NEO-SPACE Trial: Neoadjuvant Pembrolizumab-Gemcitabine-Cisplatin Followed by Concurrent Pembrolizumab-Chemoradiation and Maintenance Pembrolizumab for Stage IVA Nasopharyngeal Cancer
Phase: PHASE2
Conditions: NPC
Sponsor: Chinese University of Hong Kong

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SPONSOR: 
Comprehensive Cancer Trials Unit, Department of Clinical Oncology, The Chinese University of 
Hong Kong 
 
 
TITLE: 
NEO-SPACE trial:  
Neoadjuvant Pembrolizumab-Gemcitabine-Cisplatin followed by Concurrent Pembrolizumab-
Chemoradiation and Maintenance Pembrolizumab for Stage IVA Nasopharyngeal Cancer  
 
 
Lead Principal Investigator 
Prof Anthony Tak Cheung Chan 
Department of Clinical Oncology 
Prince of Wales Hospital 
Sir YK Pao Center for Cancer 
The Chinese University of Hong Kong 
30-32 Ngan Shing Street, Shatin, Hong Kong 
Tel: (852) 3505 1042/ Fax (852) 2632 5816 
anthony@clo.cuhk.edu.hk 
 
Co-Principal Investigator 
Dr Darren Wan-Teck Lim 
National Cancer Centre Singapore 
11 Hospital Drive 
Singapore 169610 
darren.lim.w.t@singhealth.com.sg 
 
Co-Principal Investigator 
Dr Edwin Pun Hui 
Comprehensive Cancer Trials Unit 
Department of Clinical Oncology 
Prince of Wales Hospital 
Sir YK Pao Center for Cancer 
The Chinese University of Hong Kong 
30-32 Ngan Shing Street, Shatin, Hong Kong 
Tel: (852) 3505 1042/ Fax (852) 2632 5816 
huipun@ cuhk.edu.hk 
 
Co-Principal Investigator 
Dr. Yoke-Lim Soong 
National Cancer Centre Singapore 
11 Hospital Drive 
Singapore 169610 
Soong.yoke.lim@Singhealth.com.sg 
 
Co-Principal Investigator 
Dr Darren Ming Chun POON  
Department of Clinical Oncology 
Prince of Wales Hospital 
Sir YK Pao Center for Cancer 
The Chinese University of Hong Kong 
30-32 Ngan Shing Street, Shatin, Hong Kong 
Tel: (852) 3505 1042/ Fax (852) 2632 5816 
pmc754@ha.org.hk 
 
 
 
 
 

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TABLE OF CONTENT 
1.0 
TRIAL SUMMARY .................................................................................................... 6 
2.0 
TRIAL DESIGN .......................................................................................................... 6 
2.1 
Trial Design .............................................................................................................. 6 
2.2 
Trial Diagram .......................................................................................................... 7 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................. 8 
3.1 
Primary Objective & Hypothesis ........................................................................... 8 
3.2 
Secondary Objective & Hypothesis ....................................................................... 8 
3.3 
Exploratory Objective ............................................................................................ 8 
4.0 
BACKGROUND & RATIONALE ............................................................................ 8 
4.1 
Background .............................................................................................................. 8 
4.1.1 Pharmaceutical and Therapeutic Background ....................................................... 9 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 10 
4.2 
Rationale ................................................................................................................ 10 
4.2.1 Rationale for the Trial and Selected Population .................................................. 10 
4.2.2 Justification for Dose........................................................................................... 11 
4.2.3 Preliminary Safety Data for the Proposed Combination Regimens .................... 12 
4.2.4 Rationale for Endpoints ....................................................................................... 13 
5.0 
METHODOLOGY .................................................................................................... 19 
5.1 
Study Population ................................................................................................... 19 
5.1.1 Participant Inclusion Criteria............................................................................... 19 
5.1.2 Participant Exclusion Criteria ............................................................................. 22 
5.1.3 Lifestyle Restrictions ........................................................................................... 23 
5.1.4 Pregnancy ............................................................................................................ 24 

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5.1.5 Use in Nursing Women ....................................................................................... 24 
5.2 
Trial Treatments ................................................................................................... 24 
5.2.1 Timing of Dose Administration ............................................................................. 28 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab ............................................................................................ 35 
5.2.3 Radiotherapy ..................................................................................................... 42 
5.3 
Randomization or Treatment Allocation ............................................................ 50 
5.4 
Stratification .......................................................................................................... 50 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 50 
5.5.1 Acceptable Concomitant Medications ................................................................. 50 
5.5.2 Prohibited Concomitant Medications .................................................................. 50 
5.5.3 Rescue Medications & Supportive Care ............................................................. 51 
5.6 
Participant Withdrawal/Discontinuation Criteria ............................................. 52 
5.7 
Participant Replacement Strategy ....................................................................... 53 
5.8 
Clinical Criteria for Early Trial Termination .................................................... 53 
6.0 
TRIAL FLOW CHART............................................................................................ 54 
6.1 
Study Flow Chart from Screening to End of Maintenance Chemotherapy .... 54 
6.2 
Study Flow Chart from End of Concurrent Chemo-radiation to 3 Years Post 
Treatment ............................................................................................................... 57 
7.0 
TRIAL PROCEDURES ............................................................................................ 59 
7.1 
Trial Procedures .................................................................................................... 59 
7.1.1 Administrative Procedures .................................................................................. 59 
7.1.2 Clinical Procedures/Assessments ........................................................................ 62 
7.1.3 Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory64 
7.1.4 Tumor Imaging and Assessment of Disease ....................................................... 64 
7.1.5 Laboratory Procedures/Assessments ................................................................... 71 

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7.1.6 Other Procedures ................................................................................................. 74 
7.1.7 Visit Requirements .............................................................................................. 74 
7.2 
Assessing and Recording Adverse Events ........................................................... 75 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to MSD ........................................................................................... 77 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to MSD ................... 77 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to MSD ................ 78 
7.2.4 Evaluating Adverse Events ................................................................................. 80 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ....................................... 85 
8.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 85 
8.1 
Statistical Analysis Plan Summary ...................................................................... 85 
8.2 
Statistical Analysis Plan ........................................................................................ 88 
8.2.1 Sample Size and Power ....................................................................................... 88 
8.2.2 Statistical Methods .............................................................................................. 91 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 93 
9.1 
Investigational Product ......................................................................................... 93 
9.2 
Packaging and Labeling Information .................................................................. 94 
9.3 
Clinical Supplies Disclosure ................................................................................. 94 
9.4 
Storage and Handling Requirements .................................................................. 94 
9.5 
Returns and Reconciliation .................................................................................. 94 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 95 
11.0 
References .................................................................................................................. 97 
12.0 
APPENDICES ......................................................................................................... 101 
Appendix 1: ECOG Performance Status ...................................................................... 101 
Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ... 102 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing ................................... 103 
Contraception Requirements ......................................................................................... 103 
Pregnancy Testing ......................................................................................................... 105 
Appendix 4:  Description of the iRECIST Process for Assessment of Disease 
Progression ........................................................................................................... 106 
Appendix 5: Collection and Management of Specimens for Future Biomedical 
Research ............................................................................................................... 110 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
NEO-SPACE trial: Pembrolizumab and chemoradiation in 
nasopharyngeal cancer  
Trial Tracking Number 
MISP 56746 
Trial Phase 
Phase 2 
Clinical Indication 
Previously untreated stage IVA nasopharyngeal cancer 
Trial Type 
Interventional 
Type of control 
Historical control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, Open label 
Treatment Groups  
Single arm: 
Neoadjuvant pembrolizumab-gemcitabine-cisplatin followed by 
concurrent pembrolizumab-cisplatin-radiation and then maintenance 
pembrolizumab 
Number of trial participants 
46 subjects 
Estimated enrollment period 
18 months 
Estimated duration of trial 
36 months 
Duration of Participation 
24-36 months 
Estimated average length of 
treatment per patient 
Total 51 weeks for 17 doses of pembrolizumab: 
o 
Neoadjuvant pembrolizumab-chemotherapy: 6 weeks (2 doses of 
pembrolizumab) 
o 
Concurrent pembrolizumab-chemoradiation: 9 weeks (3 doses of 
pembrolizumab 
o 
Maintenance pembrolizumab: 36 weeks (12 doses of 
pembrolizumab) 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open label, single arm, non-randomized, multi-site, phase 2 clinical trial of 
neoadjuvant pembrolizumab in combination with gemcitabine-cisplatin for 2 cycles, 
followed by concurrent pembrolizumab-cisplatin-radiation, and then maintenance 
pembrolizumab monotherapy given every 3 weeks for a total treatment duration of 12 months, 
in previously untreated stage IVA (UICC 8th Edition) nasopharyngeal cancer (NPC). 

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2.2 
Trial Diagram 
 
 

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3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective:  
To evaluate the efficacy of incorporating pembrolizumab into standard chemoradiation 
protocol in locally advanced, stage IVA NPC. 
Hypothesis:   
Pembrolizumab in combination with 2 cycles of neoadjuvant gemcitabine and cisplatin 
chemotherapy followed by concurrent pembrolizumab-cisplatin-radiation and then 
maintenance pembrolizumab for total treatment duration of one year improves progression free 
survival compared to patients treated with current standard treatment in stage IVA NPC. 
3.2 
Secondary Objective & Hypothesis 
(1) Objective:   
To determine the overall safety, tolerability, one- and two-year rates of distant metastases, loco-
regional progression, second primary cancers, and overall survival for Stage IVA 
nasopharyngeal carcinoma treated with induction pembrolizumab-cisplatin-gemcitabine 
chemotherapy followed by concurrent pembrolizumab-cisplatin-radiation and then 
maintenance pembrolizumab for total treatment duration of 12 months. 
Hypothesis:   
The sequential strategy of neoadjuvant pembrolizumab-cisplatin-gemcitabine chemotherapy 
followed 
by 
concurrent 
pembrolizumab-cisplatin-radiation 
and 
then 
maintenance 
pembrolizumab for total treatment duration of 12 months is feasible, reduces distant metastases, 
and improves local-regional control and overall survival, without increase in second primary 
cancer or death, compared to patients treated with current standard treatment in stage IVA NPC. 
3.3 
Exploratory Objective 
(1) 
Objective:  
To evaluate potential tissue and blood biomarker predictive of clinical outcome. 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 

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interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Pembrolizumab (Keytruda®) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator Brochure. 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (1).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (2, 3). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (4, 5). 
The structure of murine PD-1 has been resolved (6).  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated 
protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade (5, 7-
9).  The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
(10, 11).  As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in nasopharyngeal cancer (NPC).  

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4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Population 
Nasopharyngeal cancer (NPC) is a predominantly Asian disease, with approximately 80% of the 
world’s 86000 cases occurring in Asian countries (12). With advances in radiation technology such 
as intensity modulation radiotherapy (IMRT), local and nodal control exceeds 85-90% in most 
reported series. Distant metastasis remains the main mode of failure, particularly in locally 
advanced NPC. As an example, in a study by Pan et al (13), 5 years local and nodal control of 86% 
and 89% was achieved with concurrent chemo-IMRT respectively, but distant failure free survival 
of 77% and 72% was reported for patients with T4 and N3 disease respectively (AJCC 8th edition).  
Current strategies to reduce distant metastasis, including the use of adjuvant chemotherapy have 
been inconclusive. One major disadvantage of adjuvant chemotherapy following the completion of 
chemoradiation is that approximately half of patients are unable to complete the full 3 cycles of 
adjuvant chemotherapy, due to treatment related toxicities. The use of induction chemotherapy has 
two potential benefits: the first is to downsize the tumour, making radiotherapy more tolerable; the 
second, it allows for patients to be able to complete the chemotherapy before the onset of 
chemoradiation associated toxicities.  
There are at least two studies now supporting the use of induction chemotherapy. A recent 
publication by Ma et al (14), showed the addition of induction docetaxel, cisplatin and fluorouracil 
prior to concurrent chemoradiation resulted in 8% improvement (80% vs 72%) in 3-year failure-
free survival. Similarly, Cao et al showed that 2 cycles of cisplatin and fluorouracil prior to 
chemoradiation improved the 3 years disease free survival in patients (15). 
Gemcitabine and cisplatin has been shown to be more effective than 5-FU plus cisplatin as first-
line treatment for recurrent or metastatic nasopharyngeal carcinoma (16). There are currently no 
studies looking at the addition of anti-PD-1 monoclonal antibody such as pembrolizumab either in 
the in the induction or maintenance setting. Hence, we are proposing the use of pembrolizumab in 
combination with 2 cycles of gemcitabine and cisplatin chemotherapy followed by concurrent 
chemoradiation. Following completion of chemoradiation, patients will receive maintenance 
pembrolizumab for total treatment duration of one year. The main objective of this Phase II study 
is to test the safety, efficacy and tolerability of this combination in the setting of locally advanced 
NPC (limited to T4 or N3, stage IVA by UICC 8th edition), as this group has the greatest risk of 
recurrence after the current standard treatment. 
Preliminary evidence supporting the clinical efficacy of pembrolizumab monotherapy in NPC 
came from the KEYNOTE-028 trial, which was a global, nonrandomized, multi-cohort, phase Ib 
trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (17). Key eligibility 
criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard 

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therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. 
Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression 
or unacceptable toxicity. In the initial report, twenty-seven NPC patients was evaluated. Median 
age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for recurrent or 
metastatic NPC; 70.4% had received three or more therapies. Partial response and stable disease 
were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) 
over a median follow-up of 20 months. Drug-related adverse events that occurred in 15% or more 
of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and 
fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and 
there was one drug-related death (sepsis). It was concluded that pembrolizumab demonstrated 
antitumor activity and a manageable safety profile in patients with recurrent or metastatic NPC. 
4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 

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saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
4.2.3 Preliminary Safety Data for the Proposed Combination Regimens 
A phase 1b basket trial of pembrolizumab plus chemotherapy in patients with advanced cancer 
(PembroPlus) reported that standard dose pembrolizumab can be safely combined with 
gemcitabine, gemcitabine plus nab-paclitaxel, gemcitabine plus vinorelbine, irinotecan, and 
liposomal doxorubicin. In this study, pembrolizumab (2 mg/kg) was administered intravenously 
over 30 minutes every 21 days and infused prior to the assigned chemotherapy arm. There was no 
signal of increased immune-related adverse events, and dexamethasone pre-medication 
administered before systemic chemotherapy appear to decrease the frequency of high grade adverse 
events (18). 
Nivolumab, another anti-PD1 check point inhibitor, has been combined with gemcitabine-cisplatin, 
pemetrexed-cisplatin or paclitaxel-carboplatin given for 4 cycles followed by nivolumab 
monotherapy in CheckMate 012, a phase 1, multi-cohort study (19). The reported safety profile 
was consistent with that expected for individual agents. Discontinuation related to adverse events 
appeared greater with the combination. The observed frequencies of immune-related adverse 
events affecting skin, gastro-intestine, renal, and pulmonary organs was greater than expected with 
single agent nivolumab. However, these treatment-related adverse events were effectively 
managed with corticosteroid or infliximab and did not lead to any deaths. Chemotherapy and 
nivolumab were associated with a risk of pneumonitis; however, discontinuation as a result of 
treatment related pneumonitis occurred only during nivolumab monotherapy. These results 
suggested that corticosteroid premedication administered for chemotherapy during the combination 
cycles may have prevented or partially treated pneumonitis, which worsened during nivolumab 
monotherapy when no regular corticosteroid premedication was given. 
In a phase I/II study of pembrolizumab with gemcitabine in patients with previously treated 
advanced non-small cell lung cancer, pembrolizumab 200 mg IV D1 and gemcitabine 1250 mg/m2 
IV D1 and D8 every 3 weeks was considered feasible for on-going phase 2 evaluation (20). In 
patients with platinum-treated metastatic urothelial cancer, pembrolizumab 200 mg IV every 3 
week plus either full dose gemcitabine (1000 mg/m2 D1 and D8) or docetaxel was found to be 
feasible with encouraging anti-tumor activity (21).  

