as HBV DNA is detected) or known active 
Hepatitis C virus (defined as HCV RNA is detected) infection. 
• 
Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
subject’s participation for the full duration of the study, or is not in the best interest 
of the subject to participate, in the opinion of the treating investigator. 
• 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
• 
Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of trial treatment. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
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• 
Has had an allogenic tissue/solid organ transplant. 
 
 
7.0 
RECRUITMENT PLAN 
The clinical trial will be listed on the clinicaltrials.gov website. 
 
Patients seen in the inpatient or outpatient setting who meet eligibility criteria will be recruited 
to this study. At MSK, patients will be recruited through the Lymphoma Disease Management 
Teams. The Lymphoma Disease Management Team holds weekly interdepartmental 
meetings to identify study participants for open clinical trials. The principal investigator will be 
available to all patients for further questions and information through a contact number, 
which will be provided on the consent form. Similar recruitment procedures will be conducted 
at participating institutions. An attending physician of the Lymphoma or Hematology service 
will evaluate all patients. 
 
All eligible patients, regardless of sex and race, will be approached for participation. The 
investigators are aware of the NIH policy concerning inclusion of women and minorities in 
clinical research populations. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. Participation in the study is completely voluntary. 
Patients will be required to read, agree to, and sign an IRB-approved informed consent form 
prior to registration on this trial. Patients will not receive payment for their participation on this 
study. Patients are free to withdraw from the study without consequence at any time. 
 
A total of 19 participants will be enrolled on this study. Participants will be accrued at 
Memorial Sloan Kettering Cancer Center (MSK) and an external participating institution. 
Approximately 10 participants will participate from MSK. 
 
8.0 
PRETREATMENT EVALUATION 
Within 6 months of initiating treatment: 
• 
Hepatitis B surface antigen, core antibody 
• 
Hepatitis C antibody 
• 
HIV I/II antibodies 
Prior to initiation of treatment: 
• 
Patients will be required to have a biopsy that confirms extranodal NK/T cell 
lymphoma. If a biopsy is already done, 20 unstained slides from archived tissue will 
be requested for correlative studies. 
o Please refer to Section 10.1 Correlative Studies for more information on 
planned correlatives. 

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Within 4 weeks prior to initiation of treatment: 
• 
Referral to Radiation Oncology 
o MSK patients will be referred to MSK Main center 
• 
FDG-PET/CT Simulation [only for early stage patients who will receive radiation] 
o MSK patients will be referred to MSK Main center 
o Optional for advanced stage patients who will receive radiation 
• 
MRI nasal cavity (only for patients with nasal cavity disease) 
• 
PET/CT [only for patients not receiving radiation and being referred to Radiation 
Oncology] 
• 
Echocardiogram 
• 
Pulmonary function tests 
• 
ECG 
Within 14 days prior to initiation of treatment: 
• 
CBC 
• 
Comprehensive metabolic panel 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 Stage I, II ENKTL 
Newly diagnosed patients with early stage disease will initially receive the following study 
treatment: 
• 
Baseline FDG-PET/CT simulation will be done following an initial consultation in 
Radiation Oncology (main center) and prior to starting therapy 
• 
2 cycles of single-agent pembrolizumab, 200mg IVPB every 3 weeks 
• 
Reassessment by PET after 2 cycles of pembrolizumab 
o If no evidence of disease progression, another 2 cycles of pembrolizumab. 
o Patients with an “indeterminant response” by the LYRIC criteria (evidence of 
disease progression on PET but with clinical improvement) can be considered 
for another 2 cycles of pembrolizumab after discussion with the MSK PI.1 
o Patients with progression of disease without evidence of clinical improvement 
will proceed to 2 cycles of SMILE chemotherapy and ISRT. 
o Patients who progress to stage III or IV ENKTL will come off treatment and 
receive subsequent standard of care treatment at the discretion of the treating 
physician. 
• 
Reassessment by PET after 4 cycles of pembrolizumab 
o If CR response on PET, patients will begin 45 Gy of involved site radiation 
(ISRT) and an additional 6 months of maintenance pembrolizumab. ISRT will 
begin 2-6 weeks after cycle 4 of pembrolizumab. 
o Patients with less than CR will undergo a biopsy. If biopsy shows no 
evidence of lymphoma, patients will proceed with same treatment as those 
with PET CR. 

Memorial Sloan Kettering Cancer Center 
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o Patients with less than complete response by PET and persistent evidence of 
disease on biopsy after 4 cycles of pembrolizumab will proceed to 2 cycles of 
SMILE chemotherapy and ISRT. 
9.2 Stage III, IV ENKTL 
Newly diagnosed patients with advanced stage disease will obtain baseline FDG-PET/CT 
simulation after a Radiation Oncology consultation. They will initially receive 2 cycles of 
single-agent pembrolizumab, 200mg IVPB every 3 weeks followed by reassessment by PET. 
Patients with no evidence of disease progression will receive another 2 cycles of 
pembrolizumab. In addition, patients with an “indeterminant response” by the LYRIC criteria 
(evidence of disease progression on PET but with clinical improvement) can be considered 
for another 2 cycles of pembrolizumab after discussion with the MSK PI.1 After 4 cycles of 
pembrolizumab, those who achieve a partial metabolic response (PMR) to pembrolizumab 
will proceed to 3 cycles of SMILE chemotherapy, up to 50.4 Gy of involved site radiation 
therapy (if determined to be appropriate by a Radiation Oncology Attending and according to 
institutional standards), followed by 10 months maintenance therapy with pembrolizumab. 
Patients who do not achieve partial metabolic response to pembrolizumab will undergo 
biopsy. Those with biopsy showing evidence of lymphoma will come off study and receive 
treatment per discretion of treating physician. If the biopsy shows no evidence of lymphoma, 
patients will receive the same treatment as those with PMR. 
9.3 Pembrolizumab 
Dosing 
Dosing of pembrolizumab is outlined in Table 3.0 below. Pembrolizumab will be 
administered every 3 weeks (21 days) (+/-3 days). 
Table 3.0 Pembrolizumab Dosing 
 
Drug 
Dose/Potency 
Route of Administration 
Regimen/Treatment Period 
Pembrolizumab 
200mg Flat 
IVPB over 30 minutes 
Once every 21 days 
 
 
Administration 
Pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Schedule of Assessments 
(Section 10.0). Study treatments will be administered on an outpatient basis. Study treatment 
may be administered up to 3 days before or after (+/- 3 days) the scheduled Day 1 of each 
cycle. Subjects may be dosed with pembrolizumab no less than 17 days from the previous 
dose. Treatment related toxicity requiring treatment delay of 6 weeks or more would require 
removal from the study unless after discussion with the PI it is felt to be clinically appropriate 
for the patient to remain on study. 
Supportive Care/Premedications 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 15 of 50 
 
