Immuno-Chemotherapy as Single Treatment Modality for Larynx Preservation (ICoLP)
Phase: PHASE2
Conditions: Laryngeal Squamous Cell Carcinoma, Stage II Laryngeal Cancer AJCC v8, Stage III Laryngeal Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

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TITLE: Immuno-Chemotherapy as single treatment modality for Larynx Preservation (ICoLP) 
 
 
PI: Renata Ferrarotto, MD (Head and Neck Medical Oncology) 
 
 
Co-PIs: 
Ed Diaz Jr, MD (Head and Neck Surgery) 
 
  
 
 MDACC Protocol Number: 2018-0876 
 
 
 
 
 
Version: 1.0   Submission Date: 05 February 2019 
Version 3.0 Submission Date: 19 February 2019 
Version 3.0   Submission Date: 8 March 2019 
Version 4.0   Submission Date: 6 June 2019 

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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY .................................................................................................... 5 
2.1 
TRIAL DESIGN .......................................................................................................... 5 
2.2 
Trial Design ............................................................................................................. 5 
2.3 
Trial Diagram .......................................................................................................... 5 
3.1 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 6 
3.2 
Primary Objective(s) & Hypothesis(es) ................................................................ 6 
3.3 
Secondary Objective(s) & Hypothesis(es) ............................................................. 6 
3.4 
Exploratory Objective ............................................................................................ 7 
4.1 
BACKGROUND & RATIONALE ............................................................................ 7 
4.2 
Background ............................................................................................................. 7 
4.2.1 Pharmaceutical and Therapeutic Background ....................................................... 9 
4.2.2 Preclinical and Clinical Trial Data ...................................................................... 10 
4.3 
Rationale ................................................................................................................ 10 
4.3.1 Rationale for the Trial and Selected Population ................................................. 10 
4.3.2 Justification for Dose .......................................................................................... 10 
4.3.3 Rationale for Endpoints ...................................................................................... 12 
5.1 
METHODOLOGY ................................................................................................... 13 
5.2 
Study Population ................................................................................................... 13 
5.2.1 Participant Inclusion Criteria .............................................................................. 13 
5.2.2 Participant Exclusion Criteria ............................................................................. 14 
5.2.3 Lifestyle Restrictions .......................................................................................... 16 
5.2.4 Pregnancy ............................................................................................................ 17 

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5.2.5 Use in Nursing Women ....................................................................................... 17 
5.3 
Trial Treatments ................................................................................................... 17 
5.3.1 Timing of Dose Administration ............................................................................. 17 
5.3.2 Dose Modification and toxicity management ..................................................... 18 
5.3.2.1 Definition of Dose Limiting Toxicity ................................................................. 18 
5.3.2.2 Dose Modification and toxicity management for docetaxel and cisplatin or 
carboplatin  .......................................................................................................... 19 
5.2.2.1.2 Dose Modifications for Cisplatin or Carboplatin ............................................ 22 
5.2.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab  .......................................................................................... 22 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 29 
5.3.1 Acceptable Concomitant Medications ................................................................ 29 
5.3.2 Prohibited Concomitant Medications .................................................................. 29 
5.4 
Rescue Medications & Supportive Care ............................................................. 30 
5.5 
Participant Withdrawal/Discontinuation Criteria ............................................. 30 
5.6 
Clinical Criteria for Early Trial Termination .................................................... 31 
6.0 
STUDY FLOW CHART .......................................................................................... 32 
7.1 
TRIAL PROCEDURES ........................................................................................... 35 
7.2 
Trial Procedures .................................................................................................... 35 
7.2.1 Clinical Procedures/Assessments ........................................................................ 35 
7.2.2 Laboratory Procedures/Assessments ................................................................... 37 
7.3 
Assessing and Recording Adverse Events ........................................................... 39 
7.3.1 Definition and Reporting of an Overdose for This Protocol ............................... 41 
7.3.2 Reporting of Pregnancy and Lactation ................................................................ 41 

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7.3.3 Immediate Reporting of Adverse Events ............................................................ 41 
7.3.4 Evaluating Adverse Events ................................................................................. 43 
8.1 
STATISTICAL ANALYSIS PLAN ......................................................................... 47 
8.2 
Sample Size Calculation ....................................................................................... 47 
9.1 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES  ................................................................................................................ 50 
9.2 
Investigational Product ........................................................................................ 50 
9.3 
Clinical Supplies Disclosure ................................................................................. 50 
9.4 
Storage and Handling Requirements .................................................................. 50 
9.5 
Returns and Reconciliation .................................................................................. 51 
10.0 APPENDICES ................................................................................................................. 51 
10.1: ECOG Performance Status ..................................................................................... 51 
10.2: Common Terminology Criteria for Adverse Events V5 (CTCAE) ..................... 52 
10.3: Contraceptive Guidance and Pregnancy Testing ................................................. 52 
10.4 Larynx cancer TNM staging AJCC 8th Edition ..................................................... 55 
11.0 REFERENCES .......................................................................................................... 60 

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1.0  TRIAL SUMMARY 
 
Abbreviated Title 
ICoLP 
Trial Phase 
II 
Clinical Indication 
Larynx squamous cell carcinoma (LSCC) 
Trial Type 
Single arm 
Type of control 
NA 
Route of administration 
Intravenously 
Trial Blinding 
NA 
Treatment Groups 
One 
Number of trial participants 
Up to 25 
Estimated enrollment period 
24 months 
Estimated duration of trial 
36 months 
Duration of Participation 
Patients will be followed for 1 year 
Estimated  average  length   of 
treatment per patient 
18 weeks 
 
 
 
2.1 TRIAL DESIGN 
 
2.2 
Trial Design 
 
This is a single arm phase II study that will evaluate the combination of pembrolizumab, cisplatin, 
and docetaxel (PCD) as single treatment modality in patients with stage II or III larynx SCC. 
 