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KeyNote-059 studied the efficacy and safety of pembrolizumab alone or in combination with 
chemotherapy in patients with advanced gastric or gastroesophageal cancer. In cohort 2, 
pembrolizumab (200 mg Q3w) was combined with cisplatin (80 mg/m2 Q3W) and either 5FU or 
capecitabine. In the preliminary report of 25 patients, the overall response rate was 60% with 
acceptable safety profile (22) 
In the randomised, phase 2 cohort of the open-label KEYNOTE-021 study, the combination of 
pembrolizumab, carboplatin and pemetrexed achieved superior response rate and progression 
survival with similar rate of adverse events compared to carboplatin and pemetrexed alone (23). In 
the phase 3 KEYNOTE-189 trial, the addition of pembrolizumab to carboplatin and pemetrexed 
resulted in significantly longer overall survival and progression-free survival than chemotherapy 
alone, without increase in adverse events. Adverse events of grade 3 or higher occurred in 67.2% 
of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-
combination group (24). 
Powell et al presented preliminary report on the safety of pembrolizumab with chemoradiation in 
locally advanced squamous cell carcinoma of head and neck at ASCO 2017. Pembrolizumab can 
be safety delivered with weekly cisplatin and radiation in head and neck cancer with no new 
toxicity signals seen (25). 
Pembrolizumab in combination with cisplatin and gemcitabine is being studied in the following 
on-going clinical trials: 
- Phase Ib/II Study of Neoadjuvant Pembrolizumab With Gemcitabine-Cisplatin (Cisplatin-
Eligible) or Gemcitabine (Cisplatin-Ineligible) in Subjects With T2-4aN0M0 Urothelial Cancer: 
HCRN GU14-188 (ClinicalTrials.gov: NCT02365766). 
- Phase II Single Arm Study of Gemcitabine and Cisplatin Plus Pembrolizumab as Neoadjuvant 
Therapy Prior to Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer 
(ClinicalTrials.gov: NCT02690558) 
- A Phase III Randomized, Controlled Clinical Trial of Pembrolizumab With or Without Platinum-
Based Combination Chemotherapy Versus Chemotherapy in Subjects With Advanced or 
Metastatic Urothelial Carcinoma (ClinicalTrials.gov: NCT02853305) 
 
4.2.4 Rationale for Endpoints 
The baseline rates used in this study are based upon the completed phase II studies of RTOG 0615 
bevacizumab-cisplatin-RT (26) and cetuximab-cisplatin-RT (27). 
The primary efficacy endpoint will focus on 2-year progression free survival. This will include 
both local progression and distant metastasis, which were the major failure for T4 and N3 disease 
respectively. The progression and survival rates in this study will be compared with the historical 
rates from previous publications.  

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Since there is limited experience with the incorporation of pembrolizumab into sequential 
neoadjuvant-concurrent chemoradiation followed by maintenance pembrolizumab regimen, this 
study will determine whether the full regimen can be delivered per protocol prescription and is safe.  
A two stage design with an interim safety analysis after accrual of the first 14 subjects will be 
adopted. There is particular concern with the incidence in NPC patients receiving curative intent 
of chemoradiation schedule with increased rate of grade 4 mucositis or skin reaction, which were 
the dose-limiting toxicity for head and neck radiation and could potentially be aggravated after 
incorporation of pembrolizumab into standard chemoradiation protocol. Therefore, the incidence 
of patients with either grade 4 mucositis/skin reaction or any grade 5 adverse event attributed to 
the protocol treatment will be used to evaluate safety.  The incidence of these events will be 
examined in the first year from the start of treatment and then beyond the first year.  
Patient tolerability will be evaluated in terms of protocol treatment delivery. The protocol treatment 
regimen will be considered as 3 treatment components (neoadjuvant, concurrent and maintenance 
components) for tolerability assessment.  
 
4.2.4.1 Efficacy Endpoints 
Primary efficacy endpoint: 
-Two-year progression free survival 
 
Secondary Endpoints 
-Grade 4 mucositis/skin reaction or any Grade 5 adverse event assessed to be definitely, probably, 
or possibly related to protocol treatment during the first year 
-Grade 4 mucositis/skin reaction or any Grade 5 adverse event assessed to be definitely, probably, 
or possibly related to protocol treatment occurring after the first year; 
-Patient tolerability to each component (neoadjuvant, concurrent and maintenance part) of the 
protocol treatment regimen; 
-Other ≥ Grade 3 adverse events; 
-Death during or within 30 days of discontinuation of protocol treatment; 
-One- and two-year distant metastases rates;  
-One- and two-year local-regional progression rates;  
-One- and two-year second primary rates; 
-One- and two-year overall survival rates. 

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4.2.4.2 Biomarker Research 
Rationale for measuring PD-L1 expression 
PD-L1 expression is the most extensively studied biomarker with respect to predicting the efficacy 
of anti–PD-1 or anti–PD-L1 therapies. In pembrolizumab trials for melanoma and non–small-cell 
lung cancer (NSCLC), high PD-L1 positivity in tumor cells was strongly correlated with tumor 
response and survival. However, such a correlation was observed in HNSCC only when PD-L1 
staining in immune cells was included (28). In the phase Ib trial of pembrolizumab (KEYNOTE-
028) which only enrolled patients with PD-L1–positive tumor, pembrolizumab demonstrated 
antitumor activity and a manageable safety profile in patients with recurrent or metastatic NPC 
(RM-NPC) (17). A randomized phase III study of pembrolizumab in patients with platinum-
pretreated RM-NPC, irrespective of PD-L1 status, is currently recruiting patients 
(ClinicalTrials.gov NCT02611960) and will help to define the efficacy of pembrolizumab in 
patients with PD-L1–negative NPC. In a recent phase 2 trial of nivolumab in RM-NPC, there was 
no significant statistical association between PD-L1 expression in tumor and/or immune cells with 
survival or response. However, a higher proportion of objective responses were observed in 
patients with PD-L1-positive (> 1% expression) than those with PD-L1 negative tumors. 
Furthermore, responders who experienced a greater ‘depth’ of tumor shrinkage have PD-L1-
positive tumors. The complete responder in that study possessed the highest level of PD-L1 
expression in the immune cells (29). Therefore further study on the relationship of PD-L1 status 
and treatment outcome in previously untreated NPC cohort is warranted. 
 
Rationale for measuring plasma EBV DNA  
Pre-treatment plasma EBV DNA has been shown to correlate with cancer stage, clinical outcome 
and prognosis in NPC (30-32). Post-RT plasma EBV DNA has even better correlation with 
prognosis and has been used to monitor recurrence during post-treatment surveillance (33, 34). 
Elevated plasma EBV DNA has been shown to predate clinical recurrence by 3 to 7 months (35).  
Detectable or high level of post-RT plasma EBV DNA can predict a poor progression-free or 
overall survival when compared with those with undetectable or low EBV DNA level, and 
represent a biomarker of subclinical residual disease (33). In a phase II prospective study on 31 
loco-regionally advanced nasopharyngeal carcinoma patients who underwent neoadjuvant 
chemotherapy followed by concurrent chemoradiation, plasma EBV DNA was obtained at 
baseline, weekly during treatment, 4-6 weeks post-treatment, and q2 months for one year after 
treatment. Plasma EBV DNA level was found to be increased significantly in 8 of 9 patients who 
experienced treatment failure.  Patients who had no evidence of disease did not experience elevated 
serum EBV DNA levels (33). 
Given the above results, we will collect blood for plasma EBV DNA analysis at several specified 
time points for this current study. 
 

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Rationale for Translational Research: 
As the field of biomarker research in immune-oncology is evolving, there is as yet no standardized 
biomarker to predict the response to immune checkpoint inhibitors. We will prospectively collect 
tissue and blood samples to study immune related biomarkers. Tumor tissues will be obtained 
before and after neoadjuvant therapy, and post-RT. Plasma and immune cells will be isolated at 
study entry, post-neoadjuvant therapy, post-RT, during maintenance pembrolizumab and at the end 
of study. 
Tissue and blood samples collection schema:  
 
 
 
▪ 
Time point for fresh tumor biopsy:  
T0 – stands for timepoint 0 and is the baseline tumor biopsy (before C1D1) 
T1 – stands for timepoint 1 and is the tumor biopsy after C2D1 neoadjuvant chemo 
(before RT) 
T2 – stands for timepoint 2 and is the tumor biopsy at 6-8 weeks after completion of 
RT  
T3 – stands for timepoint 3 and is the tumor biopsy at any time during or after 
treatment completion when suspected recurrent or metastatic lesion present 

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▪ 
Time point for blood sample collection: 
o B0 – Baseline 
o B1 – Cycle 1 Day 1 
o B2 – Cycle 2 Day 1 
o B3 – Week 1(before RT) 
o B4 – Week 4 
o B5 – 1week post RT 
o B6 – 6-8 weeks post RT 
o B7-B10 – 3, 6, 9 and 12 months post RT (x4) (allow window of ± 7 days for 3 
month post-RT, and ± 10 days for time points of 6 months and beyond) 
 
1) Baseline Archival Tumor Tissue Collection  
All subjects should submit either a newly obtained core or excisional biopsy or archival tissue 
(FNA not adequate for both archival and new tissue samples) to a central lab for characterization 
of PD-L1 status.  
2) Fresh Tumor Biopsy Collection 
a) 1 core of tissue: Fixed in Formalin for Paraffin Embedding (FFPE) for immunohistochemistry 
(IHC) study  
b) 1 core of tissue: Fresh in Hypothermosol or frozen in freezing media for single cell RNA 
sequencing (scRNAseq) study  
c) 1 core of tissue: fresh frozen sample for bulk RNA/ TCR sequencing study  
3) Blood Sample Collection 
a) BD Vacutainer CPT with Sodium Citrate (8 mL x 2): for peripheral blood mononuclear cells 
(PBMC) isolation. 
b) K2EDTA Tubes for plasma DNA collection (5 mL x 1 for pEBV DNA alone; 9 ml x2 when 
collect for both pEBV DNA and ctDNA). 
 
The collected cells will be utilized for downstream profiling and functional experiments, including 
but not limited to RNA-sequencing (bulk and/or single cell), whole exome or DNA sequencing, 
TCR/BCR sequencing, Total-seq, flow cytometry, mass cytometry, and/or cell line generation for 
monocellular and/or co-culture experiments (e.g. organoids/tumoroids, fibroblasts, immune cells). 
Cell lines may be frozen down for long term storage at MSD or CUHK for future research purposes. 
 
Refer to Operations Manual for technical details. 

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Estimated blood collection volume: 
  
  
5.0 METHODOLOGY 
5.1 
Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of nasopharyngeal carcinoma (from 
primary lesion and/or lymph nodes) of WHO type II-III histology type will be enrolled in 
this study. 
2. NPC associated with EBV infection, determined as: 
a. The presence of EBV has been confirmed in the tumour by immunohistochemistry 
for EBV antigens or in situ hybridization for EBV early RNA (EBER), or 
 
Blood sample time point and volume (ml) 
Blood 
sample type 
B0 
B1 
B2 
B3 
B4 
B5 
B6 
B7 
B8 
B9 
B10 
 
ctDNA 
18 
- 
- 
18 
18 
- 
18 
18 
18 
18 
18 
 
pEBV DNA 
- 
5 
5 
- 
- 
5 
- 
- 
- 
- 
- 
 
PBMC 
16 
- 
- 
16 
16 
- 
16 
16 
16 
16 
16 
Total volume 
(mL) 
34 
5 
5 
34 
34 
5 
34 
34 
34 
34 
34 

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b. NPC occurred in association with a raised serum titre of IgA to EBV viral capsid 
antigen (VCA) or early antigen (EA) in a patient living in endemic area of high 
incidence of EBV+ undifferentiated NPC, or  
c. NPC in the context of an elevated circulating EBV genome level 
3. AJCC 8th edition Stage IVA (i.e any T4 or any N3) based on the following diagnostic 
workup: 
a. Evaluation of tumor extent with MRI of the nasopharynx and neck. If MRI is 
medically contraindicated, CT scan with ≤ 3 mm and intravenous contrast is 
acceptable. 
b. Distant metastasis staging: 
i. CT scan with contrast of the chest, abdomen, and pelvis or a total body 
PET/CT scan; 
ii. Bone scan, if a PET/CT scan is not performed. 
 
4. A male participant must agree to use contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 120 days plus an additional 120 days 
(a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose 
after the last dose of study treatment and refrain from donating sperm during this period. 
 
5. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days plus 30 days (a menstruation cycle) for study 
treatments with risk of genotoxicity after the last dose of study treatment. 
 
6. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
 
7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) 
tissue blocks are preferred to slides.  Newly obtained biopsies are preferred to archived 
tissue. 
Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing 
laboratory within 14 days from the date slides are cut.  

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8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7 days prior to the date of 
allocation/randomization.  
9. Have adequate organ function as defined in the following table (Table 1).  Specimens must 
be collected within 10 days prior to the start of study treatment. 
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL a 
Renal 
 
Creatinine OR 
Measured or calculated b creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
>50 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Proteinuria 
< 2+ by dipstick urinalysis 
If dipstick is ≥ 2+, then 24 hr urine protein 
must be < 1.0 g or urine protein creatinine 
ratio (UPC) must be < 1 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  

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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to first dosing 
(see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first 
dose of study treatment, another pregnancy test (urine or serum) must be performed and must be 
negative in order for subject to start receiving study medication. 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137). 
 
3. Has received any prior systemic anti-cancer therapy including investigational agents. 
 
4. Has received any prior radiotherapy. 
 
5. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
 
7. Has a known additional malignancy.  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. 
8. Has known active CNS metastases and/or carcinomatous meningitis.   
9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
b Creatinine clearance (CrCl) should be calculated per the Cockcroft-Gault equation. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
11. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a known history of Human Immunodeficiency Virus (HIV).  Note: No HIV testing is 
required unless mandated by local health authority. 
14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection. Subjects who have been treated and now have a viral load that is undetectable are 
eligible. 
15. Has a known history of active TB (Bacillus Tuberculosis). 
 
16. Has prior solid organ transplant or bone marrow transplant.   
 
17. 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.   
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
19. 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. 
 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 

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5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants 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).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to MSD within 2 
working days if the outcome is a serious adverse experience (eg, 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 MSD.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy must be reported to MSD and followed as described in Section 7.2.2. 
5.1.5 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, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 
Trial Treatments 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. The treatment to be used in this trial is outlined below in 
Table 2. 
 