 
There are no premedications routinely recommended unless patient has experienced 
previous infusion reaction. Subjects should be carefully monitored for infusion reactions 
during pembrolizumab administration. If an acute infusion reaction is noted, subjects should 
be managed according to 7.0 in Section 11.6. 
Dose modifications of Pembrolizumab are discussed in Section 11.5. 
9.4 SMILE 
The SMILE regimen will be administered as per institutional guidelines and is outlined in the 
table below. SMILE will begin at the discretion of the treating physician following the last 
dose of pembrolizumab and is administered every 21-28 days. 
Table 4 SMILE regimen 
 
Drug 
Dose/Potency 
Route of 
Administration 
Regimen/Treatment Period 
Methotrexate 
2000 mg/m2 
IVPB over 6 hours 
Day 1 
Leucovorin 
25mg FLAT 
IVPB q 6 hours 
Begin 30 hours after start of 
Methotrexate 
Ifosfamide 
1500mg/m2 
IVPB over 1 hour 
Days 2, 3, 4 
MESNA 
300mg/m2 
IVPB over 15 min 
30 min prior to chemo, then 4 and 
8 hours post chemo 
Etoposide 
100mg/m2 
IVPB over 1 hour 
Days 2, 3, 4 
Dexamethasone 
40mg 
IVPB 
Days 2, 3, 4 
PEG-asparaginase 
1500-2000 units/m2 
IM or IVPB over 1 hour 
Between day 5 and 8 
Pegfilgrastim 
6mg 
SC 
Between day 5 and 8 
 
9.5 Involved site radiation 
Patients with stage I or II disease will undergo involved site radiation therapy (ISRT) 
according to published ILROG guidelines for using ISRT for extranodal lymphomas.10 A total 
dose of 45 Gy (25 daily treatments) will be given with the option of increasing it to 50.4 Gy 
(28 daily treatments) for patients who have PET-positive disease after pembrolizumab. 
Involved site radiation therapy will begin 2-6 weeks following cycle 4 of pembrolizumab. 
Cycle 5 of pembrolizumab will begin 3-6 weeks following completion of radiation. Patients 
with advanced stage disease may receive ISRT if indicated. ISRT may be administered 
between cycles of SMILE or after SMILE and will be performed according to institutional 
standards. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
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Page 16 of 50 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 Evaluations during treatment for stage I, II patients: 
Study Calendar, Stage I, II 
Assessment Period 
Screening 2 
Cycle 1 
Cycle 2 
If PD with no clinical improvement, proceed to 2 cycles of SMILE 
chemotherapy and ISRT ( Involved Site Radiation Therapy ( see 
footnote 16 ] 
Cycle 3 
Cycle 4 
Involved Site Radiation Therapy ( ISRT) OR SMILE, then ISRT [ see 
footnote 17 ] 
Cycles 5 – Cycle 12 
Post-Treatment 
Study Days 
Day -28 to 1 
Day 1 
Day 8-20 
Day 1 
Day 14- 
21 
Day 1 
Day 1 
Day 14-21 
Day 1 
Day 14-21 
End of 
Treatment 
Follow 
up18 
Visit Window 1 
-28 days 
- 3 days 
+/- 3 days 
+/- 3 days +/- 3 days +/- 3 days 
+/- 3 days 
+/- 1 
month 
Informed consent 
X 
Medical History 
X 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
Review of adverse events 
X 
X 
X 
X 
X 
X 
Physical Examination 3 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 4 
X 
X 
X 
X 
X 
X 
X 
ECOG/KPS 
X 
X 
X 
X 
X 
X 
X 
Hematology 5 and 
Chemistry 6 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B and 
Hepatitis C 7 
X 
Pregnancy test 8 
X 
EBV PCR 9 
X 
X 
X 
X 
X 
X 
Referral to radiation 
oncology 
X 
FDG-PET/CT simulation10 
X 
MRI nasal cavity 
(only for patients with 
nasal cavity disease) 
X 
ECHO 
X 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
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Page 17 of 50 
ECG 
X 
Pulmonary function tests 11 
X 
Baseline Biopsy or archive 
tissue 12 
X 
Research Tumor Biopsy 13 
X 
X13 
PET/CT 
X19 
X 
X 
Cycle 8 & 
Cycle 1220 
X 
X 
Tumor assessment 14 
X 
X 
Cycle 8 & 
Cycle 12 
cfDNA21 
X 
X 
X 
X 
X21 
Pembrolizumab 15 
X 
X 
X 
X 
X 
1. Each cycle is 21 days in length. 
2. Screening assessments must be completed prior to initiation of treatment. HIV, Hep B and C tests must be done within 6 months of start of 
treatment. Baseline biopsy must be done prior to treatment. All other assessments must be done within 28 days of treatment, except for laboratory 
tests which must be done within 14 days of treatment. Lab tests CBC and comp must be repeated within 3 days of C1D1. Pregnancy test is required 
for females of child-bearing potential and must be done within 7 days of initiating treatment. 
3. Physical Examination must include height and weight. The patient’s weight in kilograms must be determined before the start of each cycle. 
4. Vital signs include: pulse, blood pressure, temperature, respiratory rate, and oxygen saturation. 
5. Hematology must include CBC with differentials. Screening CBC done within 14 days of start of treatment. Must be repeated within 3 days of C1D1. 
6. Chemistry must include comprehensive metabolic panel (albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium) magnesium, phosphorus amylase, lipase, thyroid function tests (fT4, 
and TSH) and LDH. Screening comp done within 14 days of start of treatment. Must be repeated within 3 days of C1D1. Screening magnesium, 
phosphorus, amylase, lipase, thyroid function tests (fT4 and TSH) and LDH must be done within 7 days of starting treatment. 
7. HIV, Hep B and Hep C tests include: HIV I/II antibodies, Hepatitis B surface antigen, core antibody and Hepatitis C antibody. Must be done within 6 
months of initiating treatment. 
8. Pregnancy test includes: serum β-HCG or urine pregnancy test for women of child-bearing potential. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. Screening pregnancy tests must be performed within 7 days of starting treatment. 
9. EBV PCR: screening EBV PCR must be done within 7 days of starting treatment. It is done on Cycle 2 Day 1, Cycle 4 Day 1, then odd cycles only 
starting in Cycle 5. 
10. Baseline FDG-PET/CT simulation will be done following an initial consultation in Radiation Oncology and prior to starting therapy. Only required for 
patients who will be receiving radiation therapy. 
11. Pulmonary Function tests include: DLCO at minimum. 
12. Baseline tumor biopsy: all study participants will be required to have a biopsy that confirms extranodal NK/T cell lymphoma. If a biopsy is already 
done, 20 unstained slides from archived tissue will be requested for correlative studies if possible. The biopsy must be done prior to initiation of 
treatment. 
13. Research biopsies: on-treatment biopsies are mandatory for all study participants. Biopsies will be done Cycle 1 (between days 8-20), and Cycle 4 
(between days 8-20), except in cases where due to the location of disease, biopsy would be associated with unnecessary risk to the patient. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 18 of 50 
14. Tumor Assessment: is the response assessment after PET scans. Refer to Section 12.0 Criteria for Therapeutic Response/Outcome Assessment. 
15. Pembrolizumab: Pembrolizumab is administered every 3 weeks (21 days) on Day 1 of each cycle, ± 3 days. Pembrolizumab is given 200m via IVPB 
infusion over 30 minutes (+/- 5 minutes). 
16. Reassessment by PET after 2 Cycles of pembrolizumab: If there is no evidence of disease progression, participant will receive another 2 cycles of 
pembro. If evidence of disease progression on PET but with clinical improvement, participant can be considered for another 2 cycles of pembro after 
discussion with the study PI. Patients with progression of disease without evidence of clinical improvement will proceed to 2 cycles of SMILE 
chemotherapy and ISRT. 
17. Reassessment by PET after 4 Cycles of pembrolizumab: If Complete Response (CR) by PET, patients will begin 45 Gy of involved site radiation 
(ISRT), and an additional 6 months (8 cycles) of maintenance pembrolizumab. ISRT will begin 2-6 weeks after Cycle 4 of pembrolizumab. Patients 
with less than CR will undergo a biopsy. If biopsy shows no evidence of lymphoma, patients will proceed with same treatment as those with PET CR. 
Patients with less than CR by PET and persistent evidence of disease on biopsy after 4 cycles of pembro will proceed to 2 cycles of SMILE 
chemotherapy and ISRT. 
18. Follow-up includes: standard clinic visit and laboratory tests (CBC, comp only). EBV PCR every 3 months for 3 years. Imaging to be obtained every 6 
months for 2 years post treatment. cfDNA to be collected 6 months, 1 year, and 2 years into follow up or until a new therapy is initiated. 
19. PET/CT to be completed at baseline only if the patient will not be receiving radiation therapy. 
20. Patients will be followed by PET/CT (skull apex to midthigh). If PET/CT is not feasible, patients may be followed with CT CAP plus CT nasal cavity 
(for patients with nasal cavity disease) after discussion with MSK PI. If followed by PET/CT, additional diagnostic CT is NOT required. 
21. cfDNA to be collected at C1D1, C4D1, after SMILE or at C5D1 of pembrolizumab, end of treatment, and 6 months, 1 year, and 2 years into follow up 
or until a new therapy is initiated. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 19 of 50 
10.2 Evaluations during treatment for stage III, IV patients: 
Assessment Period 
Screening 2 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
SMILE, Cycles 1 - 3 ; ISRT if indicated [ see footnote 16 ] 
SMILE 
Cycles 5 – Cycle 16 Post-Treatment 
 