 
 
 
2.3 
Trial Diagram 
 
Figure 1. Study Design. 

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Cancer stage as per TNM 8th edition [see appendix 10.5]; ECOG PS: ECOG performance status 
[see appendix 10.1]; PD: progression of disease; PR: partial response; SD: stable disease; XRT: 
radiotherapy, CT: chemotherapy; Q21D: each 21 days; post-op: post-operative; pCR: pathologic 
complete response, Definitive: Standard of care.
3.1 OBJECTIVE(S) & HYPOTHESIS(ES)
3.2
Primary Objective(s) & Hypothesis(es)
(1) Objective: To determine the clinical benefit rate (CBR) of patients with stage II or III larynx 
squamous cell carcinoma (SCC) after 2 cycles of pembrolizumab, cisplatin and docetaxel 
(PCD), and the pathologic complete response (pCR) rate after 4 cycles of PCD.
Hypothesis: In patients with stage II or III larynx SCC, PCD will lead to CBR in the
vast majority of patients. Furthermore, PCD will lead to durable pCR in a subset of patients.
3.3
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To determine safety and tolerability of PCD in patients with larynx SCC.
Hypothesis:
PCD will have the toxicity profile expected for each agent alone, without 
significant overlapping toxicity.

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(2) Objective: To determine the laryngeal preservation rate (LPR) at 2 years in the overall 
population and in the subgroup who achieves a pCR. 
 
Hypothesis: PCD in the induction setting or as single treatment modality will lead to a rate of 
laryngeal preservation at 2 years that is comparable or higher to historical controls. 
 
(3) Objective: To determine the 2 year relapse-free survival (RFS) and overall survival (OS) in 
the overall population and in the subgroup who achieves a pCR. 
 
Hypothesis: Laryngeal SCC patients treated with PCD will have favorable relapse-free 
survival and overall survival outcomes when compared to historical controls. 
 
(4) Objectives: To determine patient-reported outcomes (PROs) using M.D. Anderson Symptom 
Inventory-Head and NECK (MDASI-HN) and swallow function using Dynamic Imaging 
Grade of Swallowing Toxicity (DIGEST). 
 
Hypothesis: PCD as single treatment modality will lead to significantly better PROs and 
improved swallow and speech functions as compared to patients treated with multi-modality 
therapy. 
 
3.4 
Exploratory Objective 
 
(1) 
Objective: To assess predictive tissue and blood-based biomarkers of benefit from PCD in 
larynx SCC. 
 
Hypothesis: Analysis of tissue and blood biomarkers before and after treatment may 
identify predictive markers of benefit from PCD and will increase the understanding of 
the immune biology of locally advanced larynx SCC. 
 
 
 
4.1 BACKGROUND & RATIONALE 
 
4.2 
Background 
 
The larynx performs three vital functions: maintenance of airway patency, occlusion of the airway 
during the pharyngeal phase of swallowing, and voice production. Optimal treatment maximizes 
these functional outcomes (ie, voice quality, swallowing ability) and survival. 
 
In spite of total laryngectomy be an effective treatment for larynx squamous cell carcinoma, loss 
of the natural voice and the stigma, life style, and voice restrictions of a permanent stoma 
significantly impair quality of life, frequently leads to social isolation, and depression 1. 
Both, radiation therapy (RT) and laryngeal preservation surgery can cure a high proportion of 
patients with early stage disease (Stage I and II). RT is often preferred because functional 
outcomes, particularly voice quality, are perceived to be better. Selected patients with T2 cancers 
(eg, bulky, invasive T2 cancers with impaired cord mobility or subglottic extension) are 
appropriate for concurrent chemoradiation due to worse local control with radiotherapy alone 2-5. 

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Patients with early stage laryngeal cancer are less likely to have prolonged acute and long-term 
permanent toxicity than patients with advanced laryngeal SCC who require larger RT fields and 
concurrent chemotherapy6, however, prolonged larynx edema, chondritis, laryngeal and 
pharyngeal stenosis can occasionally occur in patients with early stage disease treated with single 
modality RT 7,8. 
 
For patients with locally advanced disease (stage III or IV), concomitant chemoradiation or 
induction chemotherapy followed by RT are acceptable standard of care treatment options as an 
organ preservation approach; however, radiotherapy with or without chemotherapy can lead to 
significant long-term morbidity and a minority of patients will have a functional anatomic 
preserved organ 9,10. 
 
Long-term results from RTOG 91-11, which included 64% of stage III patients, demonstrated 
improved long-term survival with induction chemotherapy followed by RT, likely due to long- 
term side effects attributed to concurrent chemoradiation (such as recurrent aspiration, stroke, etc..) 
not captured on the study 11,12. At one year, 23% of patients who received concurrent 
chemoradiation could only swallow liquid or soft foods, and 3% could not swallow at all. In the 
radiotherapy single modality, 15% were limited to soft food or liquids and 3% could not swallow. 
The subgroup who received sequential therapy had only 9% of patients limited to soft or liquid 
food. The 2 year disease-free interval and overall survival was approximately 55% and 75% 
respectively for all groups. Systemic therapy (Cisplatin and 5-Fluouracil) in the induction setting 
reduced the rate of distant metastasis. 
 