 

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Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Neoadjuvant phase (pembrolizumab-gemcitabine-cisplatin): 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Gemcitabine 
1000 mg/m2 
Q3W 
IV infusion 
Days 1 and 8 per 3 
week cycle 
Experimental 
Cisplatin 
80 mg/m2 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Note: 
- For two cycles. 
- Pembrolizumab will be administered prior to chemotherapy when both agents are delivered on the same 
day. 
-Body surface area (BSA) should be calculated by Du Bois formula. 
Concurrent phase (pembrolizumab-cisplatin-radiation): 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Week 1, 4 and 7 of 
IMRT 
Experimental 
Cisplatin 
40 mg/m2 
Q1W 
IV infusion 
Weekly from week 1 
to 7 of RT 
Standard of 
care 
Radiation (refer to section 5.2.3) 
Standard of 
care 
Note: 
- Cisplatin:  40 mg/m2/day, weekly during radiation, with a maximum cumulative dose of 280 mg/m2. 
- Pembrolizumab will be administered prior to chemotherapy when both agents are delivered on the same 
day. 
- Body surface area (BSA) should be calculated by Du Bois formula. 
Maintenance phase (pembrolizumab monotherapy) 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
Note: 
- Start 4 weeks after last dose of RT. 
- Continue for total of 12 doses  
Note: 
Pembrolizumab will be given for 2 doses in neoadjuvant phase, 3 doses in concurrent phase, and 12 doses 
in maintenance phase, for total of 17 doses. 
 
 
 

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General requirements for initiation of each chemotherapy cycle 
• 
ECOG Performance status < 3; 
• 
CBC/differential and chemistries obtained within 1 day prior to beginning chemotherapy, 
with adequate bone marrow function defined as follows: Absolute Neutrophil Count (ANC) ≥ 
1,000 cells/mm3 and Platelets ≥ 100,000 cells/mm3; 
• 
AST/ALT and total bilirubin < grade 2  (CTCAE, v. 4); 
• 
Serum creatinine < grade 2 (CTCAE, v. 4); 
• 
All AEs must be < grade 3 (CTCAE, v. 4).  
 
General requirement for initiation of each pembrolizumab dose 
 
Pembrolizumab should be withhold for immune-related adverse events (AEs) of grade 2 or above 
that is possibly associated with pembrolizumab (refer to Table 3). 
 
Exceptions are: 
• 
Laboratory values that do not have any clinical correlate (eg, amylase or lipase abnormality 
that is not associated with symptoms or clinical manifestations of pancreatitis). 
• 
Nausea and vomiting controlled by medical therapy. 
• 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor. 
 
 
 
Administration guideline for high-dose cisplatin (in cisplatin-gemcitabine regimen) 
High dose cisplatin is highly emetogenic. Many institutions will have standard guidelines for the 
administration of cisplatin at the doses used in this study. For purposes of this protocol, individual 
investigators may use these local guidelines for cisplatin administration. One possible approach is 
outlined below. This may need to be modified based on local guidelines and patient related factors 
(e.g. the substitution of normal saline in diabetic patients). Similarly, the anti-emetic regimen for 
this combination is to be determined by the local investigator. 
• 
High-Dose Cisplatin Anti-Emetic Administration Guidelines:  Substance P antagonist such 
as aprepitant, 125 mg PO on day 1 prior to cisplatin and 80 mg on days 2 and 3. 5-HT3 antagonists 
(e.g. ondansetron, 16 mg PO prior to cisplatin and 8 mg PO up to 3 times daily on days 2 and 3 
following cisplatin. Dexamethasone x 3 days prior to cisplatin, 12 mg PO or IV on day 1 and 8 mg 
on days 2 and 3. Use of other anti-nausea meds such as metoclopramide, lorazepam, olanzapine, 
or prochlorperazine is left to the discretion of the investigator. 
• 
Cisplatin Pre-Hydration Guidelines: Pre-hydration with 1 liter D5 ½ NS and 40 meq KCL/ 
liter x 1 liter prior to cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin. 
• 
Cisplatin Administration: Cisplatin, 80 mg/m2 over 60-120 minutes IV in 250 cc NS.  See 
section 5.2.2 for guideline on dose modifications. 

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• 
Cisplatin Post-Hydration Guidelines: Following the end of the cisplatin administration, at 
least an additional 1.5  liters of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and  25 g mannitol 
should be infused over 2-4 hours. On the second and third day following cisplatin, patient should 
be encouraged to take at least 2 liters of fluid per day orally.  Patients unable to orally self-hydrate 
should be considered for additional IV hydration on these days with NS. 
 
Administrative guideline for gemcitabine 
The preparation and administration of gemcitabine should follow local treatment guidelines. Pre-
medication with steroids prior to IV infusion is permitted as per local standard of care. However, 
the following recommendations should be taken into account. 
 
Gemcitabine infusion: 1000 mg/m2 in 250 ml NS over 30 minutes on days 1 and 8 of a 3-week 
cycle.  
Note: The final concentration of the prepared drug must be in the range of 38 mg/ml to 0.1 mg/ml. 
 
 
Myeloid growth factor use during neoadjuvant chemotherapy 
Pegfilgrastim or Filgrastim may be used according to institutional guidelines. We recommend 
following the NCCN myeloid growth factor use guidelines (see NCCN.org). However, there is lack 
of evidence on the combined use of myeloid growth factor and pembrolizumab. 
Note: Hematologic growth factors for neutropenia or anemia are not allowed during concurrent 
cisplatin and radiation treatment.  
 
Administration guidelines for low-dose cisplatin concurrent with radiation  
No concurrent cisplatin will be administered after the final week of radiation, but the final dose of 
cisplatin may be administered following the last dose of radiation if it is administered within the 
same calendar week. Investigators should strive to administer cisplatin on the same day each week 
but variance of 1 day is acceptable for vacations, holidays, etc.  If radiation treatments are held for 
toxicity, cisplatin dosing should also be held. 
High dose cisplatin is highly emetogenic. While this protocol is using an intermediate dose of 
cisplatin (40mg/m2) when administered concurrently with radiation, investigators should be 
prepared to use aggressive prophylactic antiemetics and hydration. Many institutions will have 
standard guidelines for the administration of cisplatin at the doses used in this study. For purposes 
of this protocol, individual investigators may use these local guidelines for cisplatin administration. 
One possible approach is outlined below. This may need to be modified based on local guidelines 

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and patient related factors (e.g. the substitution of normal saline in diabetic patients). Similarly, the 
anti-emetic regimen for this combination is to be determined by the local investigator. 
• 
Low-dose Cisplatin  anti-emetic administration guidelines:  5-HT3 antagonists (e.g. 
ondansetron 16 mg  PO prior to cisplatin  and 8 mg PO up to  3 times daily on days 2 and 3 
following cisplatin weekly.  Dexamethasone x 3 days starting prior to the cisplatin dose weekly, 
12 mg on day 1 and 8 mg on days 2 and 3 each week. Use of other anti-nausea meds such as 
aprepitant, metoclopramide, or prochlorperazine is left to the discretion of the investigator. 
• 
Low-dose Cisplatin pre-hydration guidelines: Pre-hydration with 1 liter D5 ½ NS and 40 
meq KCL/ liter x 1 liter prior to cisplatin. Mannitol 12.5 gm IV immediately prior to cisplatin. 
• 
Low-dose Cisplatin administration: Cisplatin, 40 mg/m2 over 30-60 minutes IV in 250 cc 
NS.  See Section 7.9 for dose modifications. See above discussion on scheduling and number of 
doses concurrent with radiation. 
• 
Low-dose Cisplatin post-hydration guidelines: Following the end of the cisplatin 
administration, an additional  liter of ½ NS with 10 meq KCL/L, 8 meq MgSO4/L, and  25 g 
mannitol should be infused over 2 hours. On the second and third day following cisplatin, patient 
should be encouraged to take at least 2 liters of fluid per day orally.  Patients unable to orally self-
hydrate should be considered for additional IV hydration on these days with NS. 
 
Administration Guideline for Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes 
is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Pembrolizumab will be administered prior to chemotherapy when both agents are delivered on the 
same day (18, 23). 
 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 

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5.2.2 Dose Modification 
Dose Modification for neoadjuvant cisplatin-gemcitabine 
 
Cisplatin Dose Levels During Neoadjuvant Cisplatin-Gemcitabine 
Starting Dose 
Dose Level -1 
Dose Level -2 
80 mg/m2 
60 mg/m2 
45 mg/m2 
 
Substitution of carboplatin for cisplatin is permitted in the case if either renal or ototoxicity as 
defined below. Investigators may choose to substitute carboplatin for cisplatin according to the 
following parameters: 
 
See section above and parameters in below sections for situations in which 
carboplatin substitution for cisplatin is permitted during neoadjuvant cisplatin-
gemcitabine 
Carboplatin Dose Levels during neoadjuvant chemotherapy 
Carboplatin Starting 
Dose 
Carboplatin Dose Level -1 
Carboplatin Dose 
Level -2 
AUC 5 
AUC 4 
AUC 3 
 
 
 
Gemcitabine Dose Levels During Neoadjuvant Cisplatin-Gemcitabine 
Starting Dose 
Dose Level -1 
Dose Level -2 
1000 mg/m2 
800 mg/m2 
600 mg/m2 
 
Cisplatin Dose Modifications for Hematologic Adverse Events during Neoadjuvant 
Cisplatin-Gemcitabine 
Chemotherapy should not be administered until the ANC is at least 1000 cells/mm3 and the platelet 
count is at least 100,000/mm3.  If these parameters are not met, then treatment should be delayed 
in weekly increments until they have recovered to this level, but no more than a 21-day delay is 
permitted.  
Dose reductions for ANC and platelets based on counts at anticipated day of treatment, ONCE 
RECOVERY TO THE ABOVE LEVELS ARE ACHIEVED: 
ANC 
 
Platelets 
Reduction 
At least 1000 mm3  
and 
At least 100,000 
None 
< 1000 mm3 
or 
< 100,000 
One dose level of BOTH 
cisplatin and gemcitabine 
 

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Cisplatin Dose Modifications for Non-Hematologic Adverse Events during neoadjuvant 
cisplatin-gemcitabine 
Neurological Events Attributable to Cisplatin (e.g. peripheral neuropathy): Grade 2, decrease 
cisplatin by one dose level. ≥ grade 3, hold cisplatin. 
Ototoxicity:  Should patients develop clinical evidence of ototoxicity, further audiometric 
evaluation is required. A neurologic deficit should be distinguished from a conductive loss from 
fluid in the Eustachian tube. Because no AE scale, including the CTCAE v. 4, has been validated 
in terms of correlation with clinically relevant hearing loss, there are no protocol mandates  
requiring dose reduction for audiogram-determined sensorineural hearing loss without an 
analogous clinical high grade ( > grade 2) hearing loss.  However, for clinical grade 3 or higher 
hearing loss, cisplatin should be held, and for grade 2 clinical hearing loss, one dose level reduction. 
Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each cisplatin 
dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not necessary for treatment 
with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine clearance should be obtained by 
urine collection or nomogram calculation (valid only if serum creatinine is not changing rapidly). 
Cisplatin must not be administered until creatinine is ≤ 1.5 or creatinine clearance > 50. Once the 
creatinine has met the above parameters, cisplatin may be restarted with the below modifications 
based on the creatinine at the time the cisplatin was held: In general, cisplatin should be held for 
weekly intervals (rather than restarting cisplatin later in the same week that a dose limiting AE is 
seen) 
Cisplatin dose modifications for creatinine during neoadjuvant cisplatin-gemcitabine 
Creatinine (mg/dL) 
 
Creatinine clearance, 
measured or 
calculated ml/min 
Cisplatin dose 
reduction 
≤ 1.5 
or 
> 50 
No change 
> 1.5 
and 
40-50 
One dose level 
 
Substitution of carboplatin for cisplatin is permitted in the case if either renal or ototoxicity as 
defined below. Investigators may choose to substitute carboplatin for cisplatin according to the 
following parameters: 
 
Carboplatin substitution for cisplatin during neoadjuvant cisplatin-gemcitabine  
for renal toxicity 
Creatinine (mg/dL) 
 
Creatinine 
clearance, measured 
or calculated 
ml/min 
Cisplatin dose 
reduction 

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≤ 1.5 
or 
 ≥ 50 
Use cisplatin 
> 1.5 
and 
40-50 
May substitute 
carboplatin at AUC 
5 
 
 
< 40 
 
Carboplatin substitution for cisplatin during neoadjuvant cisplatin-gemcitabine  
for ototoxicity 
Clinical grade 
hearing loss 
Cisplatin dose reduction 
0, 1 or 2 
Use cisplatin 
3  or greater 
May substitute carboplatin at AUC 5 
 
 
Dose Modification Guidelines for Gemcitabine Hematologic Drug-Related Events  
 
Dose reduction for day 8 gemcitabine 
ANC (x106/L)                  Platelet count 
Gemcitabine Dose 
≥1.0             and              ≥ 100 
100% 
0.5 – 0.99      or              50 – 99 
75% 
< 0.5             or                 <50 
Hold 
Note:  Day 1 of Gemcitabine may be delayed; however, held doses of gemcitabine on day 8 will 
be considered missed doses and will not be delayed or made up. 
Dose Modification Guidelines for Gemcitabine Non-Hematologic Drug-Related Events  
 
Withhold gemcitabine or reduce dose by 50% of full dose for other severe (Grade 3 or 4) non-
hematologic toxicities until resolved to Grade 0-1. 
 No dose modifications are recommended for alopecia, nausea, or vomiting. 
 Permanently discontinue gemcitabine for the following: 
 Unexplained dyspnea or other evidence of severe pulmonary toxicity 
 Severe hepatic toxicity 
 Hemolytic-uremic syndrome 

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 Capillary leak syndrome 
 Posterior reversible encephalopathy syndrome 
 
For additional guidance regarding treatment modification of gemcitabine, please refer to the United 
States package insert (or local prescribing information) for dose modifications for hematologic and 
other non-hematologic toxicities 
 
All Other Non-Hematologic Adverse Events During neoadjuvant cisplatin-gemcitabine 
For grade 3 or 4 events, drugs should be held until resolution to grade 1 or less, then both drugs 
resumed at dose level -1. Gemcitabine doses on day 8 of each cycle will not be made up but merely 
skipped for grade 3 or greater AEs occurring between days 1 and 8.  Neoadjuvant treatment should 
be stopped if greater than grade 2 AEs are not resolved to grade 1 within 3 weeks, and patient 
should proceed directly to next phase of treatment. For specific AEs clearly attributable exclusively 
to one or the other agent (cisplatin or gemcitabine), one level dose reduction only for that agent is 
required. 
 