Study Days 
Day -28 to 1 
Day 1 
Day 8-20 
Day 1 
Day 14-21 
Day 1 
Day 1 
Day 14-21 
Post- 
Cycle 1-3 
20 
Day 1 
Day 14-21 
End of 
Treatment Follow 
up17 
Visit Window 1 
-28 days 
- 3 days 
+/- 3 days 
+/- 3 days +/- 3 days +/- 3 days 
+/- 3 days 
+/- 1 
month 
Informed consent 
X 
Medical History 
X 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Review of adverse events 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 3 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 4 
X 
X 
X 
X 
X 
X 
X 
ECOG/KPS 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 5 and 
Chemistry6 
X 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis B and 
Hepatitis C 7 
X 
Pregnancy test 8 
X 
EBV PCR 9 
X 
X 
X 
X 
X 
X 
Referral to Radiation 
Oncology 
X 
FDG-PET/CT simulation10 
X 
MRI nasal cavity 
(only for patients with 
nasal cavity disease) 
X 
ECHO 
X 
ECG 
X 
Pulmonary function tests 11 
X 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
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Page 20 of 50 
Baseline Biopsy or archive 
tissue 12 
X 
Research Tumor Biopsy 13 
X 
X 
 
PET/CT 
X18 
X 
X 
X20 
Cycle 819 
Cycle 1219 
Cycle 1619 
X 
X 
 
Tumor assessment 14 
X 
X 
Cycle 819 
Cycle 1219 
Cycle 1619 
cfDNA21 
X 
X 
X21 
X 
X 
Pembrolizumab 15 
X 
X 
X 
X 
X 
1. Each cycle is 21 days in length. 
2. Screening assessments must be completed prior to initiation of treatment. HIV, Hep B and C tests must be done within 6 months of start of 
treatment. Baseline biopsy must be done prior to treatment. All other assessments must be done within 28 days of treatment, except for laboratory 
tests which must be done within 14 days of treatment. Pregnancy test is required for females of child-bearing potential and must be done within 7 
days of initiating treatment. 
3. Physical Examination must include height and weight. The patient’s weight in kilograms must be determined before the start of each cycle. 
4. Vital signs include: pulse, blood pressure, temperature, respiratory rate, and oxygen saturation. 
5. Hematology must include CBC with differential. Screening CBC done within 14 days of start of treatment. Must be repeated within 3 days of C1D1. 
6. Chemistry must include comprehensive metabolic panel (albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium, phosphorus), amylase, lipase, and thyroid function tests 
(fT4, and TSH) and LDH. Screening comp done within 14 days of start of treatment. Must be repeated within 3 days of C1D1. Screening amylase, 
lipase, thyroid function tests (fT4 and TSH) and LDH must be done within 7 days of start of treatment. 
7. HIV, Hep B and Hep C tests include: HIV I/II antibodies, Hepatitis B surface antigen, core antibody and Hepatitis C antibody. Must be done within 6 
months of initiating treatment. 
8. Pregnancy test includes: serum β-HCG or urine pregnancy test for women of child-bearing potential. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. Screening pregnancy tests must be performed within 7 days of starting treatment. 
9. EBV PCR: screening EBV PCR must be done within 7 days of start of treatment. It is done on Cycle 2 Day 1, Cycle 4 Day 1, then odd cycles only 
starting in Cycle 5. 
10. Baseline FDG-PET/CT simulation will be done following an initial consultation in Radiation Oncology and prior to starting therapy. Only required for 
patients who will be receiving radiation therapy. 
11. Pulmonary Function tests include: DLCO at minimum 
12. Baseline tumor biopsy: all study participants will be required to have a biopsy that confirms extranodal NK/T cell lymphoma. If a biopsy is already 
done, 20 unstained slides from archived tissue will be requested for correlative studies if possible. The biopsy must be done prior to initiation of 
treatment. 
13. Research biopsies: on-treatment biopsies are mandatory for all study participants. Biopsies will be done Cycle 1 (between days 8-20), and Cycle 4 
(between days 8-20), except in cases where due to the location of disease, biopsy would be associated with unnecessary risk to the patient. 
14. Tumor Assessment: is the response assessment after PET scans. Refer to Section 12.0 Criteria for Therapeutic Response/Outcome Assessment. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 21 of 50 
15. Pembrolizumab: Pembrolizumab is administered every 3 weeks (21 days) on Day 1 of each cycle, ± 3 days. Pembrolizumab is given 200m via IVPB 
infusion over 30 minutes (+/- 5 minutes). 
16. Reassessment by PET after 4 Cycles of pembrolizumab: If Partial Metabolic Response (PMR) by PET, patients may begin 45 Gy of involved site 
radiation (ISRT) if indicated, and an additional 6 months (8 cycles) of maintenance pembrolizumab. ISRT will begin 2-6 weeks after Cycle 4 of 
pembrolizumab. Patients with less than PMR will undergo a biopsy. If biopsy shows no evidence of lymphoma, patients will proceed with same 
treatment as those with PET CR. Patients with less than PMR by PET and persistent evidence of disease on biopsy after 4 cycles of pembro will be 
taken off study. 
17. Follow-up includes: standard clinic visit and laboratory tests (CBC, comp only). EBV PCR every 3 months for 3 years. Imaging to be obtained every 6 
months for 2 years post treatment. cfDNA to be collected 6 months, 1 year, and 2 years into follow up or until a new therapy is initiated. 
18. PET/CT to be completed at baseline only if the patient will not be receiving radiation therapy. 
19. Patients will be followed by PET/CT (skull apex to midthigh) If PET/CT is not feasible, patients may be followed with CT CAP plus CT nasal cavity (for 
patients with nasal cavity disease) after discussion with MSK PI. If followed by PET/CT, additional diagnostic CT is NOT required. 
20. PET/CT to be done after last cycle of SMILE only – may be done prior to treatment on C5D1. All other assessments marked should be done for every 
cycle of SMILE. 
21. cfDNA to be collected at C1D1, C4D1, C5D1 of pembrolizumab, end of treatment, and 6 months, 1 year, and 2 years into follow up or until a new 
therapy is initiated. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 22 of 50 
 