Other studies have confirmed that induction chemotherapy decreases distant metastasis in patients 
with locally-advanced HNSCC, and there is a benefit in overall response rate and survival of using 
three (Cisplatin, Docetaxel, and 5-Fluouracil or TPF) versus two (Cisplatin and 5-Fluourocil or 
PF) chemotherapy agents 13,14. TPF in larynx SCC leads to an overall response rate of 85%15; 
however, toxicity limits the use of triple agent chemotherapy in a significant proportion of patients. 
 
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 
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. 
Keytruda® (pembrolizumab) 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. It has been 
FDA approved for the treatment of recurrent or metastatic head and neck SCC 16 given its 
encouraging activity in this patient population. Exploratory analysis of prospective clinical trials 
suggest that clinical benefit of single agent pembrolizumab is higher when PD-L1 is expressed in 
at least 1% of the tumor cells and/or in lymphocytes and macrophages in the tumor 
microenviroment, which occurs in approximately 78% of head and neck squamous cell carcinoma 
[PMID: 27718784, 30509740, 27646946].For more details on specific indications refer to the 
Investigator brochure. 
 
 

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In metastatic non-small cell lung cancer (NSCLC), pembrolizumab combined with platinum-
doublet chemotherapy has improved overall response rates and overall survival in two randomized 
phase III trials when compared to chemotherapy alone without a significant increase in toxicity and 
irrespective of PD- L1 status. Dexamethasone as pre-medication was used as per standard guidelines 
and did not seem to impact the benefit of pembrolizumab added to chemotherapy. Pembrolizumab 
combined to platinum and pemetrexed or platinum and paclitaxel/nab-paclitaxel are currently 
standard of care first line systemic therapy in NSCLC [PMID: 30429032, 30280635, 29658856]. 
 
Considering the encouraging activity and safety profile seen with carboplatin, paclitaxel and 
pembrolizumab in metastatic non-small cell lung cancer; that most benefit from TPF in head and 
neck SCC is thought to be derived from cisplatin and docetaxel; and that 5-FU requires continuous 
infusion and has diarrhea as a common adverse event, we believe that pembrolizumab combined 
with cisplatin and docetaxel will be well tolerated and have significant activity in patients with 
stage II or III larynx SCC. Furthermore, we hypothesize that a proportion of patients treated with 
this regimen will achieve a durable pathologic complete response and will be cured with single 
modality systemic therapy. 
 
 
 
 
4.2.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades18. 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 19,20. 
 
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) 21,22. 
 
The structure of murine PD-1 has been resolved 23. 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- 

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associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade 22,24- 
26. 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 
27,28. As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention 
in larynx squamous cell carcinoma. 
 
4.2.2 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Pembrolizumab Preclinical and Clinical data. 
 
4.2 
Rationale 
 
4.2.1 Rationale for the Trial and Selected Population 
 
Our group has demonstrated in a single arm phase II study that 33% of patients with T2-4, N0-1 
larynx SCC treated with TIP (paclitaxel, ifosfamide, cisplatin) achieved a complete pathologic 
response (pCR) with durable remission and no evidence of disease recurrence at 5 years 29. A 10- 
year update of this study revealed that none of the patients who achieved a pCR and were disease- 
free at 5 years recurred (unpublished data, manuscript in preparation), suggesting that a subset of 
larynx SCC can be cured with systemic therapy alone. The functional outcomes of patients who 
received systemic therapy as a single treatment modality were remarkable with normal speech and 
swallow functions. 
 
Larynx SCC is a tobacco-induce neoplasm with a high mutation-burden, which usually correlates 
with response to pembrolizumab. It is overall a chemotherapy-sensitive disease, however, 
responses are in general short-lived. Chemotherapy can lead to immunogenic cell death and can 
augment tumor immunity. PD-1 inhibitors can lead to expansion of intratumoral memory T cells, 
which can lead to durable responses 30. Based on the encouraging results reported in the Keynote- 
021 trial with platinum doublet combined with pembrolizumab, as discussed in Section 4.1 17, we 
propose cisplatin, docetaxel, and pembrolizumab will be safe and effective in patients with stage 
II or III larynx SCC and will lead to cure as a single treatment modality in a subset of patients. 
 
 
 
 
4.2.2 Justification for Dose 
 
4.2.2.1 Chemotherapy 
 
The standard dose of Cisplatin and Docetaxel used in head and neck squamous cell carcinoma is 
75 mg/m2 for both agents administered intravenously over one hour each Q3W 13,15. Body surface 
area (BSA) for chemotherapy dose calculation will be determined according to the following 
formula: BSA (m2) = [height (cm) x weight (Kg) / 3600]. 
 
The actual body weight will be used for BSA calculation, but the investigators will consider 
adjusted or ideal body weight if the BSA exceeds 2.0 m2. BSA should be recalculate prior to the 
start of every cycle of therapy. 
 
For patients with contra-indication to cisplatin, carboplatin AUC 6 using the Calvert method can 

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be used. 
 
Carboplatin dose (mg) = AUC x [GFR (ml/min) + 25 (ml/min)]. 
 