Cisplatin dose modification during concurrent radiation 
Note: If adverse events prevent the administration of cisplatin during radiation, the patient may 
continue to receive pembrolizumab and radiation therapy. 
Patients will be examined and graded for subjective/objective evidence of developing toxicity 
weekly according to CTCAE, v. 4 while receiving concurrent cisplatin with radiotherapy.  
Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction that, in the 
judgment of the clinician, warrants a break. For chemotherapy attributable AEs requiring a break 
in treatment, resumption of concurrent cisplatin may begin when AEs have recovered to the levels 
specified below. If an AE does not resolve to the levels specified in the sections below prior to the 
calendar week of the last radiation treatment, treatment off protocol can continue according to the 
judgment of the treating physician. 
There will be no dose re-escalation for concurrent cisplatin.  
Chemotherapy dosage modifications are based upon laboratory values obtained within the 24 hours 
prior to cisplatin and interim non-hematologic toxicities during the week prior to a particular 
cisplatin dose. 
The dose modifications for cisplatin (below) are intended to be permanent (i.e., if the patient’s dose 
is reduced to dose level -1, it remains at the reduced dose level). 
Cisplatin Dose Modifications for Hematologic Adverse Events during Concurrent 
Radiation 
Starting Dose 
Dose Level -1 
Dose Level -2 

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40 mg/m2 
30 mg/m2 
23 mg/m2 
 
Chemotherapy must not be administered until the ANC is ≥ 1,000 and platelets are ≥ 100,000. If 
not, delay 7 days. Cisplatin should be held every week until the above ANC and platelet parameters 
are met. Dose reductions when cisplatin is resumed after delay for low ANC or platelets will be as 
follows, based upon counts at time cisplatin was held. 
ANC 
 
Platelets 
Reduction 
≥ 1000 mm3  
and 
≥ 75,000 
None 
< 1000 mm3 
or 
< 75,000 
One dose level 
Note: Hematologic growth factors for neutropenia or anemia are not allowed during concurrent 
cisplatin and radiation treatment. 
Substitution of carboplatin for cisplatin  is permitted in the case if either renal or ototoxicity as 
defined below. Investigators may choose to substitute carboplatin for cisplatin according to the 
following parameters: 
 
See section above and parameters in below sections for situations in which 
carboplatin substitution for cisplatin is permitted during concurrent chemoradiation 
Carboplatin Dose Levels during concurrent chemoradiation 
Carboplatin Starting 
Dose 
Carboplatin Dose Level -1 
Carboplatin Dose 
Level -2 
AUC 2 
AUC 1.5 
AUC 1 
 
 
If carboplatin has been substituted for cisplatin during neoadjuvant treatment, carboplatin 
substitution should continue during the concurrent treatment.  DOSE REDUCTIONS TO 
CISPLATIN OR CARBOPLATIN DURING NEOADJUVANT PHASE NEED NOT 
TRANSFER TO THE CONCURRENT SETTING UNLESS THERE IS NOT RESOLUTION OF 
TOXICITIES. 
 
Cisplatin Dose Modifications for Non-Hematologic Adverse Events during Concurrent 
Radiation 
Neutropenic Fever: Temperature of 38.5°C with ANC < 1000 is an expected potential complication 
of concurrent chemotherapy and radiotherapy or chemotherapy alone. If neutropenic fever is noted, 
the chemotherapy dose reduction will be determined by the weekly blood counts. See above. 

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Renal Adverse Events: Dose will be modified based on the serum creatinine prior to each cisplatin 
dose. If the serum creatinine is ≤ 1.5 mg/dL, creatinine clearance is not necessary for treatment 
with full dose. If the serum creatinine is > 1.5 mg/dL, a creatinine clearance should be obtained by 
urine collection or nomogram calculation (valid only if serum creatinine is not changing rapidly). 
Cisplatin must not be administered until creatinine is ≤ 1.5 or creatinine clearance ≥ 50 ml/min. 
Once the creatinine has met the above parameters, cisplatin may be restarted with the below 
modifications based on the creatinine at the time the cisplatin was held: In general, cisplatin should 
be held for weekly intervals (rather than restarting cisplatin later in the same week that a dose 
limiting AE is seen). 
Cisplatin dose modifications for creatinine during concurrent radiation 
Creatinine (mg/dL) 
 
Creatinine clearance, 
measured or 
calculated ml/min 
Cisplatin dose 
reduction 
≤ 1.5 
or 
≥ 50 
No change 
> 1.5 
and 
40-50 
One dose level 
 
 
< 40 
Hold drug 
 
Carboplatin substitution for cisplatin during concurrent chemoradiation  
for renal toxicity 
Creatinine (mg/dL) 
 
Creatinine 
clearance, measured 
or calculated 
ml/min 
Cisplatin dose 
reduction 
≤ 1.5 
or 
 ≥ 50 
Use cisplatin 
> 1.5 
and 
40-50 
May substitute 
carboplatin at AUC 
2 
 
 
< 40 
 
Neurologic (neuropathy) adverse events: 
 
Grade (CTCAE, v. 4) 
Dose Reduction 
0-1 
None 
2 
One dose level 
3-4 
Hold drug 
 
 
Ototoxicity:  Should patients develop clinical evidence of ototoxicity, further audiometric 
evaluation is required. A neurologic deficit should be distinguished from a conductive loss from 
obstruction of the Eustachian tube leading to a middle ear effusion. Because no AE scale, including 

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the CTCAE, v. 4, has been validated in terms of correlation with clinically relevant hearing loss, 
there are no protocol mandates requiring dose reduction for audiogram-determined sensorineural 
hearing loss without an analogous clinical high grade ( > grade 2) hearing loss. However, for 
clinical grade 3 or higher hearing loss, cisplatin should be held and for grade 2 clinical hearing 
loss, one dose level reduction, or carboplatin substitution as specified below. 
 
Carboplatin substitution for cisplatin during concurrent chemoradiation for 
ototoxicity 
Clinical grade 
hearing loss 
Cisplatin dose reduction 
0, 1 or 2 
Use cisplatin 
3  or greater 
May substitute carboplatin at AUC 2 
 
 
All Other Non-Hematologic Adverse Events Attributable to Cisplatin (or carboplatin, in the case 
of substitution)  during Concurrent Radiation: For > grade 2, hold cisplatin (or carboplatin, in the 
case of substitution), re-evaluate weekly until AE grade falls to 0 or 1, then restart cisplatin at one 
lower dose level.  
Note: Do not hold cisplatin (or carboplatin, in the case of substitution) for > grade 2 lymphopenia, 
hypoalbuminemia, mucositis, or dysphagia. 
 
5.2.2 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 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 3. 

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

 
 
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Grade 4 
Permanently 
discontinue 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
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 3 or 4  
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 
• 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 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 

 
 
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Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 

 
 
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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 
4.  
 
Table 4  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

 
 
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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 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 

 
 
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Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 

 
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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
5.2.3 Radiotherapy 
5.2.3.1 Equipment 
Radiotherapy must be given using Intensity Modulated Radiotherapy (IMRT) techniques. This 
includes megavoltage equipments capable of delivering static-gantry intensity modulation 
beams with a multileaf collimator or dynamic intensity modulation (e.g. VMAT and 
Tomotherapy). Image Guided Radiotherapy (IGRT) is optional except when reduced Planning 
Target Volume (PTV) margins of less than 5mm are used. 
5.2.3.2 Immobilisation and Localisation 
Patient should have dental clearance to minimize risk of dental complications after treatment. 
Ideally, this should be performed prior to induction chemotherapy, as it may be difficult to 
schedule dental clearance once chemotherapy has commenced due to increased risk of 
infection. 
The patient should lie on a flat top table in supine position with the neck in neutral position. 
Patient is immobilized with immobilization device that should at least include the head and 
neck, but immobilization techniques that include the shoulders is strongly recommended.  
Treatment planning CT scans (with intravenous iodine contrast enhancement, unless 
contraindicated) of all tissues to be irradiated must be acquired with the patient in the treatment 
position and using the same immobilization device as for treatment to define gross target 
volume(s), and clinical target volume(s). Scan thickness of ≤ 3 mm contiguous slices is 
recommended, particularly through region that contains the primary tumour. 
Contrast enhanced MRI scan (within 3 weeks of radiotherapy planning) is required for “T” 
staging and to assist in definition of target volumes unless medically contraindicated. 
Whenever possible, the MRI scan should be set up as close as possible to the treatment position. 
Image registration with planning CT scans should be performed in a region of interest 
encompassing the GTV, skull base, brainstem, and optic chiasm. 
This procedure must be performed prior to induction chemotherapy. Radiotherapy simulation 
procedure will have to be repeated after Day 1 (before Day 8) of second cycle of induction 

 
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chemotherapy. This is to allow adequate time for planning so as not to delay the subsequent 
concurrent chemo-radiation treatment. Patients undergoing post-induction treatment planning 
scans should be immobilized in as similar position as possible with the pre-induction treatment 
position 
. 
5.2.3.3 Target Volumes 
Gross Tumor Volume 
The primary Gross Tumor Volume (GTVp) is defined as all known gross disease determined 
from clinical information, endoscopic findings, CT, MRI, and PET-CT. It is recommended that 
the GTV is contoured in collaboration with a head and neck radiologist. 
Grossly positive lymph nodes (GTVn) are defined as: 
- Retropharyngeal LNs >5 mm or cervical LNs >10 mm in shortest diameter (11 mm for 
subdigastric node)  
- Three or more contiguous and confluent LNs, each with shortest diameter of 8-10 mm  
- LNs of any size with central necrosis or a contrast-enhanced rim  
- LNs of any size with extracapsular extension 
- LNs of any size with overt FDG uptake on FDG-PET scan signifying malignant involvement 
(Those LNs not fulfilling the above criteria are considered as equivocal) 
Clinical Target Volume (CTV) 
Primary CTV 
CTVp1 = High 
risk primary 
tumour CTV 
▪ 
GTVp + ≥3 mm margin (0 mm if close to critical neurological structure) 
▪ 
Whole nasopharynx (recommended but not mandatory)  

 
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CTVp2 = 
intermediate risk 
(subclinical 
sites) 
▪ 
CTVp1 + 5 mm margin (1 mm if close to critical neurological structure), 
but to include high-risk subclinical local sites: 
• 
Whole nasopharynx (if not included in CTVp1) 
• 
Sphenoid sinus : Lower half if T1-2 
 
: Entire sinus if T3-4 
• 
Clivus    
: Anterior 1/3 if no gross clivus invasion 
  
 
 
: Whole clivus if gross invasion 
• 
Ipsilateral cavernous sinus : if T3-4 
• 
Base of skull : lateral border of Foramen Ovale, Foramen Rotundum  
and Petrous tips 
• 
Nasal cavity and maxillary sinuses : posterior fourth (to ensure 
adequate inclusion of the pterygo-maxillary fissure and pterygo-
palatine fossae) 
• 
Bilateral pterygoid fossae 
• 
Bilateral parapharyngeal spaces  
 
Nodal CTV 
CTVn1 = High 
risk nodal CTV 
▪ 
GTVn + ≥3 mm margin (consider 10mm expansion if extracapsular 
extension present) 
CTVn2 = 
Intermediate 
risk (subclinical 
sites) 
▪ 
CTVn1 + 5 mm margin 
▪ 
For All cases - Retropharyngeal, Level II, III and Va lymph nodes, 
bilaterally (as defined by the cervical lymph node levels as set out in expert 
consensus guidelines in 2013 (Gregoire et. al.)) 
▪ 
Ipsilateral level IB if: 
• 
there is gross level IB or II nodes on that side 
• 
structures that drain to level Ib as the first echelon site (oral cavity, 
anterior half of nasal cavity) 
▪ 
This should be anatomically edited at the sternocleidomastoid muscle 
border as appropriate, rather than just simple geometric expansion. 

 
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CTVn3 =  Low 
risk (subclinical 
sites) 
▪ 
If nodal involvement is confined to level II nodes only, the treating 
radiation oncologist may include bilateral cervical lymph node levels IV 
and Vb (as defined by the cervical lymph node levels as set out in expert 
consensus guidelines in  2013 (Gregoire et. al.)) in CTVn3 so that a lower 
prophylactic dose can be delivered 
▪ 
Alternatively, the treating radiation oncologist may also include the 
bilateral cervical lymph node levels IV and Vb under CTVn2 
▪ 
This should be anatomically edited at the sternocleidomastoid muscle 
border as appropriate, rather than just simple geometric expansion. 
CTVn4 =  
Equivocal 
lymph nodes 
▪ 
The treating Radiation Oncologist has the option of prescribing an 
intermediate dose of 62.7 Gy, to small volume equivocal level IB lymph to 
limit dose delivered to the mandible or equivocal level IV and VB lymph 
nodes to limit the dose delivered to the brachial plexus.  
▪ 
GTVn + ≥3 mm margin 
 
 
Pre-induction and Post-induction GTVs and CTVs 
This trial involves the use of induction chemotherapy prior to definitive concurrent chemo-
radiation. As much as possible, the pre-induction GTVs that can be fully covered to the full 
therapeutic dose without exceeding the maximal tolerance of critical OARs should be used. 
However, in cases where pre-induction tumours that abuts critical OARs (chiasm, brainstem 
and spinal cord) showed gross regression following chemotherapy, post-induction GTV at the 
area(s) abutting the critical OARs (chiasm, brainstem and spinal cord) may be used to avoid 
excessive risk of damage. It is important to ensure that the pre-induction GTV that abuts critical 
OARs is covered at least by CTVp2. Pre-induction base of skull involvement should be treated 
to full therapeutic dose (CTVp1).  
 
Planning Target Volume (PTV) 
A margin of 5 mm around the CTVs is required in all directions to compensate for the 
variability of treatment set up and internal organ motion. If the investigator wants to reduce 
the PTV margin below 5 mm, daily IGRT must be employed.  
 
If expansion of CTVs results in PTVs that extend beyond the patient’s external contour, the 
PTVs should be trimmed to within 5mm from the external contour. For gross disease that 
extends to within 5mm of external surface, the use of tissue equivalent material (bolus) is 
recommended. 
 

 
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Organs at Risk (OARs) 
OARs are contoured according to the following published guidelines (36, 37): 
1. 
Brouwer CL, Steenbakkers RJ, Bourhis J, et al. CT-based delineation of organs at risk 
in the head and neck region: DAHANCA, EORTC, GORTEC, HKNPCSG, NCIC CTG, 
NCRI, NRG Oncology and TROG consensus guidelines. Radiother Oncol. 2015 
Oct;117(1):83-90. doi: 10.1016/j.radonc.2015.07.041. Epub 2015 Aug 13. 
2. 
Sun Y, Yu XL, Luo W. Recommendation for a contouring method and atlas of organs 
at risk in nasopharyngeal carcinoma patients receiving intensity-modulated radiotherapy. 
Radiother Oncol. 2014 Mar;110(3):390-7. doi: 10.1016/j.radonc.2013.10.035. Epub 2014 Apr 
7. 
 