 
10.3 Correlatives 
We propose a series of correlative studies to evaluate for pre-treatment and post-treatment 
predictors of response or resistance to pembrolizumab in ENKTL: 
Tissue biopsies 
Pre-treatment biopsies will be required prior to initiation of study treatment unless 
archival tissue is available. On-treatment biopsies will be performed during Cycle 1 
(between days 8-20), except in cases where due to the location of disease, biopsy 
would be associated with unnecessary risk to the patient. In addition, biopsies will be 
performed after 4 cycles of pembrolizumab for patients who do not achieve complete 
metabolic response. Tissue will be collected, processed, and stored for planned 
correlative studies including; 
1. Immunohistochemistry for MHC-I, MHC-II, B2M, PD-1, PD-L1, PD-L2, FoxP3, 
CD68, CD4, and CD8 to evaluate for both cell autonomous and non-cell 
autonomous markers of immune evasion and elucidate mechanisms of action. 
2. Molecular profiling by MSK IMPACT assay to evaluate for mutations and altered 
expression profiles associated with disease response and resistance. In most 
cases, patients will have this as done as part of their clinical workup. 
Blood Collection 
Additionally, based upon prior reports regarding the prognostic and predictive value of 
plasma EBV DNA levels in ENKTL9, we will evaluate EBV DNA levels by PCR at 
baseline and during therapy to clarify its significance for patients with ENKTL treated 
with checkpoint inhibitors. We are collecting blood for analysis of EBV DNA levels by 
PCR at baseline, C2D1, C4D1, and then odd cycles starting Cycle 5. Following 
completion of treatment, EBV PCR will be evaluated every 3 months for 3 years. 
 
Cell-free DNA 
 
Cell-free DNA (cfDNA) will be extracted from serum samples obtained at C1D1, 
C1D4, after completion of SMILE or C5D1 of pembrolizumab, EOT, and 6 months, 1 
year and 2 years into follow-up or until a new therapy is initiated. Shallow whole 
genome sequencing be used to detect copy number alterations in order to confirm 
tumor vs host origin and quantify tumor-specific cell-free DNA. Targeted 
resequencing using the MSKCC HemePACT assay will be performed on cell-free 
DNA to identify genomic alterations present at baseline, on treatment, and in follow- 
up. 
 
10.4 MSK IMPACT Testing 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 

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IRB Number: 18-393 A(22) 
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Page 23 of 50 
 
 
Such information will not include identifying information such as name. It is also stated in the 
Research Authorization that research data (e.g. genomic sequence) may be shared with 
regulators. The requirements for submission of genotype/phenotype data into the NIH 
dbGAP or any other public database will be followed as per the MSK IRB SOP for Genomic 
Data Sharing. 
 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational “next-generation” profiling in a research (non-CLIA) environment will 
be found to have somatic or germline mutations in genes that are known to be associated 
with an increased risk of cancer or other diseases. It will be stated in the consent that the 
participants will not receive any specific results from research tests. The consent will tell 
participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSK Clinical Genetics Service or Clinical Genetics 
Service at their site. 
 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the MSK IRB Genomic Advisory Panel (GAP). 
The finding will be reviewed by the GAP to determine whether the incidental finding should 
be discussed with the participant. For MSK patients, in the event that the GAP determines 
that the finding should be discussed with the participant, and the participant has consented 
to be re-contacted, then the treating/consenting physician shall be contacted by the panel 
and asked to refer the participant to the Clinical Genetics Service for further discussion of 
the research finding. 
 
The following information must be provided to GAP for review: 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, saliva) 
• 
Incidental Finding 
• 
Collection Protocol # 
• 
Contact: ocrgapirb@mskcc.org 
 
For non-MSK patients being treated at one of the participating institutions, in the event the 
GAP determines that the finding should be discussed with the participant, and the participant 
has consented to be re-contacted, the findings will be returned to the Site Principal 
Investigator. Site policies on returning these research findings to the patient should be 
followed. 
 
10.5 Future Unspecified Use of Biospecimens 
The protocol includes an informed consent document and research authorization that meets 
statutory guidelines. Each participating site will have its own consent form meeting the 
requirements described in this section. The consent form will inform patients of the purpose 
of the bank, their rights in relation to it, and the safeguards in place to protect the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 24 of 50 
 
 
confidentiality of their health information. The consent will state that some of the 
biospecimens will be saved to use for future research. 
 
Type of future use 
The consent specifically describes the types of future research that may be performed, 
including use of tissues to develop new drugs with cancer-associated molecular targets, 
development of cell lines, future use of cell lines to define cancer phenotype and (somatic) 
genotype, DNA sequence analysis of tumor compared to normal and identification of tumor- 
associated proteins as diagnostic or prognostic markers. It will be stated that researchers at 
MSK may either keep indefinitely or dispose of any leftover blood or tissues or other 
samples, including DNA that the samples contain. Blood and tissues will be stored with 
identifiers in secure tissue or fluid banks. It is stated that the samples could be lost or ruined 
because of mechanical failure, and that MSK cannot guarantee that samples will be stored 
indefinitely. The samples will be stored for as long as deemed useful for research purposes. 
 
Consent for future use and re-contact 
Patients are asked in a series of check boxes at the end of the consent if 1) they permit their 
biospecimen samples to be stored and used in future research to learn about or prevent 
cancer or side effects of treatment, or to develop new treatments; 2) if they permit their 
samples to be stored and used in future research to learn about, prevent, or treat diseases 
other than cancer; or 3) if they permit their samples, with personal identifiers protected, to be 
used for research about inherited genetic factors, 4) if they permit their samples to be used 
for genetic analysis of the tumor and normal tissue to learn about the causes of cancer, 5) 
participants are asked if they agree to be contacted in the future as part of research studies 
for additional health information or to be asked to participate in future biospecimen research 
studies and 6) if they consent to be contacted to discuss research findings which may come 
from their sample. Finally, if not available (e.g. deceased), if they wish to have their designee 
designated on the consent to be contacted. 
 