 
 
4.2.2.2 Pembrolizumab 
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: 
 
x 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), 
 
x Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
 
x 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 
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 

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complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 

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4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
 
Pathologic complete response has predicted improved long-term outcomes in many 
neoadjuvant trials in breast cancer 31. Concomitant systemic therapy and radiation therapy for 
organ preservation is a standard of care treatment for larynx SCC11 and has recently become 
an accepted treatment modality in rectal cancer, sparing unnecessary morbidity, mortality, 
and functional consequences associated with radical surgery without loss of oncological 
safety 32,33. 
 
Larynx SCC is an overall chemo – and radio- sensitive tumor. There is evidence that when 
pathologic complete response is achieved in larynx SCC, irrespective of its means (if by 
systemic therapy as single modality or by concurrent radiotherapy), a proportion of patients 
will be cured29. Sparing radiation therapy or surgery can significantly improve the function 
of the preserved organ and maintain patient’s quality of life, therefore, patient reported- 
outcomes is a secondary endpoint and will be assessed longitudinally with validated tools 
(MDASI-HN and DIGEST). Importantly, if patients recur, particularly in the context of close 
follow-up, they are highly salvageable with total laryngectomy or radiotherapy plus or minus 
chemotherapy. 
 
Since the higher risk of recurrence are within the first 2 years following definitive treatment, 
and in order to compare our results with the available literature, our secondary endpoints 
include laryngeal preservation rate, relapse-free survival, and overall survival at 2 years. 
 
 
 
 
4.2.3.2 Biomarker Research 
 
There is substantial interest in identifying biomarkers predictive of response to immune 
checkpoint inhibitors plus or minus chemotherapy in invasive solid tumors. As such, the 
biomarkers to be evaluated on this study aim at: 
 
 
(1) identifying the population more likely to benefit from pembrolizumab, cisplatin and docetaxel, 
 
 
(2) characterizing the immune response before and after treatment, 
 
 
(3) evaluating the interplay between the immune system, genetic, epigenetic, transcriptomic 
and phenotypic changes before and after treatment with pembrolizumab, cisplatin, and 
docetaxel. 
 
Because the biomarker research embedded in this protocol is exploratory, a broad panel of 
markers will be studied utilizing the most updated knowledge from other clinical and pre- 
clinical studies related to immune checkpoint blockade at the time of the analysis. 

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5.1 METHODOLOGY 
 
5.2 
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 newly diagnosed, previously untreated, histologically confirmed stage II to 
III larynx squamous cell carcinoma will be enrolled in this study. 
 
Male participants: 
 
2. A male participant must agree to use a contraception as detailed in Section 10.3 . of this 
protocol during the treatment period and for at least 150 days after the last dose of study 
treatment and refrain from donating sperm during this period. 
 
 
 
Female participants: 
 
3. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at         least         one         of          the          following          conditions          applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Section 10.3 of this 
protocol 
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Section 10.3 during the 
treatment period and for at least 150 days after the last dose of study treatment. 
 
 
 
4. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. 
 
 
5. Have measurable disease based on RECIST 1.1. 
 
 
6. Have provided archival tumor tissue sample (minimum of 20 unstained slides) 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. 
 
 
 
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
 
8. 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. 

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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 or ≥5.6 mmol/La 
Renal 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
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. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
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. 
 
 
 
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 treatment (see 
Section 10.3). If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 

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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 prior systemic anti-cancer therapy including investigational agents within 
4 weeks prior to study treatment. 
 
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 
or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
 
Note: If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment. 
 
 
 
4. 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. 
 
 
5. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent. 
 
 
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, with the 
exception of dexamethasone, that can be given the day prior (D0) until 4 days after 
chemotherapy (D4) up to 16 mg per day for prevention of chemotherapy-induced nausea, 
fluid retention, and/or allergic reaction. 
 
7. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years. Note: Participants with basal or squamous cell carcinoma of the 
skin, transitional cell carcinoma of urothelial cancer, carcinoma in situ (e.g. breast 
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy, and 
prostate cancer patients in active surveillance are not excluded. 
 
8. 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 

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therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
 
9. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
 
10. Has an active infection requiring intravenous antibiotic therapy. 
 
11. Has a known history of Human Immunodeficiency Virus (HIV). 
 
12. 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 < 615 IU/L) infection. 
Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health 
authority. 
 
13. Has a known history of active TB  (Bacillus Tuberculosis). 
 
 
14. 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. 
 
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 150 days after the 
last dose of trial treatment. 
 
17. as had a solid organ transplant and/or allogenic bone marrow transplant. 
 
 
 
 
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, dysphagia, nausea or vomiting. 
 
5.1.3.2 Contraception 
 
Pembrolizumab and chemotherapy may have adverse effects on a fetus in utero.  Refer to Section 
10.3 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). 

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5.1.4 Pregnancy 
 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment. 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 Merck 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 Merck. 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 Merck 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 
 
The systemic therapy treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
 
Drug 
Dose 
Frequency 
Route 
Treatment Period 
Use 
*Cisplatin 
75 mg/m2 
Q3W 
IV 
D1 of each 3W cycle, up 
to 4 cycles 
Standard 
*Docetaxel 
75mg/m2 
Q3W 
IV 
D1 of each 3W cycle, up 
to 4 cycles 
Standard 
Pembrolizumab 
200 mg 
Q3W 
IV 
D1 of each 3W cycle, up 
to 8 cycles 
Experimental 
**Carboplatin 
AUC 6 
Q3W 
IV 
D1 of each 3W cycle, up 
to 4 cycles 
** Standard 
* The use of Cisplatin and Docetaxel is standard of care in the induction setting for the patient 
population being studied, however, the combination of these two chemotherapy agents with 
pembrolizumab is experimental 
 
** Carboplatin will only be used instead of cisplatin if the study subject has any contra-indication 
to cisplatin or develop a significant adverse-event during treatment attributable to cisplatin (Eg: 
nausea and vomiting, increase in serum creatinine) 
 
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). Pembrolizumab will be 

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administered first, followed by docetaxel and then cisplatin. Trial treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. MDACC will use its own 
commercial supply of chemotherapy in this study. Pembrolizumab will be provided at no cost to 
the patient by Merck. 
 