Required OARs: 
• Brainstem 
• Spinal cord 
• Optic chiasm 
• Optic Nerve- Left and Right 
• Parotid – Left and Right 
• Parotids - Combined  
• Eye- Left and Right  
• Lens- Left and Right  
• Cochlea- Left and Right 
• Internal Acoustic Meatus- Left and 
Right 
• Temporal lobe-Left and Right 
• Constrictor-Superior 
• Constrictor-Middle 
• Constrictor-Inferior 
• Constrictor-Cricopharyngeus 
• Constrictor-Esophagus 
• Brachial Plexus- Left and Right *  
• Glottic larynx 
• Oral cavity 
• Mandible 
• Temporo-Mandibular Joint 
• Pituitary 
• Thyroid gland 
 

 
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5.2.3.4 Treatment Planning 
Dose Prescription 
Treatment will be delivered once daily, 5 fractions per week, over 6.5 to 7 weeks (33 or 35 
fractions) in accordance with department standards of care. All targets will be treated 
simultaneously. 
 
In 33 fractions (preferred) 
In 35 fractions 
PTV1 (CTVp1 and CTVn1 + 
margins) 
69.96 Gy at 2.12 Gy per 
fraction 
70 Gy at 2 Gy per fraction 
PTV2 (CTVp2 and CTVn2 + 
margins) 
59.4 Gy at 1.8 Gy per fraction 
60.2 Gy in 1.72 Gy per fraction 
PTV3 (CTVn1 + margins) 
54.12 Gy at 1.64 Gy per 
fraction 
56 Gy at 1.6 Gy per fraction 
PTV4 (CTVn4 + margins) 
62.7 Gy at 1.9 Gy per fraction 
63 Gy in 1.8 Gy per fraction 
 
Planning Priorities 
The planning priorities for dose coverage and constraints will be in the following order: 
1) Critical Normal Structure Constraints: Specifically, the brain stem, optic chiasm, and spinal 
cord, which take priority over coverage of the tumor. If the tumor extends close to optic 
structures, the treating physician must discuss the possibility of blindness due to radiation 
therapy during the Informed Consent process; 
2) Dose Specifications; 
3) Planning Goals: Salivary glands; 
4) Planning Goals: All other normal structures. 
 
DVH’s must be generated for all OARs. Maximum doses stated below are defined as to the 
maximum dose for a volume of 0.03 cc. 
Target volume compliance criteria 
PTV 
Dosimetric parameter 
Per Protocol 
Acceptable Variation 
PTV1 
V100% 
95% 
90% 
D99% 
≥90% 
≥85% 
D0.03cc 
≤115% 
≤120% 
PTV2 
V59.4Gy (33#) or 
V60.2Gy (35#) 
≥95% 
≥90% 

 
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PTV3 
V54.12Gy (33#) or 
V56Gy (35#) 
≥95% 
≥90% 
PTV4 
V62.7Gy (33#) or 
V63Gy (35#) 
≥95% 
≥90% 
 
Normal Structure Constraints and Compliance Criteria 
Structure 
Dosimetric parameter 
Per Protocol 
Acceptable Variation 
Brainstem 
D0.03cc 
≤54Gy 
≤60Gy 
Spinal cord 
D0.03cc 
≤45Gy 
≤50Gy 
Optic chiasm 
D0.03cc 
≤54Gy 
≤56Gy 
Optic nerve 
D0.03cc 
≤54Gy 
≤60Gy 
Mandible/TMJ 
D0.03cc 
≤70Gy 
≤75Gy 
Brachial plexus 
D0.03cc 
≤66Gy 
≤70Gy 
Temporal lobe 
D0.03cc 
≤70Gy 
≤75Gy 
Parotid gland  
Mean 
≤26Gy 
≤33Gy 
 
Only the true critical structures, not the PRVs are evaluated. In overlap situations, treatment 
planning should attempt to balance the tradeoff between dose to the CTV and protection of the 
critical structure. 
 
Recommended Constraints Criteria for Other Normal Tissues 
Structure 
Dosimetric parameter 
Recommended Constraints 
Oral cavity (excluding PTV’s) 
Mean dose 
≤40Gy 
Each cochlea 
D0.03cc 
≤55Gy 
Mean dose 
≤45Gy 
Eyes 
D0.03cc 
≤55Gy 
Lens 
D0.03cc 
≤15Gy 
Glottic larynx 
Mean dose 
≤40Gy 
Constrictor muscles 
Mean dose 
≤50Gy 
 
5.2.3.5 Image Guidance for IGRT When Using Reduced Margins 
Patients treated with reduced PTV margins of <5mm will require daily IGRT. This can be 
achieved using any one or more of the following techniques: 

 
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 Orthogonal kilovoltage (KV) images 
 Linac mounted conebeam kV or MV CT images 
 Linac mounted helical MV CT images (e.g. Tomotherapy) 
 
5.2.3.6 Patient Monitoring During Radiotherapy 
Weekly review 
Concurrent chemo-radiation is expected to result in significant toxicities in about two third of 
patients. Hence, patients should be reviewed at least once a week during radiotherapy for 
management of acute radiotherapy toxicities. Parameters to be collected are: 
• Weight 
• ECOG 
• Acute toxicities (CTCAE v4.0) for: 
 
• Dry mouth 
 
• Dysphagia 
 
• Dysgeusia 
 
• Pharyngolaryngeal pain 
 
• Oral pain 
 
• Hoarseness 
 
• Mucositis oral 
 
• Dermatitis radiation 
 
• Any other significant acute toxicities (including but not limited to fatigue, regional 
 
   alopecia, hoarseness and transient ear discomfort) 
• NGT use (Yes/No) 
 
Patients with significant weight loss (≥10% baseline) should be advised to have a nasogastric 
tube (NGT) insertion. 
Treatment interruption 
Patients with NPC are considered to be ‘Category one’ patients. Hence, although interruptions 
in radiotherapy may be necessary due to severe acute toxicities, it is strongly discouraged. The 
reason for and the length of any such interruption must be documented. Treatment interruptions 
that exceeds five normally-scheduled treatment days will be considered as a Deviation 
Unacceptable for the protocol.  
 

 
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5.3 
Randomization or Treatment Allocation 
This is an open label, single arm, non-randomized trial. All eligible subjects will be allocated 
to the single experimental treatment arm. 
5.4 
Stratification 
There is no stratification required. 
 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 

 
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• Radiation therapy not specified in the protocol 
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.  
 
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV contrast dye) is 
permitted. 
 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 

 
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bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
5.6 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant  or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment. 
• The participant  has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 

 
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• The participant is lost to follow-up 
• Administrative reasons 
 
5.7 
Participant Replacement Strategy 
Subjects who withdrew consent but has not received any study related treatment is not 
evaluable for any of the study endpoints, and will be replaced. 
 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
 

 
 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart from Screening to End of Maintenance Chemotherapy 
Trial Period: 
Screening Phase 
Treatment Cycles 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
Induction 
Concurrent 
1 week 
post 
CCRT 
Maintenance 
1 
2 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
Q3w 
X 12# 
3M 
post 
RT 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 3 
± 7 
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
ECOG Performance Status 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Audiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-NP 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
Radiotherapy Simulation 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Acute radiation toxicity scoring as 
per section 5.2.4.6 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 

 
 
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Trial Period: 
Screening Phase 
Treatment Cycles 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
Induction 
Concurrent 
1 week 
post 
CCRT 
Maintenance 
1 
2 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
Q3w 
X 12# 
3M 
post 
RT 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 3 
± 7 
Dental clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Lab test as per Table 6 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
X4 
 
Coagulation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC d/c 
 
 
D8 
D8 
 
 
 
 
 
 
 
 
 
 
CBC d/c, RLFT Bone profile 
 
 
X 
 
 
X 
X 
 
X 
X 
 
X 
 
 
Hepatitis B Surface Antigen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or Serum 
-HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
MRI Post Nasal Space and Neck 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
Distal Staging 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood (refer to section 4.2.4.2 and 7.1.4.3) 
Archival Tissue Collection  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma EBV DNA/ctDNA 
 
B0 
B1 
B2 
B3 
 
 
B4 
 
 
 
B5 
B6 
B7 
PBMC 
 
B0 
 
 
B3 
 
 
B4 
 
 
 
 
B6 
B7 
Tumor biopsy 
 
T0 
 
T1 
(after 
C2D1, 
before 
RT)) 
 
 
 
 
 
 
 
 
T2 
(6-8 
wk 
post-
RT) 
 

 
 
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Trial Period: 
Screening Phase 
Treatment Cycles 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) 
Induction 
Concurrent 
1 week 
post 
CCRT 
Maintenance 
1 
2 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
Q3w 
X 12# 
3M 
post 
RT 
Scheduling Window (Days): 
 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 3 
± 7 
Notes: 
1. 
Radiotherapy simulation procedure includes immobilization, planning CT and MRI scan as per section 5.2.4.2 and should be done within 28 days 
prior to commencement of induction chemotherapy. 
2. 
Radiotherapy simulation procedure will have to be repeated after Day 1 of second cycle of induction chemotherapy. This is to allow adequate time 
for planning so as not to delay the subsequent concurrent chemo-radiation treatment. 
3. 
CT Post Nasal Space and Neck may be used if MRI is medically contraindicated 
4. 
Magnesium is only required during neoadjuvant and concurrent phase. Urinalysis and thyroid function test (FT4 and TSH) is only required to be 
repeated every other cycle during maintenance phase.  
 
 
 

 
 
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6.2 
Study Flow Chart from End of Concurrent Chemo-radiation to 3 Years Post Treatment 
Trial Period: 
 
Post-Treatment (time from end of chemo-radiation) 
Title 
Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
6m 
12m 
18m 
24m 
30m 
36m 
 
 
 
 
 
 
Scheduling Window (Days): 
At time of 
Discontinuation 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-study anticancer therapy 
status 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Survival Status 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Local Control Status 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Distal Control Status 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Second Primary Cancer 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Full Physical Examination 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Audiogram 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
FACT-NP 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Radiotherapy Simulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
Late radiation toxicity scoring 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Lab test as per Table 6 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 

 
 
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Trial Period: 
 
Post-Treatment (time from end of chemo-radiation) 
Title 
Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
6m 
12m 
18m 
24m 
30m 
36m 
 
 
 
 
 
 
Scheduling Window (Days): 
At time of 
Discontinuation 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
± 10 
Efficacy Measurements 
MRI Post Nasal Space and Neck 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Distal Staging 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood (refer to section 4.2.4.2 and 7.1.4.3) 
Tumor biopsy (at any time during 
or after treatment completion when 
suspected recurrent or metastatic 
lesion present) 
T3 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma EBV DNA/ctDNA 
 
 
B8-9 
B10 
 
 
 
 
 
 
 
 
 
 
PBMC 
 
B8-9 
B10 
 
 
 
 
 
 
 
 
 
 
Notes: 
1. 
CT Post Nasal Space and Neck may be used if MRI is medically contraindicated 
2. 
Distant staging can be either CT chest/abdomen and bone scan or FDG PET-CT 
3. 
Local or Regional Relapse is defined as reappearance of tumor after complete response. If possible, relapse should be confirmed by biopsy. 
4. 
Distant Metastasis: Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is recommended where possible.  
 
 
 

 
 
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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
MSDMSD for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 

 
 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 

 
 
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7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  
7.1.1.5.4 Survival Status 
The investigator or qualified designee will determine patient’s survival status. Date and cause 
of death is to be recorded. Overall survival is defined as time from allocation until death from 
any cause. 
7.1.1.5.5 Local Control Status 
Local or regional relapse is defined as reappearance of tumor after complete response. If 
possible, relapse should be confirmed by biopsy. The investigator or qualified designee will 
determine if patient’s local control status. Date of relapse, and sites (local and or regional) 
should be recorded 
7.1.1.5.6 Distal Control Status 
Distant metastasis is defined as radiological clear evidence of distant metastases (lung, bone, 
brain, etc.). Where possible, biopsy is recommended. A solitary, spiculated lung mass/nodule 
is considered a second primary neoplasm unless proven otherwise in a patient with a smoking 
history. The investigator or qualified designee will determine patient’s distant control status. 
Date of distant metastasis and sites of metastasis should be recorded. 
7.1.1.5.7 Second Primary Cancer 
Tumor reappearing within the initial and immediate adjoining anatomical region of the primary 
will be considered local recurrence. Multiple lung nodules/masses are considered distant 
metastases from the index cancer unless proven otherwise. Where possible, biopsy is 
recommended to confirm second primary cancer. The investigator or qualified designee will 
determine patient’s second cancer status. Date of diagnosis of second cancer, and site should 
be recorded 
 
7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to treatment allocation at each local study site.  

 
 
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Each subject will be assigned only one screening number.  Screening numbers must not be re-
used for different subjects. 
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit. 
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 6.1.   
The outcome of screening and the reason for all screening failure should be documented. 
7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Details regarding administration of trial treatment are outlined in Section 5.2 - Trial Treatment. 
Interruptions from the protocol specified treatment plan for greater than 3 weeks between 
pembrolizumab doses for non-drug-related or administrative reasons (see section 5.2.1.2 for 
drug-related modifications) require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management. 
Administration of trial treatment will be documented by the investigator and/or designated 
staff.  The total volume of pembrolizumab infused will be compared to the total volume 
prepared to determine compliance with each dose of pembrolizumab administered.   
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. 
 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   

 
 
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7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
 
7.1.2.6 Audiogram 
Audiometric assessment must be done by a certified audiologist.  
 
7.1.2.7 Functional Assessment of Cancer Therapy-Nasopharyngeal (FACT-NP) 
FACT-NP is a fully scalable, cancer-specific Patient Reported Outcome instrument containing 
43 items, scored on a range of 0-172. The instrument has been psychometrically validated 
(Tong 2009) and has been used in Hong Kong to assess concerns specific to the nasopharyngeal 
cancer population. FACT-NP is available in English, traditional and simplified Chinese 
versions. FACT-NP is estimated to take approximately 12 minutes.  
7.1.2.8 Radiotherapy Simulation 
Refer to section 5.2.3.2 

 
 
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7.1.2.9 Acute Radiation Toxicity Scoring 
Refer to section 5.2.3.6 
7.1.2.10 Dental Clearance 
Refer to section 5.2.3.2 
7.1.2.11 Late Radiation Toxicity Scoring 
Refer to section 7.2.4 
 
7.1.3 Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
This will be performed in accordance to the flow chart in Section 6. 
 