Participants will not be provided with specific results of research tests performed on their 
collected human biologic specimens. 
 
Use of identifiable information for genetic studies 
In the course of this research it is possible that some patients whose tumors are analyzed 
through investigational “next-generation” profiling in a research (non-CLIA) environment will 
be found to have somatic or germline mutations in genes that are known to be associated 
with an increased risk of cancer or other diseases. It will be stated in the consent that the 
participants will not receive any specific results from research tests. The consent will tell 
participants that if they wish to have genetic testing done for personal reasons than they 
should make an appointment with the MSK Clinical Genetics Service or Clinical Genetics 
Service at their site. 
 
If in the course of this research a research finding is obtained that, in the opinion of the 
investigator, may be critical to the preventive care of the participant or their family, the 
investigator can communicate that finding to the MSK IRB Genomic Advisory Panel (GAP). 
The finding will be reviewed by the GAP to determine whether the incidental finding should 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 25 of 50 
 
 
be discussed with the participant. For MSK patients, in the event that the GAP determines 
that the finding should be discussed with the participant, and the participant has consented 
to be re-contacted, then the treating/consenting physician shall be contacted by the panel 
and asked to refer the participant to the Clinical Genetics Service for further discussion of 
the research finding. 
 
The following information must be provided to GAP for review: 
• 
Participant Name/MRN # 
• 
Type of Biospecimen (tissue, blood, saliva) 
• 
Incidental Finding 
• 
Collection Protocol # 
• 
Contact: ocrgapirb@mskcc.org 
 
For non-MSK patients being treated at one of the participating institutions, if the GAP 
determines the finding to be reportable to the participant and the participant has consented 
to be re-contacted, results will be returned to the Site Principal Investigator via the study 
team. Site policies on returning these research findings to the patient should be followed. 
 
We anticipate that other research assays may be incorporated into this protocol as 
technology evolves. 
 
Voluntariness of research participation 
It is stated that taking part in this tissue and blood bank is voluntary and patients have the 
right to withdraw at any time. Participation in the study will not impact on the clinical care 
patients receive. 
 
Withdrawal 
Participants may decide at a later date that they do not want identified blood and tissue 
samples to be stored in the tissue bank and /or used for future research. If participants 
decide to withdraw from the study, specimens that have not yet left the specimen archive will 
not be used in new studies and any remaining portions of samples that have not been used 
for research will be used only for clinical purposes or, if requested by the patient, 
destroyed. For specimens already shipped out from the archive, it may not be possible to 
locate the samples or stop already ongoing research. When a participant withdraws from the 
protocol, the MSK study team should be notified immediately. If a non-MSK participant 
withdraws from the study, the MSK study staff member will notify the MSK database teams. 
The withdrawal request will be documented in CRDB and the system updated accordingly. 
In addition, a note-to-file documenting the patient withdrew must be filed in his/her medical 
records. 
 
Rights after death 
The consent states that if the research participant dies or is unable to make his/her wishes 
known, all of their rights to decide about future uses of the blood or tissues will pass to the 
authorized representative of the estate. If there is no representative of the estate, the rights 
pass to the next of kin. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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Risks of research participation 
The greatest risk is release of information from health or research records in a way that 
violates privacy rights. MSK and any participating sites will protect records so that name, 
address, phone number, and any other information that identifies the participant will be kept 
private. It will be stated to the participant that the chance that this information will be given 
to an unauthorized individual without the participant’s permission is very small. 
 
Costs/compensation 
There is no cost to the participant to enroll in this research. Tissue or blood obtained in this 
research may be used to make a cell line, and these may be patented or licensed and thus 
may have significant commercial value. The participant is informed that there are no plans 
to provide financial compensation for use of their human biologic specimens, nor are there 
plans for the participant to receive money for any new products, tests, and discoveries that 
might come from this research. 
 
Biospecimen Privacy 
Medical information is confidential. The participant’s personal identity will not be used in 
reports that are written about the research. The MSK IRB/PB will review all requests for 
research performed involving biospecimens ascertained through this protocol. Blood and 
tissue samples may be stored with a code linked to the patient’s medical record. The results 
of any research using blood or tissues will not be placed in the medical record. 
 
The consent indicates that samples and genetic information collected may be shared with 
other qualified researchers and placed in online databases. An example of an online 
database is the NIH dbGAP database, which is monitored by the National Institutes of 
Health, and may be made accessible to investigators approved by the U.S. government. 
Such information will not include identifying information such as name. It is also stated in the 
Research Authorization (HIPAA Authorization) that research data (e.g. genomic sequence) 
may be shared with regulators. The requirements for submission of genotype/phenotype 
data into the NIH dbGAP or any other public database will be followed as per the IRB SOP 
for Genomic Data Sharing. 
 
Use of banked samples (at MSK) 
When samples are to be analyzed, the individual investigator needs to write an IRB 
biospecimen protocol. This protocol is fast-tracked through MSK Research Council review 
and is reviewed at the MSK IRB by the expedited review process. This protocol is only for 
research that will be done on biospecimens obtained under identified protocols and their 
informed consent and research authorization that include the institutional future use 
questions. The consent and research authorization for the use of the biospecimens will be 
waived as per 45 CFR 46.116(d) and 45 CFR 164.512(i)(2)(ii). 
 
11.0 TOXICITIES/SIDE EFFECTS 
11.1 Adverse Events Definitions 

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An AE is any untoward medical occurrence in a study subject and does not necessarily have 
a causal relationship with this treatment. 
 
An AE therefore can be any unfavorable and unintended sign (including laboratory finding), 
symptom or disease temporally associated with participation in an investigational study, 
whether or not considered drug-related. In addition to new events, any increase in the severity 
or frequency of a pre-existing condition that occurs after the subject signs a consent form for 
participation is considered an AE. This includes any side effect, injury, toxicity, or sensitivity 
reaction. 
 
Whenever possible, the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 should be used to describe the event and for assessing the severity of AEs. Any events 
representing a change in the CTCAE Grade need to be reported in CRDB. This includes any 
change in laboratory values. 
 
For AEs not adequately addressed in the CTCAE, the severity table (Table 5.0) below may 
be used: 
Table 5.0 AE Severity Table 
 
Severity 
Description 
GRADE 1 – Mild 
Transient or mild discomfort; no limitation in activity; 
no medical intervention/therapy required. 
GRADE 2 – Moderate 
Mild to moderate limitation in activity—some 
assistance may be needed; no or minimal medical 
intervention/therapy required. 
GRADE 3 – Severe 
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy 
required, hospitalizations possible. 
GRADE 4 – Life-threatening 
Extreme limitation in activity, significant assistance 
required; life-threatening (immediate risk of death); 
significant medical intervention/therapy required, 
hospitalization or hospice care probable. 
GRADE 5 – Fatal 
Death 
 
Any condition, laboratory abnormality, or physical finding with an onset date prior to the subject 
signing consent for study participation is considered to be pre-existing in nature and part of the 
subject’s medical history. 
 