5.2.1.1 Description, Handling and Administration of Docetaxel 
 
Docetaxel will be prepared and administered according to local practice and in accordance with 
the most recent Package Insert/Data Sheets. 
 
Dexamethasone will not be given prophylactic on Day 0 for fluid retention prior to cycle 1, 
however, it can be added as a prophylactic medication (up to 16 mg per day the day before and the 
day after administration) in case severe fluid retention is observed after cycle 1. 
 
5.2.1.2 
Description, Handling and Administration of Cisplatin or Carboplatin 
 
Cisplatin or Carboplatin will be prepared and administered according to local practice and in 
accordance with the most recent Package Insert/Data Sheets. 
 
Pre-medication for Cisplatin: All patients will receive intravenously anti-emetics and appropriate 
hydration prior to and after cisplatin administration according to current institutional guidelines. 
Anti-emetics include dexamethasone 12 mg, fosaprepitant 150 mg, and ondensantron 8 mg. 
 
Patients will be counseled to take dexamethasone 4 mg per oral bid and ondansentron 8 mg tid for 
2 to 3 days after chemotherapy (D2-D4). 
 
5.2.1.3 Description, Handling and Administration of Pembrolizumab 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Site 
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). 
 
 
5.2.2 Dose Modification and toxicity management 
 
Toxicities will be graded by using the NCI CTCAE version 5. Refer to the following website for 
the CTCAE manual or the CTCAE document: http://ctep.cancer.gov 
 
 
5.2.2.1 Definition of Dose Limiting Toxicity 
 
A dose limiting toxicity (DLT) will be defined as Grade 4 neutropenia lasting ≥ 7 days, Grade 3 
or 4 febrile neutropenia, Grade 4 anemia, Grade 4 thrombocytopenia or any non-hematologic 

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toxicity Grade 3 or greater that per Principal Investigator judgement is clinically significant and 
either possibly, probably or definitely attributable to study therapy. Exceptions include grade 3 
infusion reactions that resolve within 24 hours, grade 3 diarrhea, nausea, and/or vomiting that 
responds to standard medical treatment within 48 hours, grade 3 electrolyte disturbances that 
respond to correction within 24 hours), and grade 3 endocrine disorder (thyroid, pituitary, and/or 
adrenal insufficiency) that is managed with or without systemic corticosteroid therapy and/or 
hormone replacement therapy and the subject is asymptomatic. 
 
 
 
 
5.2.2.2 Dose  Modification  and  toxicity  management  for  docetaxel  and  cisplatin  or 
carboplatin 
 
The dose modifications outlined below are considered general guidelines. The investigator should 
use his or her best judgment when determining treatment interruptions and dose modifications. For 
example, some grade 2 non-hematologic toxicities may require treatment delays and/or dose 
reductions, and some grade 3 or 4 organ toxicities (e.g., hepatic, renal, cardiac, central nervous 
system) may require a permanent treatment discontinuation. If one chemotherapy agent (docetaxel 
or cisplatin/carboplatin) needs to be discontinued, the other chemotherapy agent 
(cisplatin/carboplatin or docetaxel) may be continued. Docetaxel or cisplatin/carboplatin dose will 
not be re-escalated once it has been reduced for toxicity. 
Prior to receiving any dose of docetaxel and cisplatin / carboplatin, patients must have an ANC 
≥1.5 x 109/L and a platelet count ≥100 x 109/L. If the ANC is < 1.5 x 109/L and platelet count is < 
100 x 109/L, the treatment should be delayed for ≤ 3 weeks. If the patient is unable to be treated 
after a 3-week delay, the patient will be discontinued from chemotherapy. Patients who have 
discontinued chemotherapy will be allowed to continue on pembrolizumab. 
 
5.2.2.1.1 Dose Modifications for Docetaxel 
The dose of docetaxel will be reduced according to the following guidelines. 
 
Thrombocytopenia 
- If grade 4 thrombocytopenia occurs, the dose of docetaxel will be reduced by 25% for subsequent 
cycles. If grade 4 thrombocytopenia persists despite dose reduction, docetaxel treatment will be 
discontinued. 
 
Neutropenia 
The dose of docetaxel will be reduced for the following neutropenic conditions as outlined in 
Table 3: 
- Grade 4 neutropenia lasting ≥ 7 days 
- Grade 3 or 4 febrile neutropenia 
 
Table 3: Docetaxel Dose Modifications for Neutropenia 
 
 
Dose Description 
Docetaxel Dose (mg/m2) 
 
starting dose 
75 mg/m2 

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1st dose reduction due to neutropenia 
(patients not receiving prophylactic growth factor 
support) 
75 mg/m2 
add growth factor support 
1st dose reduction due to neutropenia 
(patients receiving prophylactic growth factor support) 
65 mg/m2 
continue growth factor support 
2nd dose reduction due to neutropenia 
50 mg/m2 
continue growth factor support 
 
 
If grade 4 neutropenia or grade 3-4 febrile neutropenia persists despite dose reduction to 50 
mg/m2 with growth factor support, docetaxel treatment will be discontinued. 
 