7.1.4 Tumor Imaging and Assessment of Disease 
7.1.4.1 Initial Tumor Imaging 
Evaluation of tumor extent is required within 28 days prior to allocation. 
For loco-regional staging, contrast enhanced MRI of the nasopharynx and neck is preferred. If 
MRI is medically contraindicated, contrast enhanced CT scan with ≤ 3 mm contiguous slices 
with contrast and bone windows (to evaluate base of skull involvement) may be used. 
For distal disease staging, full body FDG PET-CT is preferred. Alternatively, contrast 
enhanced CT of the chest, abdomen and bone scan may be used. 
The site study team must review screening images to confirm the participant has measurable 
disease per RECIST 1.1. 
7.1.4.2 Tumor Imaging During the Study 
7.1.4.2.1 Tumor Imaging After Day 1 (before Day 8) of second cycle of induction 
chemotherapy 
Contrast enhanced MRI of the nasopharynx and neck has to be repeated with radiotherapy 
simulation procedure will have to be repeated after Day 1 (before Day 8) of second cycle of 
induction chemotherapy. This is to allow adequate time for planning so as not to delay the 
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treatment planning scans should be immobilized in as similar position as possible with the pre-
induction treatment position. If MRI is medically contraindicated, contrast enhanced CT scan 
with ≤ 3 mm contiguous slices with contrast and bone windows (to evaluate base of skull 
involvement) may be used. Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts.   
7.1.4.2.2 Tumor Imaging 3 Months Post Chemo-radiation 
This first post treatment scan to assess response should be performed at 12 weeks (+/-7 days) 
from the end of radiotherapy. Contrast enhanced MRI of the nasopharynx and neck is 
preferred. If MRI is medically contraindicated, contrast enhanced CT scan with ≤ 3 mm 
contiguous slices with contrast and bone windows (to evaluate base of skull involvement) may 
be used. 
7.1.4.2.3 Annual Imaging 
This first post treatment annual scan to assess response should be performed at 52 weeks (+/-
10 days) from the end of radiotherapy. 
For loco-regional staging, contrast enhanced MRI of the nasopharynx and neck is preferred. If 
MRI is medically contraindicated, contrast enhanced CT scan with ≤ 3 mm contiguous slices 
with contrast and bone windows (to evaluate base of skull involvement) may be used. 
For distal disease staging, full body FDG PET-CT is preferred. Alternatively, contrast 
enhanced CT of the chest, abdomen and bone scan may be used. 
More frequent imaging may be performed if clinically indicated.   
Participants who receive additional imaging for confirmation do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point.   
Per iRECIST (Section 7.1.4.2.6), disease progression should be confirmed by the site 4 to 
8 weeks after first radiologic evidence of PD in clinically stable participants.  Participants 
who have unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Section 7.1.4.2.6.  Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable.  Participants who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment.  Exceptions are detailed in Section 7.1.4.2.6. 

 
 
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7.1.4.2.4 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used to monitor disease status until the start of a new 
anticancer treatment, disease progression, death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
7.1.4.2.5 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment).  
7.1.4.2.6 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local 
radiology, according to the rules below.  This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 4, with 
additional detail in the iRECIST publication (38).  iRECIST will be used by the Investigator 
to assess tumor response and progression, and make treatment decisions.   
 
 

 
 
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Table 5 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required. 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor). 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments. 
Continue study treatment at the 
Investigator’s discretion. 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor image should 
occur according to the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1.. 

 
 
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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 

 
 
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7.1.4.3 Mandatory Tumor Tissue Collection and Correlative Studies Blood Sampling 
7.1.4.3.1 PD-L1 Status 
All subjects should submit either a newly obtained core or excisional biopsy or archival tissue 
(FNA not adequate for both archival and new tissue samples) to a central lab for 
characterization of PD-L1 status prior to treatment allocation. 
Note: Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from site slide section date , otherwise a new specimen will 
be requested. 
If the sample is determined to be non-evaluable by the central lab, a new sample should be 
submitted if available. This may include additional cut slides that are outside of the 14 -day 
window noted above. 
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Operations Manual. 
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
ordinarily be discarded at the end of the main study will be retained for Future Biomedical 
Research. 
7.1.4.3.2 Plasma Epstein - Barr virus DNA (pEBV DNA) 
Blood for plasma EBV DNA analysis is to be drawn at baseline before start of any neoadjuvant 
chemotherapy (B0), then every 3 weeks during neoadjuvant pembrolizumab-cisplatin-
gemcitabine chemotherapy (B1 and B2) and concurrent pembrolizumab-cisplatin-radiation 
(B3 and B4), at 1 week after completion of IMRT (B5), 6-8 weeks post-RT( B6), and every 3 
months during maintenance pembrolizumab (B7-10). 
• Time point for the blood collection: 
o B0* – Baseline 
o B1 – Cycle 1 Day 1 
o B2 – Cycle 2 Day 1 
o B3* –Week 1 (before RT) 
o B4* – Week 4 
o B5 – 1week post RT 
o B6* – 6-8 weeks post RT 
o B7-B10* – 3, 6, 9 and 12 months post RT (x4) 
 
*Blood for pEBV DNA can be collected in same EDTA tube at time point for both pEBV 
DNA and ctDNA collection at B0, B3, B4, B6, B7-10 (see 7.1.4.3.3 below). 

 
 
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All samples are to be submitted for central testing. Collection, storage, and shipment 
instructions for the samples will be provided in the Operations Manual. 
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
ordinarily be discarded at the end of the main study will be retained for Future Biomedical 
Research. 
7.1.4.3.3 Blood for circulating tumor DNA (ctDNA) and peripheral blood mononuclear 
cells (PBMC) isolation 
Blood for ctDNA and PBMC isolation will be collected at baseline before start of any 
neoadjuvant chemotherapy (B0), before start of RT (week 1; B3) and during RT (week 4; B4), 
at 6-8 weeks post-RT (B6) and 3, 6, 9 and 12 months post-RT (B7-10). 
All samples are to be submitted for central testing. Collection, storage, and shipment 
instructions for the samples will be provided in the Operations Manual. 
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
ordinarily be discarded at the end of the main study will be retained for Future Biomedical 
Research. 
 
7.1.4.3.4 Fresh tumor biopsy for molecular studies 
Fresh tumor biopsy will be collected at the following time point: 
T0 – stands for timepoint 0 and is the baseline tumor biopsy (before C1D1) 
T1 – stands for timepoint 1 and is the tumor biopsy after C2D1 neoadjuvant chemo (before 
RT) 
T2 – stands for timepoint 2 and is the tumor biopsy at 6-8 weeks after completion of RT  
T3 – stands for timepoint 3 and is the tumor biopsy at any time during or after treatment 
completion when suspected recurrent or metastatic lesion present 
 
Fresh tumor biopsy will be processed for molecular studies as below: 
a) 1 core of tissue: Fixed in Formalin for Paraffin Embedding (FFPE) for 
immunohistochemistry (IHC) study  

 
 
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b) 1 core of tissue: Fresh in Hypothermosol or frozen in freezing media for single cell RNA 
sequencing (scRNAseq) study  
c) 1 core of tissue: fresh frozen sample for bulk RNA/ TCR sequencing study  
All samples are to be submitted for central testing. Collection, storage, and shipment 
instructions for the samples will be provided in the Operations Manual. 
If the subject signs the Future Biomedical Research consent, any leftover samples that would 
ordinarily be discarded at the end of the main study will be retained for Future Biomedical 
Research. 
  
7.1.5 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.   

 
 
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Table 6 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Free thyroxine (T4) 
WBC (total and differential) 
Blood Urea Nitrogen or Urea 
Specific gravity  
Thyroid stimulating hormone (TSH) 
Red Blood Cell Count 
Calcium 
Microscopic exam (If abnormal 
results are noted)  
Blood for correlative studies 
Absolute Neutrophil Count 
Creatinine 
Urine pregnancy test † 
 
Absolute Lymphocyte Count 
Glucose 
 
 
 
Lactate dehydrogenase (LDH) 
 
 
Coagulation:* 
International normalized ratio 
(INR) OR prothrombin time (PT) 
Activated partial thromboplastin 
time (aPTT) 
Phosphorus/phosphate 
 
 
 
Magnesium 
 
 
 
Potassium   
 
 
 
Sodium 
 
  
 
Total Bilirubin 
 
 
 
Total protein 
 
 
 
Uric Acid  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
* Only required at main study screening 

 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
 
7.1.6 Other Procedures 
7.1.6.1 Withdrawal/Discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.   
7.1.6.2 Blinding/Unblinding 
[Not applicable] 
 
7.1.7 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.7.1 Screening 
7.1.7.1.1 Screening Period 
Main study screening period is -28 to -1 day. During the main study screening period, subjects 
will sign informed consent and receive clinical assessments once meet the inclusion criteria. 
Please refer to section 6.0 – Trial Flow Chat. 
7.1.7.2 Treatment Period 
 Pembrolizumab in combination with gemcitabine-cisplatin for 2 cycles at week 1&2 and week 
4&5 (±3days), then followed by concurrent pembrolizumab-cisplatin-radiation from week 7 to 
week 14, and then maintenance pembrolizumab monotherapy given every 3 weeks for 12 doses. 
Please refer to section 6.0 – Trial Flow Chat. 

 
 
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7.1.7.3 Post-Treatment Visits 
7.1.7.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment 
should also be followed and recorded.   
7.1.7.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase. Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression, death, end of the 
study.  Information regarding post-study anti-cancer treatment will be collected if new 
treatment is initiated. 
 
7.1.7.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first.  
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the MSD’s product, is also an adverse event. 

 
 
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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
MSD product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by MSD for human use. 
Adverse events may occur during the course of the use of MSD product in clinical trials, or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
● All AEs from the time of treatment allocation through 30 days following cessation of study 
treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if 
the participant initiates new anticancer therapy, whichever is earlier must be reported by the 
investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment allocation 
through 120 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy  must be reported by the 
investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify MSD. 

 
 
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7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to MSD 
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 MSD product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of MSD’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 MSD Global Safety. (Attn: Worldwide Product 
Safety; FAX 215-661-6229) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to MSD 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 

 
 
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Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
MSD Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to MSD 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of MSD’s 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the MSD in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by MSD for collection purposes. 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
 
Refer to Table 7 for additional details regarding each of the above criteria. 
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 that occurs to any participant must be reported within 24 
hours to the Sponsor and within 2 working days to MSD 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 serious adverse event, or follow up to a 
serious adverse event, including death due to any cause whether or not related to the MSD 
product, must be reported within 24 hours to the Sponsor and within 2 working days to MSD 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to MSD product that is brought to the attention of the investigator at 

 
 
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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 MSD Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the MSD 
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 MSD Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to MSD & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to MSD 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 MSD 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 MSD product, must be reported within 2 working days to MSD Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of MSD product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 

 
 
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*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.  
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
 
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Table 7 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of MSD product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to MSD within 2 working 
days to meet certain local requirements); or 

 
 
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Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
MSD within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause MSD product to be discontinued? 
Relationship to 
MSD Product  
Did MSD product cause the adverse event? The determination of the likelihood that MSD  product caused the adverse event will be provided by an investigator who is 
a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between MSD product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely MSD product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to MSD product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of MSD product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

 
 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to MSD 
Product 
(continued)  
Dechallenge 
Was MSD product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to MSD product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MSD PRODUCT, OR IF REEXPOSURE TO MSD PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO 
THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding MSD product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of MSD product relationship). 
Yes, there is a reasonable 
possibility of MSD product 
relationship. 
There is evidence of exposure to MSD product.  The temporal sequence of the AE onset relative to the administration of MSD product is reasonable.  
The AE is more likely explained by MSD product than by another cause. 

 
 
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No, there is not a reasonable 
possibility of MSD product 
relationship 
Participant did not receive the MSD  product OR temporal sequence of the AE onset relative to administration of MSD product is not reasonable OR 
the AE is more likely explained by another cause than the MSD product.  (Also entered for a participant with overdose without an associated AE.) 

 
 
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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to the conduct of any analysis, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, will be documented in a 
supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study (this includes the exploratory analyses for the Optional Sub-Study protocol 
which will also be documented in a separate sSAP). Post hoc exploratory analyses will be 
clearly identified in the CSR. 
 
8.1 
Statistical Analysis Plan Summary 
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2. 
 
Study Design Overview 
A phase 2 study of neoadjuvant pembrolizumab-
gemcitabine-cisplatin followed by concurrent 
pembrolizumab-cisplatin-radiation and then maintenance 
pembrolizumab in previously untreated stage IVA 
nasopharyngeal cancer 
Treatment Assignment 
Open label, single arm, non-randomized 
Analysis Populations 
Safety: all subjects received at least one dose of 
pembrolizumab (safety population)  
Efficacy: intent-to-treat (ITT) in eligible population 
Primary Endpoint 
-Two-year progression free survival 
Key Secondary Endpoints 
-Grade 4 mucositis/skin reaction or any Grade 5 adverse 
event assessed to be definitely, probably, or possibly related 
to protocol treatment during the first year 

 
 
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-Grade 4 mucositis/skin reaction or any Grade 5 adverse 
event assessed to be definitely, probably, or possibly related 
to protocol treatment occurring after the first year; 
-Patient tolerability to each component (neoadjuvant, 
concurrent and maintenance part) of the protocol treatment 
regimen; 
-Other ≥ Grade 3 adverse events; 
-Death during or within 30 days of discontinuation of 
protocol treatment; 
-One- and two-year distant metastases rates;  
-One- and two-year local-regional progression rates;  
-One- and two-year second primary rates; 
-One- and two-year overall survival rates. 
Independent Review of 
Adverse Events related to 
Safety Endpoints 
All grade 3/4 mucositis/skin reactions (of any attribution) 
and all grade 5 adverse events will be assessed by an 
independent oncologist not associated with this study. The 
grade and attribution will be reported in two ways: as 
scored by the treating institution and as scored by the 
independent reviewer. 
Interim Reports to Monitor 
Study Progress 
Interim reports will be prepared twice each year until the 
final analysis has been completed.   
In general, these reports will contain information about the 
accrual rate with projected completion date for the accrual 
phase, exclusion rates and reasons, pretreatment 
characteristics of patients accrued, compliance rate of 
treatment delivered with respect to the protocol 
prescription, and the frequency and severity of adverse 
events.  
This study will be monitored by the Comprehensive Cancer 
Trials Unit (CCTU) of The Chinese University of Hong 
Kong. Study data will be submitted in Case Report Form by 
electronic means to CCTU data manager. 

 
 
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Interim Analysis of Adverse  
Events 
Interim analysis will be conducted after accrual of 14 
eligible patients.  
Patient accrual will be suspended after 14 eligible patients 
has been entered and the study will not be reopened to 
accrual until the data for the first evaluation after the 
concurrent phase have been received for all 14 eligible 
patients and the rate of adverse events is determined to be 
acceptable. While the co-primary safety endpoint is the rate 
of Grade 4 mucositis /skin reaction and any Grade 5 adverse 
events in the first year, for practical reasons the analysis to 
evaluate the rates will only require that data for the 
concurrent phase have been received for all 14 eligible 
patients. Many patients also will have data by this time of 
the maintenance phase, and these data will be included. The 
suspension will be 3-6 months in duration, allowing time 
for patients to complete the concurrent component and for 
the data analysis to be performed. Every method should be 
made to complete the RT delivery to all eligible patients 
before the interim analysis started. 
The rates of all Grade 3/4 mucositis/skin reaction or all 
Grade 5 adverse event by grade and attribution will be 
reported in two ways: as scored by treating institution and 
as scored by the independent reviewer. Patients with Grade 
4 mucositis/skin reaction or any Grade 5 adverse event as 
described in section 8.2.1 will be identified. 
At the interim safety analysis, if there are 3 or more such 
events out of 14 eligible patients by either institutional 
scoring or independent review, the study Principle 
Investigators (PIs) will review the data pertaining to these 
events. After their review, the PIs and study statistician will 
make a recommendation to the Trial Steering Committee, 
and the corporate sponsor for their consideration. These 
committee and individuals jointly will decide the future 
course of action for the study, including if a specific 
treatment component need to be dropped or modified (refer 
to section 8.2.2, Analysis for Reporting the Initial 
Treatment Results).   
If there are 3 or more such events observed prior to the 
accrual of 14 eligible patients in the first stage before 

 
 
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formal interim analysis, or 4 or more such events observed 
prior to the accrual of 42 eligible patients in stage II, 
confirmed by either institutional scoring or independent 
review, the study accrual will be suspended immediately. 
The study PIs will review the data pertaining to these 
events. After their review, the study PIs and study 
statistician will make a recommendation to the Trial 
Steering Committee, and the corporate sponsor for their 
consideration. These committee and individuals jointly will 
decide the future course of action for the study, including if 
a specific treatment component need to be dropped or 
modified (refer to section 8.2.2, Analysis for Reporting the 
Initial Treatment Results).   
 