11.2 Causality 
Using the following criteria, the relationship of the AE to the study drug should be assessed 
as follows: 
• 
Yes: The event is suspected to be related if: 
o There is a clinically plausible time sequence between onset of the AE and 
administration of study treatment; and/or 
o There is a biologically plausible mechanism for the study treatment to cause or 
contribute to the AE; and/or 

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o The event responds to withdrawal of the study intervention (dechallenge) and/or 
recurs with rechallenge (when clinically feasible); and/or 
o The AE cannot be reasonably attributed to concurrent/underlying illness, other drugs, 
or procedures 
• 
No: 
o The AE is more likely to be explained by the subject’s clinical state, underlying 
disease, concomitant medication, study or non-study procedure; and/or 
o The time of occurrence of the AE is not reasonably related to administration of study 
treatment; and/or 
o The event is unlikely to be related to the investigational procedures(s) 
11.3 Adverse Events Reporting Procedures 
All AEs (e.g., any new event or worsening in severity or frequency of a pre-existing condition 
or laboratory finding) with an onset date after the subject signs consent for study participation 
must be promptly documented on the appropriate summary. Details of the event must include 
severity, relationship to study drug, duration, action taken, and outcome. 
 
All AEs that are considered related to study procedures must be followed to resolution or 
stabilization if improvement is not expected. 
AEs should be reported from the time the subject signs consent through 30 days post-last 
study intervention. In addition, the Investigator should report any AE that may occur after this 
time period that is believed to have a reasonable possibility of being associated with study 
intervention. If a subject discontinues study prior to receiving any study intervention, AEs must 
be reported through the end-of-study visit. AEs which completely resolve and then recur 
should be recorded as a new AE. For subjects who complete the end of study visit less than 
30 days following the last study intervention, a follow up of ongoing AEs should be attempted 
by telephone and documented in the subject’s source. AEs continuing at 30 days post-last 
treatment should have a comment in the source by the Investigator that the event has stabilized 
or is not expected to improve. 
 
The Principal Investigator is responsible for evaluating all AEs, obtaining supporting 
documents, and determining that documentation of the event is adequate. Adverse events will 
be assigned a severity grade using the NCI CTCAE grading scale v4.0 and recorded. 
Furthermore, the occurrence of grade 2 or higher immune-related adverse events will be 
collected and designated as immune-related events of clinical interest (irAEs). 
 
11.4 Pembrolizumab side effects and supportive care 
Refer to package insert for frequency of side effects 
 
 
11.5 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
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 

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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. 
 
Table 6 Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 
4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper. 
• 
Monitor participants 
for signs and 
symptoms of 
pneumonitis 
• 
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid 
treatment 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently discontinue 
Add prophylactic 
antibiotics for 
opportunistic 
infections. 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor participants 
for signs and 
symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal 
pain, blood or mucus 
in stool with or without 
fever) and of bowel 
perforation 
(i.e., peritoneal signs 
and ileus). 
• 
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis. 
Recurrent Grade 
3 or Grade 4 
Permanently discontinue 

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• 
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids. If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion. 
AST / ALT 
elevation or 
Increased bilirubin 
Grade 2 a 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5- 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable 
Grade 3b or 4c 
Permanently discontinue 
• Administer 
corticosteroids 
(initial dose of 1- 
2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• Administer anti- 
hyperglycemic 
in participants 
with 
hyperglycemia 
• 
Monitor participants 
for hyperglycemia or 
other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated. 
• 
Monitor for signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non- 
selective beta- 
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
• Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine or 
liothyroinine) 
• 
Monitor for signs and 
symptoms of thyroid 
disorders. 

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per standard of 
care 
Nephritis grading 
according to 
increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 1 to 
2 mg/kg or 
equivalent) 
followed by 
taper. 
• 
Monitor changes of 
renal function 
Grade 3 or 4 
Permanently discontinue 
Neurological 
Toxicities 
Grade 2 
Withold 
• Based on 
severity of AE, 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently Discontinue 
Myocarditis 
Grade 1 
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
Grade2, 3 or 4 
Permanently discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withold 
• Based on 
severity of AE, 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently Discontinue 
All other AEs 
Intolerable/ 
persistent Grade 2 
Withhold e 
• Based on type 
and severity of 
AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes 
Grade 3 
Withhold or discontinue 
based on the type of 
event. Events that 
require discontinuation 
include and not limited 
to: Gullain-Barre 
Syndrome, encephalitis, 
vasculitis and sclerosing 
cholangitis 
Grade 4 or 
recurrent Grade 3 
Permanently discontinue 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x 
ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 
x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline 
normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
NOTE: 
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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11.6 Dose modification and toxicity management of infusion-reactions related 
to pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 7. 
 
Table 7 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
Non-irAE will be managed as appropriate, following clinical practice recommendations. 

Page 33 of 50 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
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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 
Stop Infusion. 
Participant may be 
Requires therapy or 
Additional appropriate medical therapy may 
premedicated 1.5h (± 30 
infusion interruption but 
include but is not limited to: 
minutes) prior to infusion of 
responds promptly to 
IV fluids 
pembrolizumab with: 
symptomatic treatment 
Antihistamines 
Diphenhydramine 50 mg po 
(e.g., antihistamines, 
NSAIDs 
(or equivalent dose of 
NSAIDs, narcotics, IV 
Acetaminophen 
antihistamine). 
fluids); prophylactic 
Narcotics 
Acetaminophen 500-1000 mg 
medications indicated 
Increase monitoring of vital signs as medically 
po (or equivalent dose of 
for ≤24 hrs 
indicated until the participant is deemed 
analgesic). 
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 
Grades 3 or 4 
Stop Infusion. 
No subsequent dosing 
Grade 3: 
Additional appropriate medical therapy may 
Prolonged (i.e., not 
include but is not limited to: 
rapidly responsive to 
Epinephrine** 
symptomatic 
IV fluids 
medication and/or brief 
Antihistamines 
interruption of infusion); 
NSAIDs 
recurrence of 
Acetaminophen 
symptoms following 
Narcotics 
initial improvement; 
Oxygen 
hospitalization 
Pressors 
indicated for other 
Corticosteroids 
clinical sequelae (e.g., 
Increase monitoring of vital signs as medically 
renal impairment, 
indicated until the participant is deemed 
pulmonary infiltrates) 
medically stable in the opinion of the investigator. 
Grade 4: 
Hospitalization may be indicated. 
Life-threatening; 
**In cases of anaphylaxis, epinephrine should be 
pressor or ventilatory 
used immediately. 
support indicated 
Participant is permanently discontinued from 
further study drug treatment. 