Hepatic Dysfunction 
The dose of docetaxel will be reduced for abnormal liver function test as outlined in Table 4: 
 
Table 4: Docetaxel Dose Modifications for Abnormal Liver Function 
 
Direct 
Bilirubin 
 
Alkaline 
Phosphatase 
SGOT or SGPT 
Action 
 
 
 
 
> ULN 
 
 
 
 
OR 
 
 
 
 
> 5 x ULN 
OR 
> 5 x ULN 
Delay treatment d3 
weeks until recovery. 
If recovered*, reduce 
docetaxel dose by 
25%. If not 
recovered in d3 
weeks, discontinue 
docetaxel. 
 
dULN 
 
AND 
 
d5 x ULN 
AND 
1.6 – 5 x ULN 
Reduce docetaxel 
dose by 25% 
 
*Direct bilirubin dULN and alkaline phosphatase d5 x ULN and SGOT or SGPT d5 x ULN 
 
Note: a maximum of two dose reductions per patient are allowed. If liver toxicities persist despite 
two dose reductions, docetaxel treatment will be discontinued. 
 
 
 
Stomatitis 
 
x If grade 3 or 4 stomatitis occurs, the dose of docetaxel will be reduced 25% for subsequent 
cycles. If grade 3 or 4 stomatitis persists despite dosereduction, docetaxel treatment will 
be discontinued. 
 
Peripheral Neuropathy 
 
x If grade 3, or clinically significant grade 2 (as judged by the investigator) neuropathy 
occurs, the dose of docetaxel will be reduced by 25%. If grade 3, or clinically significant 
grade 2 (as judged by the investigator) neuropathy persists despite two dose reductions, 
docetaxel treatment will be discontinued. 

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x If grade 4 neuropathy occurs, docetaxel treatment will be discontinued. 
 
Hypersensitivity Reactions 
 
x There are no dose reductions for hypersensitivity reactions. Management of acute 
hypersensitivity reaction should follow the Institutional guidelines. Re-treatment with 
docetaxel will be allowed at the investigator’s discretion. 
 
xIf grade 4 hypersensitivity reactions occur, docetaxel treatment willbe discontinued. 
 
 
 
 
Fluid Retention 
 
xThere are no dose reductions for fluid retention. 
 
 
 
Patients developing new onset edema, progression of existing edema, or another sign of fluid 
retention (e.g. 2 pound weight gain), prophylactic dexamethasone on the day prior to 
chemotherapy will be added on the subsequent cycle and patients will be treated with oral 
diuretics. Regimens found to be effective in the management of fluid retention due toTaxotere 
are listed below. 
x Triamterene/hydrochlorothiazide one capsule (37.5 mg / 25 mg) po qd up to tid. 
 
x Furosemide 40 mg po daily if edema progresses despite Triamterene/hydrochlorothiazide 
therapy. Potassium supplementation should be given as needed. 
 
x If after a two-week trial, furosemide 40 mg po qd is ineffective, the patient may be treated 
with furosemide 20 mg po daily plus metolazone 2.5 mg po daily with potassium 
supplementation as needed. 
 
 
 
Further therapy should be customized depending upon the clinical situation. The clinical 
tolerance of the patient, the overall tumor response and the medical judgment of the investigator 
will determine if it is in the patient’s best interest to continue or discontinue treatment. 
 
 
 
Other Non-Hematologic Toxicities 
 
x If grade 3 or 4 clinically significant (as judged by the treating physician) non- 
hematologic toxicities occur (other than those listed above), docetaxel treatment will be 
withheld until the toxicity has resolved to ≤ grade 1 and then reinstituted (if medically 
appropriate) at a 25% dose reduction. If a grade 3 or 4 clinically significant toxicity 

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recurs despite two dose reductions, docetaxel treatment willbe discontinued. 
 
x If treatment is withheld for > 3 weeks due to a grade 3 or 4 toxicity, docetaxel treatment 
will be discontinued. 
 
5.2.2.1.2 Modifications for Cisplatin or Carboplatin 
 
If any grade 3 or 4 toxicity occurs that is consistent with the cisplatin or carboplatin side effect 
profile (e.g., renal toxicity manifested by BUN and serum creatinine elevation, tinnitus and 
audiologic impairment in the high frequency range [4000 to 8000 Hz], nausea and vomiting, 
hyperuricemia, mild to moderate anemia, and irreversible peripheral neuropathy), the dose of 
cisplatin or carboplatin will be reduced as outlined in Table 5. Additionally, the investigator may 
choose to switch from cisplatin to carboplatin (or vice versa) during cycles 2 to 4 as an attempt 
to minimize the incidence or severity of platinum-related toxicities. 
 
 
Table 5: Cisplatin/Carboplatin Dose Modifications 
 
 
 
Dose Level 
Cisplatin Dose (mg/m2) 
Carboplatin Dose (AUC) 
0 
Starting Dose 
75 mg/m2 
6 
 
-1 
60 mg/m2 
5 
-2 
50 mg/m2 
4 
 
 
If toxicities persist despite two dose reductions, cisplatin or carboplatin treatment will be 
discontinued. 
 
 
 
5.2.2.2 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 

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guidelines for irAEs associated with pembrolizumab are provided in Table 6. 