Independent Trial Steering 
Committee 
The Trial Steering Committee is responsible to review the 
trial progress and safety issues. The committee will be 
composed of two oncologists and one statistician, who are 
independent of the clinical trial team. 
Sample Size and Power 
The total sample size required for the study is 46 patients. 
(Refer to section 8.2.1) 
Statistical Methods for Key 
Efficacy and Safety 
Analyses 
Refer to section 8.2.2 
 
8.2 
Statistical Analysis Plan 
8.2.1 Sample Size and Power 
Interim analysis for safety endpoints 
The baseline rates used in this study are based upon the completed phase II studies of RTOG 
0615 bevacizumab-cisplatin-RT (26) and cetuximab-cisplatin-RT (27). 
Since there is limited experience with the proposed protocol regimen, the study will determine 
whether it can be delivered per protocol prescription and is safe. All grade 3/4 mucositis/skin 
reactions (of any attribution) and all grade 5 adverse events will be assessed by an independent 
oncologist not associated with this study. An interim safety analysis after accrual of first 14 
subjects will be conducted. 

 
 
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There is particular concern with the incidence in NPC patients with increased rate of grade 4 
mucositis or skin reaction, which were the dose-limiting toxicity for head and neck radiation 
and could potentially be aggravated after incorporation of pembrolizumab into standard 
chemoradiation protocol. Therefore, the incidence of patients with either grade 4 
mucositis/skin reaction or any grade 5 adverse event attributed to the protocol treatment will 
be used to evaluate safety.  The incidence of these events will be examined in the first year 
from the start of treatment and then beyond the first year. The interim safety analysis will 
examine safety based only upon the first year because follow-up for this time period will be 
complete and the incidence is expected to be lower beyond the first year.  
The targeted sample size is based upon the incidence of patients with either grade 4 
mucositis/skin reaction or any grade 5 adverse events assessed to be definitely, probably, or 
possibly related to protocol treatment during the first year. The unacceptable rate for such 
adverse events is set at ≥ 15% and the acceptable rate at ≤ 5%. Then the statistical hypothesis 
would be:  
 
H0: Incidence of patients with either grade 4 mucositis/skin reaction or any grade 5 
adverse event for the protocol treatment regimen ≤ 0.05 
 
HA: Incidence of patients with either grade 4 mucositis/skin reaction or any grade 5 
adverse event for the protocol treatment regimen ≥ 0.15 
The following table gives the number of patients with the above specified adverse events that 
are considered unacceptable as calculated by the method of Fleming (39) for a two-stage design 
where the type I error and the statistical power were set at 0.14 and 0.83, respectively.  The 
first stage will utilize one-third of the required sample size thus permitting an earlier formal 
evaluation of adverse events. 
Number of patients with specified  adverse events 
Total number of evaluable 
patients 
3 
14 
4 
42 
 
The first stage required 14 eligible patients; three or more events would be considered 
unacceptable. At the second stage, four events in 42 patients were regarded as unacceptable. 
To allow for up to 10% of patients later found to be ineligible or not start protocol treatment, 
four more patients will be entered on the study in addition to the 42 evaluable subjects. 
Therefore the total sample size required for the study is 46 patients.  Two of these four 

 
 
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patients will be entered for the first stage of the study, and the remaining two patients will be 
entered for the second stage.  
Patient tolerability also will be evaluated in terms of protocol treatment delivery. The protocol 
treatment regimen will be considered as 3 treatment components (neoadjuvant, concurrent and 
maintenance phase) for tolerability assessment. A tolerability rate of 75% will be considered 
the minimum acceptable rate for a treatment component, while a rate less than 50% will be 
considered unacceptably low.  If the true tolerability rate is 75% or more, there is less than a 
1% chance that the regimen will be identified as unacceptable assuming a binomial distribution 
with a one-sided test. If the true tolerability rate is 50% or less, there is less than a 1% chance 
that the regimen will be identified as acceptable assuming a binomial distribution with a one-
sided test. 
 
Primary efficacy endpoint 
Treatment efficacy will be evaluated as the primary efficacy endpoint (2-year progression free 
survival) and as other secondary endpoints. The rates of local control, distant metastasis, 
progression free survival, and overall survival in this study will be compared with the historical 
rates from previous publications. The addition of pembrolizumab is hypothesized to reduce 
rate of both local recurrence and distant metastases. 
According to the data form the Hong Kong NPC study group 0502 trial (Chan AT, Hui EP et 
al, JCO 2018 in press),  the progression free survival rate in the total plasma EBV DNA 
screening population (n=789) by stage (UICC 1997) is as follows: 
 
Overall Stage 
(UICC 1997) 
N 
No. of 
event 
No. of event 
before 2 year 
1-yr rate 
(%) 
2-yr rate 
(%) 
3-yr rate 
(%) 
5-yr rate 
(%) 
IIB 
222 
57 
31 
91.0 
86.0 
80.7 
76.1 
III 
381 
104 
70 
88.7 
81.5 
77.7 
72.1 
IVA 
113 
55 
35 
83.1 
68.9 
62.0 
52.8 
IVB 
73 
36 
25 
76.5 
65.4 
54.2 
49.8 
IVA-IVB 
(=stage IVA in 
UICC 2018) 
186 
91 
60 
80.5 
67.4 
59.0 
51.4 
 
Based on the historic data, the 2-year progression free survival for UICC 2018 Stage IVA 
(correspond to stage IVA and IVB in UICC 1997) ranged from 65.4% to 68.9%. We assume 
that the 2-year progression fee survival will be improved  at least from 66.0% to 83.0% (better 
than Stage III) with the combined chemo-immunotherapy regimen.  

 
 
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Ho: The 2-year rate of progression-free survival should be ≤ 0.66 
H1: The 2-year rate of progression-free survival should be ≥ 0.83  
 
By using Fleming one-stage design where type I error and statistical power was set as 0.05 
and 0.80, respectively.  
Number of patients with events   
within 2 years 
Total number of evaluable patients 
10 
42 
 
The number of evaluable patients required is 42. If 10 or more patients developed events 
(progression or death) within 2 years, this would be considered unacceptable. If less than 9 
patients had the events, we can then reject Ho and conclude that the combined treatment is 
effective. 
 
8.2.2 Statistical Methods 
The rates of tolerability and adverse events will be estimated using a binomial distribution 
along with their associated 95% confidence intervals.  Only adverse events assessed by the 
treating institution as definitely, probably, or possibly related to protocol treatment will be 
considered in evaluating the primary endpoint.  Rates of distant metastases, local-regional 
progression, and second primary tumors will be estimated using the cumulative incidence 
method while progression-free and overall survival rates will be estimated using the Kaplan-
Meier method. Only the first event will be considered when evaluating efficacy endpoints other 
than overall survival.  All failure times will be measured from the date of registration. The 
following table shows how each first event would be counted for local-regional progression, 
distant metastases, second primary tumors, and progression-free survival. 
First Event 
Additional Information 
Needed 
Local-Regional 
Progression 
 
Distant 
Metastases 
Second 
Primary 
Tumors 
Progression-Free  
Survival 
None 
 
Censored 
Censored 
Censored 
Censored 
Local-Regional 
progression 
 
Failure 
Competing risk Competing risk 
Failure 
Distant metastasis 
 
Competing risk 
Failure 
Competing risk Failure 
Second primary tumor 
 
Competing risk 
Competing risk Failure 
Censored 
Death  
COD=study cancer 
Failure 
Competing risk Competing risk Failure 
Death  
COD=SPT 
Competing risk 
Competing risk Failure 
Failure 
Death  
COD=protocol treatment Competing risk 
Competing risk Competing risk Failure 
Death  
COD=other cause 
Competing risk 
Competing risk Competing risk Failure 

 
 
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Death 
COD=unknown 
Failure 
Competing risk Competing risk Failure 
Non-protocol radiation 
therapy  
 
Failure 
Competing risk Competing risk 
Failure 
Non-protocol 
chemotherapy (or 
biologic)  
 
Failure 
Competing risk Competing risk 
Failure 
Surgery of primary 
Pathology=tumor 
Failure 
Competing risk Competing risk Failure 
Surgery of primary 
Pathology=no tumor 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Surgery of primary 
Pathology=unknown 
Failure 
Competing risk Competing risk Failure 
Surgery of nodes 
 15 weeks from RT end 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Surgery of nodes 
> 15 weeks from RT end; 
pathology=tumor 
Failure 
Competing risk Competing risk 
Failure 
Surgery of nodes 
> 15 weeks from RT end; 
pathology=no tumor 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Non-event, 
continue 
Surgery of nodes 
> 15 weeks from RT end; 
pathology=unknown 
Failure 
Competing risk Competing risk 
Failure 
COD = cause of death 
Analysis for Reporting the Initial Treatment Results  
The analysis to report the initial results of treatment will be undertaken when each patient has 
been potentially followed for a minimum of 12 months.  Only eligible patients with both on-
study and follow-up information that has started protocol treatment will be included.  The 
emphasis of this analysis will be on treatment compliance and adverse events.  The usual 
components of this analysis are: 
• 
Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion;  
• 
Patient accrual rate; 
• 
Institutional accrual; 
• 
Distribution of important baseline prognostic variables; 
• 
Frequency and severity of adverse events; 
• 
Compliance rate for treatment delivery with respect to the protocol prescription; 
• 
Observed results with respect to the study endpoints described in section 8.1. 
The rates of adverse events and tolerability will be estimated along with their associated 95% 
confidence intervals.  Patients with Grade 4 mucositis/skin reaction or any Grade 5 adverse 
event as described in Section 8.2.1 will be identified. If there are 4 or more such patients out 
of the first 42 eligible patients by either institutional scoring or independent review, the 
protocol treatment will be considered to have an unacceptably high adverse event rate to use 
this treatment without modification in subsequent follow-up phase III trial. In addition, the 

 
 
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tolerability rate for each treatment component (neoadjuvant, concurrent and maintenance phase) 
will be computed. If the percentage is less than 50% for a component, then that component 
will be considered to have an unacceptably low tolerability rate to use without modification in 
the follow-up phase III trial, then the treatment component will be dropped or modified.  
Analysis for Reporting the Final Treatment Results 
 
The analysis to report the final results of treatment will be undertaken when each 
patient has been potentially followed for a minimum of 2 years.  Only eligible patients with 
both on-study and follow-up information that started protocol treatment will be included.  The 
emphasis of this analysis will be on local-regional progression and distant metastases.  The 
usual components of this analysis are: 
• 
Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion;  
• 
Patient accrual rate; 
• 
Institutional accrual; 
• 
Distribution of important baseline prognostic variables; 
• 
Frequency and severity of adverse events; 
• 
Compliance rate for treatment delivery with respect to the protocol prescription; 
• 
Observed results with respect to the endpoints described in Section 8.1. 
 
The rates of local-regional progression, distant metastases, second primary tumors, 
progression-free survival, and overall survival at one and two years will be estimated along 
with their associated 95% confidence intervals. These rates also will be compared with 
historical rates from previous publications.  
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 

 
 
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Pembrolizumab will be provided by MSD as summarized in Table 8. 
Table 8 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
All commercially available products not included in Table 8 (e.g. gemcitabine, cisplatin, and 
other supportive medications) will be provided by hospital pharmacy at study site as per local 
guideline.  
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from MSD or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 

 
 
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institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol. 
 
10.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the subject agrees 
to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. By signing this 
protocol, the investigator agrees to treat all subject data used and disclosed in connection with 
this trial in accordance with all applicable privacy laws, rules and regulations. 
10.2 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial. 
 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Section 12.1 - 
MSD Code of Conduct for Clinical Trials. 
 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents. The investigator shall prepare and maintain 

 
 
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complete and accurate trial documentation in compliance with Good Clinical Practice 
standards and applicable federal, state and local laws, rules and regulations; and, for each 
subject participating in the trial, provide all data, and, upon completion or termination of the 
clinical trial, submit any other reports to the Sponsor as required by this protocol or as 
otherwise required pursuant to any agreement with the Sponsor. 
 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae. By signing this protocol, the investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed. 
The Sponsor will determine the minimum retention period and upon request, will provide 
guidance to the investigator when documents no longer need to be retained. The sponsor also 
recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All trial documents sh all be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by the 
Sponsor prior to destroying trial and/or subject files. ICH Good Clinical Practice guidelines 
recommend that the investigator inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed. The investigator will promptly inform the Sponsor of any 
regulatory authority inspection conducted for this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened. 

 
 
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In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC. 
 
10.3 Declaration of Helsinki 
 
We abide to the declaration of Helsinki. 
 
10.4 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and functional 
area standard operating procedures (SOPs) to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical trial. 
 
10.5 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature. By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate. 
Detailed information regarding Data Management procedures for this protocol will be provided 
separately. 
 