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Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 

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Other Considerations 
Contraception 
Pembrolizumab and the agents in SMILE may have adverse effects on a fetus in utero. 
Furthermore, it is not known if pembrolizumab has transient adverse effects on the 
composition of sperm. 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 

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Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if 
considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
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. 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment, the subject will immediately 
be removed from the study. The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated. The outcome of 
the pregnancy will be reported to the Sponsor and to Merck without delay and within 24 
hours to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Merck. If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to Merck and followed as described above. 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
11.7 SMILE side effects and supportive care 

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Refer to product insert for the individual drugs. Dose modifications allowed according to 
treating physician. 
11.8 Radiation side effects and supportive care 
Side-effects vary depending on the specific head/neck site(s) treated and total dose 
administered but can potentially include: 
Very Likely: 
Sores in the mouth and/or throat 
Temporary decrease in taste and/or smell 
Thick saliva 
Tanning or redness of the skin in the area being treated with radiation 
Ear pain and/or pressure 
Fatigue 
Weight loss 
Transient and rarely permanent hair loss in the area treated with radiation 
 
Likely: 
Decrease in function of the thyroid gland (if thyroid is in the ISRT field) 
Transient odynophagia 
 
Very Rare But Potentially Serious: 
Loss of teeth, or cavities in the teeth, if strict dental care is not followed and/or 
hypersensitivity of teeth 
Serious damage to the spinal cord, nerves in the neck, jawbone, voice box, skin, or other 
parts of the treated area that may require a major operation to correct and although it is rare, 
it can be life threatening 
Temporary pain or scarring around nerves in the shoulder that could cause numbness and/or 
weakness 
Difficulty with swallowing and eating with the possibility of inhaling food and/or liquids into the 
lungs – which could also result in pneumonia 
Serious ear infections and/or hearing loss 
Damage to the spinal cord leading to permanent weakness and/or symptoms like a “stroke”. 
 
 
12.0 CRITERIA FOR STAGING AND THERAPEUTIC RESPONSE/OUTCOME 
ASSESSMENT 
Patients with ENKTL will be staged using the Ann Arbor criteria prior to initiation of treatment 
(outlined in Table 8.10 Response to treatment will be assessed using the Lugano 
Classification.11 Definitions for response are outlined in Table 9 below. In addition to the 
criteria described below, patients with residual PET-avidity, but with a biopsy showing no 
evidence of lymphoma, will be considered CR. Furthermore, although the Lugano 
Classification defines partial metabolic response (PMR) simply as “reduced FDG-uptake 
compared to baseline”, normal variations in FDG-avidity of lesions can be observed between 
PET scans. To avoid declaring normal variations in SUV as PMR, we will use the definition 

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of PMR defined by PERCIST which defines PMR as 30% or more reduction in SUV from 
baseline.12 
Responses for patients with evidence of disease progression on PET will be further classified 
using the LYRIC criteria1 (outlined in Table 10 below) when appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 8 Ann Arbor Staging Criteria 

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Table 9 Revised Criteria for Response Assessment11 

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Table 10 LYRIC Criteria for Indeterminate Response (IR) 
 
 
 
 
 
 
 
 
 

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13.0 CRITERIA FOR REMOVAL FROM STUDY 
Patients will be followed on study until progression of disease or 2 years following completion 
of study treatment. 
The following patients will be removed from study: 
• Patients whose treating physicians determine that it is in their best interest to be removed 
from the study. 
• Patients who develop unacceptable toxicity. 
• Patients who request that they be removed from study. This will not compromise the care 
they receive at this institution. 
• Patients who are non-compliant with treatment or follow-up. 
 
 
14.0 BIOSTATISTICS 
Primary objectives: 
The primary objective of this pilot study is to assess the complete response (CR) rate to 
pembrolizumab in untreated ENKTL following pembrolizumab. Patients who receive any 
number of cycles of pembrolizumab and undergo response assessment or come off study 
before response assessment for disease progression will be evaluable for response. CR will 
be defined as complete metabolic response or negative biopsy in the setting of residual PET 
avidity. Although there are marked differences in progression free survival for patients with 
early stage disease (stage I,II) versus advanced stage disease (stage III, IV), complete 
response rate to treatment (such as SMILE) is similar regardless of stage.4 Therefore, for the 
primary objective, early stage and advanced stage patients will be analyzed together. Early 
stage disease is more common and thus we expect that 66% of patients enrolled onto this 
study will have early stage disease. If pembrolizumab is efficacious in untreated ENKTL, the 
treatment approach evaluated in this study will be evaluated in a larger phase II study. Based 

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upon expression of PD-L1 in ENKTL and experience in the relapsed/refractory setting, we 
expect that the clinical or pathologic complete response rate to pembrolizumab in untreated 
disease will be at least 40%. We plan to enroll 19 patients with untreated ENKTL. Assuming 
a complete response rate of 40%, the 95% confidence interval with a sample size of 19 is 0.18- 
0.62, i.e. the width of the interval is 0.44. Patients who are removed prior to the first response 
evaluation will be counted as non-responders. 
This study is expected to enroll 19 patients over 2 years. 
Secondary objectives: 
The secondary objectives of the study are safety of the treatment program, overall response 
rate (ORR) and partial metabolic response (PMR) rate to pembrolizumab, progression free 
survival (PFS), and overall survival (OS). Adverse events related to treatment will be tabulated 
and analyzed using descriptive statistics. ORR and PMR rates will be assessed after 4 cycles 
of pembrolizumab and calculated along with an exact 95% confidence interval. Progression 
free survival (PFS) and overall survival (OS) will be calculated using the method of Kaplan- 
Meier. Time origin for PFS and OS are time of treatment initiation. PFS and OS will be 
analyzed separately for early and advanced stage patients. 
 
Exploratory objectives: 
 
1. Explore mechanism of action and markers of response and resistance through 
assessment of baseline and on-treatment biopsies. 
a. Evaluation of association between expression of MHC-I, MHC-II, B2M, PD- 
1, PD-L1, PD-L2, FoxP3, CD68, CD4, and CD8 by tumor cells and 
achievement of complete response to therapy will be assessed by Wilcoxon rank 
sum test. Due to the small sample size, the association between these 
biomarkers and PFS will be assessed descriptively by dichotomizing the 
biomarkers by median and generating Kaplan-Meier curves of PFS for each group 
and comparing them visually. 
b. Molecular profiling of baseline and on-treatment biopsies and association with 
response will be assessed by Wilcoxon rank sum test. Due to the small sample 
size, the association between these biomarkers and PFS will be assessed 
descriptively by dichotomizing the biomarkers by median and generating Kaplan- 
Meier curves of PFS for each group and comparing them visually. 
2. Evaluate plasma EBV PCR as a marker of response to therapy and/or early predictor of 
relapse. Associated between EBV DNA and response will be assessed using Wilcoxon 
rank sum test. Due to the small sample size, the association between this biomarker and 
PFS will be assessed descriptively by dichotomizing the biomarkers by median and 
generating Kaplan-Meier curves of PFS for each group and comparing them visually. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
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15.0  RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. The individual signing the Eligibility Checklist is confirming 
whether or not the participant is eligible to enroll in the study. 
 
Study staff is responsible for ensuring that all institutional requirements necessary to enroll a 
participant to the study have been completed. 
 