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Table 6 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
 
General instructions: 
 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
 
Pneumonitis 
Grade 2 
Withhold 
xAdminister corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
x 
Monitor participants for signs and 
symptoms of pneumonitis 
x 
Evaluate participants with suspected 
 
Grade 3 or 4, or 
recurrent Grade 2 
 
Permanently 
discontinue 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
x 
Add prophylactic antibiotics for 
opportunistic infections 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
xAdminister corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
 
 
 
Grade 4 
Permanently 
discontinue 
x 
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). 
x 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 
x 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 

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feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
x Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
x 
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 
x 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 E-cell 
failure 
Withhold 
x Initiate insulin replacement 
therapy for participants with 
T1DM 
x Administer anti-hyperglycemic in 
participants with hyperglycemia 
x 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
x Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
x 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
x Treat with non-selective beta- 
blockers (eg, propranolol) or 
thionamides as appropriate 
x 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
x Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
x 
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2 
Withhold 
 
x 
Monitor changes of renal function 

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Nephritis and 
Renal 
dysfunction 
Grade 3 or 4 
Permanently 
discontinue 
x Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Myocarditis 
Grade 1 or 2 
Withhold 
x Based on severity of AE 
administer corticosteroids 
x 
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 
x Based on type and severity of AE 
administer corticosteroids 
x 
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). 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
7. 
Table 7: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

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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 
Antihistamine
s 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 
  
with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
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) 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamine
s NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
No subsequent dosing 

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Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5 (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. The reason for 
interruption should be documented in the patient's study record. 
 
 
 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant's primary physician. 
 
5.3.1 Acceptable Concomitant Medications 
 
Concomitant medication will only be recorded in the medical record. 
 
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. 
 
5.3.2 Prohibited Concomitant Medications 
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
x Immunotherapy not specified in this protocol 
 
x Chemotherapy not specified in this protocol 
 
x Investigational agents other than pembrolizumab 
 
x Radiation therapy 
 
x 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. 
 
x Systemic glucocorticoids for any purpose other than prophylactic dexamethasone for 
chemotherapy induced nausea, vomiting, and/or edema, or to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology. 

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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. 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4    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 6]. 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 
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 7] 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. 
 
5.5 
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 if study 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons. 
 
A participant must be discontinued from study treatment for the following reasons: 
 
x The   participant   or   participant’s   legally   acceptable   representative   requests   to 
discontinue study treatment 
 
x Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
 
x Initiation of any new anticancer therapy not specified in this protocol 
 
x Unacceptable adverse experiences as described in Section 5.2.2. 

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x The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator, placed the participant at unnecessary risk from continued 
administration of study treatment. 
 
x The participant  has a confirmed positive serum pregnancy test 
 
x Noncompliance with study treatment or procedure requirements 
 
x Recurrent Grade 2 pneumonitis 
 
x The participant is lost to follow-up 
 
x Administrative reasons 
 
5.6 
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 
 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 

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Trial Period: 
Screening 
 
 
Treatment  
 
 
 
Post-Treatment 
Treatment Cycle/Title: 
1 
2 
3 
4 
5a 
6a 
7a 
8a  
Follow Up Visitsb 
Scheduling Window (Days): 
-28 to -1 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
± 
3 
± 
3 
 
 
3 weeks (± 1 week) after last cycle of 
treatment 
Every 6-12 weeks (± 1 
week) 
up to 2 years 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics, Medical, Tobacco/Alcohol 
History 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xi  
Trial Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
X  
 
Review Adverse Events (AEs)c 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Pregnancy Test – Urine or Serum E-HCG 
X 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSHd 
X 
 
X  
X  
X  
X  
Tumor Imaginge 
X 
 
X  
X  
 
 
X  
X 
Videostroboscopye 
X 
 
X  
X  
 
 
X  
X 
Laryngeal exame,f 
X 
 
 
 
X  
 
 
X  
X 
Modified Barium Swallow (MBS)e 
X 
 
 
 
X  
 
 
 
 
X 
 
 
 
6.0 STUDY FLOW CHART 
 
 
 
 
 
 
Phase

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Trial Period: 
Screening 
Phase 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
1 
 
2 
 
3 
 
4 
 
5a  
6a 
7a 
8a 
Follow Up Visitsb 
Scheduling Window (Days): 
-28 to -1 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
 
 
± 
3 
± 
3 
± 
3 
3 weeks (± 1 week) after last cycle of 
treatment 
Every 6-12 weeks (± 1 
week) 
up to 2 years 
Archival or Newly Obtained Tissue 
Collectione 
X 
 
 
 
 
X  
 
 
Patient-reported outcomes (PROs)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Correlative Studies Blood Collectionh 
X 
 
X  
X  
 
 
X 
X 
 
 
a Cycle 5 to 8 consists of pembrolizumab single agent for patients who achieved a pathologic complete response (pCR). 
 
b Time of initiation and frequency of follow-up visits and procedures (videostroboscopy and fiberoptic laryngeal exam) will depend on 
patient’s outcome following systemic therapy. For patients who did not achieve a pCR, the follow-up visits will occur after standard of 
care (radiation therapy plus or minus chemotherapy or surgery). 
 
c During the Post-Treatment period, AEs will be reviewed through 90 days following cessation of treatment or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, whichever is earlier. Persistent SAE will be followed until 
resolution or stabilization. 
 
d T3 will be measured at the Screening Phase. During the Treatment Phase, only TSH and FT4 will be checked prior to each treatment 
cycle. T3 will only be repeated at the discretion of the treating physician, if abnormalities on TSH or FT4 are noted during treatment. 
 
e Procedures such as videostoboscopy, laryngeal exam and biopsy will be obtained prior to administration of treatment during the 
treatment period. Archival tissue is allowable at screening but biopsy is mandatory prior to cycle 5 for patients without progression after 
2 cycles. The window for the procedures is (± 2 weeks). Post-treatment MBS occur at 3-6 months and 18-24 months after end of 
locoregional therapy. For patient who achieve a pathologic complete response, the post-treatment MBS will occur only at 3-6 months. 
 
f Laryngeal exam includes operative direct laryngoscopy after 4 cycles of systemic therapy, and fiberoptic laryngeal examination during 
follow-up. 