11.0 REFERENCES 
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chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
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Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity. 
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7. 
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 
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Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits 
T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574:37-41. 
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Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229:114-25. 
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Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, 
et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell 
Biol. 2005;25:9543-53. 
11. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev. 2010;236:219-42. 
12. 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer 
incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 
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Pan JJ, Ng WT, Zong JF, Lee SW, Choi HC, Chan LL, et al. Prognostic nomogram for 
refining the prognostication of the proposed 8th edition of the AJCC/UICC staging system for 
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Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, et al. Induction chemotherapy 
plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in 
locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised 
controlled trial. Lancet Oncol. 2016;17:1509-20. 
15. 
Cao SM, Yang Q, Guo L, Mai HQ, Mo HY, Cao KJ, et al. Neoadjuvant chemotherapy 
followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in 
locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised 
controlled trial. Eur J Cancer. 2017;75:14-23. 
16. 
Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, et al. Gemcitabine plus cisplatin 
versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a 
multicentre, randomised, open-label, phase 3 trial. Lancet. 2016;388:1883-92. 
17. 
Hsu C, Lee SH, Ejadi S, Even C, Cohen RB, Le Tourneau C, et al. Safety and Antitumor 
Activity of Pembrolizumab in Patients With Programmed Death-Ligand 1-Positive 
Nasopharyngeal Carcinoma: Results of the KEYNOTE-028 Study. J Clin Oncol. 
2017;35:4050-6. 
18. 
Weiss GJ, Waypa J, Blaydorn L, Coats J, McGahey K, Sangal A, et al. A phase Ib study 
of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Br J 
Cancer. 2017;117:33-40. 
19. 
Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. 
Nivolumab in Combination With Platinum-Based Doublet Chemotherapy for First-Line 
Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2016;34:2969-79. 
20. 
Sanborn RE, Duffy RM, Fisher BK, Perlewitz KS, Redmond WL, Kpguchi Y. A phase 
I/II study of pembrolizumab (P) with gemcitabine (G) in patients (Pts) with previously-treated 

 
 
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advanced non-small cell lung cancer (NSCLC): Phase I safety results. DOI: 
101200/JCO20173515_supple20605, Journal of Clinical Oncology 35, no 15_suppl. 2017. 
21. 
Primo L, Beckett L, Li Y, Parikh M, Robles D, Aujla P. Combination checkpoint 
immunotherapy and cytotoxic chemotherapy: Pembrolizumab (Pembro) plus either docetaxel 
or gemcitabine in patients with advanced or metastatic urothelial cancer. DOI: 
101200/JCO2017356_suppl 398 Journal of Clinical Oncology 35, no 6_suppl (February 2017) 
398-398. 2017. 
22. 
Wainberg et al. KEYNOTE-059: Efficacy and Safety of Pembrolizumab (pembro) 
Alone or in Combination with Chemotherapy (chemo) in Patients (pts) With Advanced Gastric 
or Gastroesophageal (G/GEJ) Cancer. Oral Presentation: ESMO 2017: 8-12 September 2017 
in Madrid, Spain. 
23. 
Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, 
et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-
squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label 
KEYNOTE-021 study. Lancet Oncol. 2016;17:1497-508. 
24. 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. 
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J 
Med. 2018;378:2078-92. 
25. 
Powell SF, Gitau MM, Sumey CJ, Reynolds J, Terrell AM, Lohr MM, et al. Safety of 
Pembrolizumab with Chemoradiation (CRT) in Locally Advanced Squamous Cell Carcinoma 
of the Head and Neck (LASCCHN). Presented at: 2017 ASCO Annual Meeting, June 2-6, 
2017; Chicago, Illinois 2017. 
26. 
Lee NY, Zhang Q, Pfister DG, Kim J, Garden AS, Mechalakos J, et al. Addition of 
bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal 
carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol. 2012;13:172-80. 
27. 
Ma BB, Kam MK, Leung SF, Hui EP, King AD, Chan SL, et al. A phase II study of 
concurrent cetuximab-cisplatin and intensity-modulated radiotherapy in locoregionally 
advanced nasopharyngeal carcinoma. Ann Oncol. 2012;23:1287-92. 
28. 
Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor 
Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or 
Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-
012 Expansion Cohort. J Clin Oncol. 2016;34:3838-45. 
29. 
Ma BBY, Lim WT, Goh BC, Hui EP, Lo KW, Pettinger A, et al. Antitumor Activity 
of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, 
Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). J Clin Oncol. 
2018:JCO2017770388. 
30. 
Lo YM, Chan LY, Lo KW, Leung SF, Zhang J, Chan AT, et al. Quantitative analysis 
of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. 
Cancer Res. 1999;59:1188-91. 
31. 
Lo YM, Chan AT, Chan LY, Leung SF, Lam CW, Huang DP, et al. Molecular 
prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-
Barr virus DNA. Cancer Res. 2000;60:6878-81. 

 
 
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32. 
Kim KY, Le QT, Yom SS, Ng RHW, Chan KCA, Bratman SV, et al. Clinical Utility 
of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients. 
Int J Radiat Oncol Biol Phys. 2017;98:996-1001. 
33. 
Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al. Plasma Epstein-Barr 
virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal 
carcinoma. J Natl Cancer Inst. 2002;94:1614-9. 
34. 
Lin JC, Wang WY, Chen KY, Wei YH, Liang WM, Jan JS, et al. Quantification of 
plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl 
J Med. 2004;350:2461-70. 
35. 
Chan AT, Ma BB, Lo YM, Leung SF, Kwan WH, Hui EP, et al. Phase II study of 
neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in 
patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with 
plasma Epstein-Barr virus DNA. J Clin Oncol. 2004;22:3053-60. 
36. 
Brouwer CL, Steenbakkers RJ, Bourhis J, Budach W, Grau C, Gregoire V, et al. CT-
based delineation of organs at risk in the head and neck region: DAHANCA, EORTC, 
GORTEC, HKNPCSG, NCIC CTG, NCRI, NRG Oncology and TROG consensus guidelines. 
Radiother Oncol. 2015;117:83-90. 
37. 
Sun Y, Yu XL, Luo W, Lee AW, Wee JT, Lee N, et al. Recommendation for a 
contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving 
intensity-modulated radiotherapy. Radiother Oncol. 2014;110:390-7. 
38. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 
2017;18:e143-e52. 
39. 
Fleming TR. One-sample multiple testing procedure for phase II clinical trials. 
Biometrics. 1982;38:143-51. 
 
 

 
 
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12.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 5.1.1:  
● 
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● 
Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 9 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant. 

 
 
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○ 
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile penetration. 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10 
during the protocol-defined time frame in Section 5.1.1.  
 
Table 10 Highly Effective Contraception Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of < 1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment.  The 

 
 
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reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
Delete footnote “b” for all trials evaluating pembrolizumab as monotherapy.  Include for all trials 
evaluating pembrolizumab as a combination therapy. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential]  after the last dose of study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected, after the last dose of 
study treatment, and as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 

 
 
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Appendix 4:  Description of the iRECIST Process for Assessment of Disease 
Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 5 and Figures 1 and 3).  This decision 
by the Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of 
disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 

 
 
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 

 
 
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Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on 
which iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”.  This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 6. 

 
 
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Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except 
in one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
scan the burden of new lesions has increased from its smallest value (for new target lesions, 
their sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD 
or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution 
to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication (38). 
 
 

 
 
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Appendix 5: Collection and Management of Specimens for Future Biomedical Research 
1. 
Definitions 
a. 
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may be used 
to see how well the body responds to a treatment for a disease or condition.1 
b. 
Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2 
c. 
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2 
d. 
DNA: Deoxyribonucleic acid. 
e. 
RNA: Ribonucleic acid. 
2. 
Scope of Future Biomedical Research 
The specimens collected in this trial as outlined in Section 7.1.4.4 – Future Biomedical 
Research 7.1.4.4 – Future Biomedical Research will be used to study various causes for how 
subjects may respond to a drug/vaccine. Future biomedical research specimen(s) will be stored 
to provide a resource for future trials conducted by study Principle Investigator (PI) focused 
on the study of biomarkers responsible for how a drug/vaccine enters and is removed by the 
body, how a drug/vaccine works, other pathways a drug/vaccine may interact with, or other 
aspects of disease. The specimen(s) may be used for future assay development and/or 
drug/vaccine development. 
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need. All specimens will be used by PI or designees and research will be monitored 
and reviewed by a committee of our scientists and clinicians. 
3. 
Summary of Procedures for Future Biomedical Research 
a. 
Subjects for Enrollment 
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-trial. 
b. 
Informed Consent 

 
 
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Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all subjects or legal guardians, at a trial visit by the 
investigator or his or her designate. Informed consent for Future Biomedical Research should 
be presented to the subjects on Visit 1. If delayed, present consent at next possible Subject 
Visit. Informed consent must be obtained prior to collection of all Future Biomedical Research 
specimens. Consent forms signed by the subject will be kept at the clinical trial site under 
secure storage for regulatory reasons. Information contained on the consent form alone cannot 
be traced to any specimens, test results, or medical information once the specimens have been 
rendered de-identified 
Each informed consent approved by an ethics committee is assigned a unique tracking number. 
The tracking number on this document will be used to assign specimen permissions for each 
specimen into the central encrypted database. 
c. 
eCRF Documentation for Future Biomedical Research Specimens 
Documentation of both consent and acquisition of Future Biomedical Research specimens will 
be captured in the electronic Case Report Forms (eCRFs). Reconciliation of both forms will 
be performed to assure that only appropriately- consented specimens are used for this sub-
trial's research purposes. Any specimens for which such an informed consent cannot be verified 
will be destroyed. 
d. 
Future Biomedical Research Specimen Collections 
Blood specimens for DNA or RNA isolation will usually be obtained at a time when the subject 
is having blood drawn for other trial purposes. Specimens like tissue and bone marrow will 
usually be obtained at a time when the subject is having such a procedure for clinical purposes. 
Specimens will be collected and sent to the laboratory designated for the trial where they will 
be processed (e.g., DNA or RNA extraction, etc) following the institutional approved policies 
and procedures for specimen handling and preparation. 
If specimens are collected for a specific genotype or expression analysis as an objective to the 
main trial, this analysis is detailed in the main body of this protocol (Section 8.0 – Statistical 
Analysis Plan). These specimens will be processed, analyzed, and the remainder of the 
specimen will be destroyed. The results of these analyses will be reported along with the other 
trial results. A separate specimen will be obtained from properly-consented subjects in this 
protocol for storage in the biorepository for Future Biomedical Research. 
4. 
Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact little 
or no research can be conducted without connecting the clinical trial data to the specimen. The 

 
 
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clinical data allow specific analyses to be conducted. Knowing subject characteristics like 
gender, age, medical history and treatment outcomes are critical to understanding clinical 
context of analytical results. 
To maintain privacy of information collected from specimens obtained for Future Biomedical 
Research, the institution has developed secure policies and procedures. All specimens will be 
de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which does 
not contain any personally identifying information embedded within it. The link (or key) 
between subject identifiers and this first unique code will be held at the trial site. No personal 
identifiers will appear on the specimen tube. 
This first code will be replaced with a second code at a designated storage/lab facility. The 
second code is linked to the first code via a second key. The specimen is now double coded. 
Specimens with the second code are sometimes referred to as de- identified specimens. The 
use of the second code provides additional confidentiality and privacy protection for subjects 
over the use of a single code. Access to both keys would be needed to link any data or 
specimens back to the subject's identification. 
The second code is stored separately from the first code and all associated personal specimen 
identifiers. A secure link, the second key, will be utilized to match the second code to the first 
code to allow clinical information collected during the course of the trial to be associated with 
the specimen. This second key will be transferred under secure procedures by the designated 
facility to a central encrypted database. The second code will be logged into the primary 
biorepository database and, in this database, this identifier will not have identifying 
demographic data or identifying clinical information (i.e., race, sex, age, diagnosis, lab values) 
associated with it. The specimen will be stored in a designated biorepository site with secure 
policies and procedures for specimen storage and usage. 
The second key can be utilized to reconstruct the link between the results of future biomedical 
research and the clinical information, at the time of analysis. This linkage would not be possible 
for the scientist conducting the analysis, but can only be done by the central encrypted database 
under strict security policies and procedures. The encrypted database will link the information 
and then issue a de-identified data set for analysis. The only other circumstance by which future 
biomedical research data would be directly linked to the full clinical data set would be those 
situations mandated by regulatory authorities (e.g., EMEA, FDA), whereby this information 
would be directly transferred to the regulatory authority. 
5. 
Biorepository Specimen Usage 
Specimens obtained for the Biorepository will be used for analyses using good scientific 
practices. However, exploratory analyses will not be conducted under the highly validated 

 
 
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conditions usually associated with regulatory approval of diagnostics. The scope of research 
performed on these specimens is limited to the investigation of the variability in biomarkers 
that may correlate with a clinical phenotype in subjects. 
Analyses utilizing the Future Biomedical Research specimens may be performed by PI, or an 
additional third party (e.g., a university investigator) designated by PI. The investigator 
conducting the analysis will be provided with double coded specimens. Re-association of 
analysis results with corresponding clinical data will only be conducted by the PI from the 
encrypted database. Any contracted third party analyses will conform to the specific scope of 
analysis outlined in this sub-trial. Future Biomedical Research specimens remaining with the 
third party after the specific analysis is performed will be returned to the sponsor or destroyed 
and documentation of destruction will be reported to PI. 
6. 
Withdrawal from Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their specimens 
and all derivatives destroyed. Subjects may withdraw consent at any time by contacting the 
principal investigator for the main trial. If medical records for the main trial are still available, 
the investigator will contact PI and a form will be provided by PI to obtain appropriate 
information to complete specimen withdrawal. Subsequently, the subject's specimens will be 
removed from the biorepository and be destroyed. A letter will be sent from PI to the 
investigator confirming the destruction. It is the responsibility of the investigator to inform the 
subject of completion of destruction. Any analyses in progress at the time of request for 
destruction or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research trial data and results. No new analyses would 
be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens. In this situation, the request for specimen 
destruction cannot be processed. 
7. 
Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential analysis 
for up to 20 years from acquisition. Specimens may be stored for longer if a regulatory or 
governmental authority has active questions that are being answered. In this special 
circumstance, specimens will be stored until these questions have been adequately addressed. 
Specimens from the trial site will be shipped to a central laboratory and then shipped to the 
designated biorepository. The specimens will be stored under strict supervision in a limited 
access facility which operates to assure the integrity of the specimens. Specimens will be 

 
 
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destroyed according to institutional policies and procedures and this destruction will be 
documented in the biorepository database. 
8. 
Data Security 
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by PI. This is done to separate the future exploratory test 
results (which include genetic data) from the clinical trial database thereby maintaining a 
separation of subject number and these results. The separate databases are accessible only to 
the authorized Sponsor and the designated trial administrator research personnel and/or 
collaborators. Database user authentication is highly secure, and is accomplished using 
network security policies and practices based in international standards to protect against 
unauthorized access. The encrypted database maintains control over access to all specimen 
data. These data are collected for future biomedical research purposes only as specified in this 
sub- trial will not be used for any other purpose. 
 9. 
Reporting of Future Biomedical Research Data to Subjects 
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to the 
trial participant. Some guidelines advocate a proactive return of data in certain instances. No 
information obtained from exploratory laboratory studies will be reported to the subject or 
family, and this information will not be entered into the clinical database maintained by PI on 
subjects. Principle reasons not to inform or return results to the subject include: lack of 
relevance to subject health, limitations of predictive capability, concerns of misinterpretation 
and absence of good clinical practice standards in exploratory research typically used for 
diagnostic testing. 
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as to 
how to offer clinical diagnostic testing to subjects enrolled and will be advised that counseling 
should be made available for all who choose to participate in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after completion 
of a clinical trial, PI will publish the results without revealing specific subject information, 
inform all trial sites who participated in the clinical trial and post anonymized results on our 
website or other accredited website(s) that allow for public access (e.g., disease societies who 
have primary interest in the results) in order that physicians and patients may pursue clinical 
diagnostic testing if they wish to do so. 
11. 
Risks versus Benefits of Future Biomedical Research 

 
 
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For future biomedical research, risks to the subject have been minimized. No additional risks 
to the subject have been identified as no additional specimens are being collected for Future 
Biomedical Research (i.e., only leftover samples are being retained). 
The PI’s institution has developed strict security, policies and procedures to address subject 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused. 
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, age, 
toxicities, etc.) to be re-associated to double coded specimens at the time of data analysis. 
These subject data will be kept in a separate, secure database, and all specimens will be stripped 
of subject identifiers. No information concerning results obtained from future biomedical 
research will be entered into clinical records, nor will it be released to outside persons or 
agencies, in any way that could be tied to an individual subject. 
13. 
Questions 
Any questions related to the future biomedical research should be directly to study PI. 
14. 
References 
1. 
National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker 
2. 
International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC DATA 
AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-for-
genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-sample-
cod.html