See related Clinical Research Policy and Procedure #401 (Protocol Participant Registration): 
https://one.mskcc.org/sites/pub/clinresearch/Policies/CR%20401.pdf 
 
15.2 
Randomization 
N/A 
16.0 DATA MANAGEMENT ISSUES 
This is a multicenter trial that will be coordinated by the Multi-Site Compliance Office at MSK. 
An MSK Clinical Research Coordinator (CRC) or equivalent at each participating site, will be 
assigned to the study at each institution. The responsibilities of the MSK CRC include project 
compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, 
problem resolution and prioritization, and coordination of the activities of the protocol study 
team. 
The data collected for this study will be entered into a secure database system, Medidata 
Rave. Source documentation will be available to support the computerized patient record. 
MSK will be the data coordinating center and will be responsible for reporting to the funding 
source (as applicable) and governing agencies. 
 
16.1 
Quality Assurance 
Registration reports will be generated to monitor patient accruals and the completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
Random sample data quality and protocol compliance audits will be conducted by the study 
team as on ongoing review process. 

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IRB Number: 18-393 A(22) 
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16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
 
The DSM Plans at MSKCC were established and are monitored by the MSK Clinical Research 
Administration Office. The MSKCC Data and Safety Monitoring Plans can be found on the 
MSKCC Intranet at: 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC Data and Safety Monitoring 
Plans.pdf 
 
There are several different mechanisms at MSKCC by which clinical trials are monitored for 
data, safety and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus there 
are two institutional committees that are responsible for monitoring the activities of our clinical 
trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I 
and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
The MSK DSMC will monitor safety and data quality across all participating institutions (MSK 
and external sites). Regular study teleconferences with all participating institutions will be held 
to discuss SAEs or other toxicities and study progress. 
 
Final data sets for publication are required to be locked and stored centrally for potential future 
access requests from outside entities. 
 
 
17.0 PROTECTION OF HUMAN SUBJECTS 
All the patients will be required to sign an IRB-approved informed consent and will have all 
their questions fully addressed before enrolling in the study. During informed consent, it will be 
made clear to the patient that participation is voluntary. All the data will be confidential, 
maintained in a password protected electronic database and will comply with all HIPAA 
guidelines. 

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Every effort will be made to maintain patient confidentiality. Research and hospital records are 
confidential. Patient’s name or any other personally identifying information will not be used in 
reports or publications resulting from this study. The Food and Drug Administration or other 
authorized agencies (e.g., qualified monitors) may review patients’ records and pathology 
slides, as required. 
17.1 
Privacy 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant’s name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified researchers. 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 46 of 50 
 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office 
 
17.2.1 Merck Global Safety Reporting (MSK ONLY) 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study that 
occurs to any subject must be reported within 2 working days to Merck Global Safety if it 
causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study whether or not related to the Merck product, must be reported within 2 
working days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 47 of 50 
 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
 
17.2.2 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229). 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must 
be reported within 2 working days to Merck Global Safety if it causes the participant to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 2 working days to Merck 
Global Safety. 
 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 17.2.3 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or equal 
to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab 
value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
 
17.2.3 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 48 of 50 
 
 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
 
 
18.0 INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 49 of 50 
 
 
 
 
19.0 REFERENCES 
1. 
Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF, 
Armand P. Refinement of the Lugano Classification lymphoma response criteria in the era of 
immunomodulatory therapy. Blood 2016;128:2489-96. 
2. 
Steven H. Swerdlow EC, Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri, Harald Stein, 
Jurgen Thiele, and James W. Vardiman, eds. WHO Classification of Tumours of Haematopoietic 
and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer (IARC); 
2008. 
3. 
Lee J, Suh C, Park YH, Ko YH, Bang SM, Lee JH, Lee DH, Huh J, Oh SY, Kwon HC, Kim 
HJ, Lee SI, Kim JH, Park J, Oh SJ, Kim K, Jung C, Park K, Kim WS. Extranodal natural killer T-cell 
lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2006;24:612-8. 
4. 
Yamaguchi M, Kwong YL, Kim WS, Maeda Y, Hashimoto C, Suh C, Izutsu K, Ishida F, Isobe 
Y, Sueoka E, Suzumiya J, Kodama T, Kimura H, Hyo R, Nakamura S, Oshimi K, Suzuki R. Phase II 
study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal 
natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2011;29:4410-6. 
5. 
Lunning MA, Pamer E, Wintman L, Bhatt V, Yahalom J, Moskowitz AJ, Goldberg JD, Straus 
DJ, Hamlin P, Zelenetz AD, Horwitz SM. Modified SMILE in the Treatment of Natural Killer T-Cell 
Lymphoma, Nasal and Nasal Type: A Single Center US Experience. ASH Annual Meeting Abstracts 
2011;118:2688-. 
6. 
Qi S, Yahalom J, Hsu M, Chelius M, Lunning M, Moskowitz A, Horwitz S. Encouraging 
experience in the treatment of nasal type extra-nodal NK/T-cell lymphoma in a non-Asian population. 
Leukemia & lymphoma 2016;57:2575-83. 
7. 
Chen BJ, Chapuy B, Ouyang J, Sun HH, Roemer MG, Xu ML, Yu H, Fletcher CD, Freeman 
GJ, Shipp MA, Rodig SJ. PD-L1 expression is characteristic of a subset of aggressive B-cell 
lymphomas and virus-associated malignancies. Clinical cancer research : an official journal of the 
American Association for Cancer Research 2013;19:3462-73. 
8. 
Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, Khong PL, Loong F, Au-Yeung R, 
Iqbal J, Phipps C, Tse E. PD1 blockade with pembrolizumab is highly effective in relapsed or 
refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017;129:2437-42. 
9. 
Lei KI, Chan LY, Chan WY, Johnson PJ, Lo YM. Diagnostic and prognostic implications of 
circulating cell-free Epstein-Barr virus DNA in natural killer/T-cell lymphoma. Clinical cancer 
research : an official journal of the American Association for Cancer Research 2002;8:29-34. 
10. 
Edge SB, B. D. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. 
11. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance 
AL, Lymphoma G, Eastern Cooperative Oncology G, European Mantle Cell Lymphoma C, Italian 
Lymphoma F, European Organisation for R, Treatment of Cancer/Dutch Hemato-Oncology G, Grupo 
Espanol de Medula O, German High-Grade Lymphoma Study G, German Hodgkin's Study G, 
Japanese Lymphorra Study G, Lymphoma Study A, Group NCT, Nordic Lymphoma Study G, 
Southwest Oncology G, United Kingdom National Cancer Research I. Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2014;32:3059-68. 
12. 
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving 
Considerations for PET response criteria in solid tumors. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine 2009;50 Suppl 1:122S-50S. 

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IRB Number: 18-393 A(22) 
Approval date: 28-Aug-2025 
Page 50 of 50 
 
 
 
 
20.0 APPENDICES 
Appendix A: Multicenter Addendum 
Appendix B: Biospecimen Collection and Shipping Manual 
Appendix C: Multicenter External Site SAE Report Form