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g PROs will be collected every 12 weeks (± 1 week) during follow-up. 
 
hIn the Post-Treatment phase, one additional blood collection for correlative studies will happen at the 1 year time-point (± 6 weeks), 
and/or at the time of progression, if it occurs. Only patients who receive 6 cycles of systemic therapy will have a blood collection for 
correlative studies at the first follow-up visit. 
 
i Concomitant medications will be recorded up to 30 days following the last dose of study treatment. 

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7.1 TRIAL PROCEDURES 
 
7.2 
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 Merck 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. 
 
7.2.1 Clinical Procedures/Assessments 
 
7.2.1.1 Tumor Imaging and Assessment of Disease 
 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT) and 
magnetic resonance (MRI). If only one test can be done, CT will be prioritized. The head and 
neck should be imaged at all time points specified at the Study Flow Chart. A CT chest or PET- 
CT will be required only at Screening. If only one image modality can be done (CT or MRI), 
the same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast should be used in a participant throughout the study to optimize the reproducibility of 
the assessment of existing and new tumor burden and improve the accuracy of the assessment 
of response or progression based on imaging. Expedited confirmation of measurable disease 
based on RECIST 1.1 (by CT/MRI imaging or videostroboscopy picture) at Screening should 
be used to determine participant eligibility. 
 
Immobilization 
 
For reproducibility of imaging acquisition, and since we expect 60-70% of patients will require 
radiation therapy, patients will be positioned in a stable supine position capable of allowing 
accurate reproducibility of the target position between treatments. An immobilization scheme 
include dedicated head and neck coils, a flat insert table with an indexed base plate, an 
individualized dental immobilization apparatus, and a thermoplastic head and shoulder mask. 
 
Simulation 
 
All patients will receive an initial standard CT simulation which will cover the head and neck 
with an adequate margin for generation of digitally reconstructed radiographs (DRRs) and 
treatment planning with non-coplanar fields. Patients will also receive a pre-therapy 
immobilized MR-simulation, which will be co-registered to the CT simulation. Preferably, 
dual energy CT scans with acquisitions at 80/100/120/140 kVp can be acquired for the contrast 
CT, ideally with reconstruction of ≤2mm. 
 
All used images are to be acquired, whenever possible, in the treatment position. At a 
minimum, one non-MRI imaging modality (i.e. contrast CT or PET-CT) should be obtained in 

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treatment immobilization and coregistered with the simulation MRI, which must be performed 
in the treatment position. Patients will be planned for MR-simulation serially on treatment as 
per Study Flow Chart, which will be registered to the CT study closest to that time point. 
 
7.1.1.1.1  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. 
 
7.2.1.2 Assessment of pathologic complete response (pCR) 
 
After completion of cycle 4, patients will undergo imaging (same as baseline, preferably a 
computed tomography). Subjects will then undergo operative direct laryngoscopy, tumor 
mapping, and biopsy of any residual abnormality in the operating room. If no gross residual 
tumor is present, biopsies will be taken at the site of the tumor epicenter (based on pretreatment 
videostroboscopy) and adjacent mucosa. For patients with an endoscopic and histologic 
complete response (pCR), four additional cycles of pembrolizumab single agent will be 
administered. Patients with residual disease will proceed with local therapy. 
 
7.2.1.3 Preferred treatment for patients who do not achieve a pCR 
 
After 4 cycles of systemic therapy, patients who achieve a partial response should proceed with 
single modality radiation therapy. Concurrent systemic therapy and radiation (ideally with 
cisplatin or cetuximab) or surgery will be the treatment of choice and strongly encouraged in 
patients who experience stable disease or disease progression after 2 or 4 cycles of induction 
pembrolizumab, cisplatin and docetaxel. The decision between concurrent systemic therapy 
and radiotherapy versus surgery will be based on the best judgement of the treating physicians 
and multidisciplinary consensus. 
 
The preferred cisplatin dosing and schedule during concurrent chemoradiation is 40 mg/m2 
once a week (Q1W) for 6-7 doses. When cetuximab is chosen, loading dose of 400 mg/m2 
should be administered within 1 week prior to the initiation of radiation therapy, followed by 
250 mg/m2 IV Q1W for 6-7 doses. Alternative regimens (less preferably) include cisplatin 100 
mg/m2 Q3W for 2-3 doses or carboplatin AUC 2 IV Q1W for 6-7 doses during radiotherapy. 
 
Radiotherapy will be delivered according to institutional guidelines. IMRT or protons is 
allowed. 
 
7.2.1.4 Videostroboscopy and Fiberoptic Laryngeal Examination 
 
Videostroboscopy and Fiberoptic Laryngeal Examination will be performed as per institutional 
guidelines at the time points specified in the Study Flow Chart. If the primary tumor is not 
clearly visualized by imaging of the head and neck, a picture of the lesion will be taken during 
the videostroboscopy procedure and will be used for comparison and response assessment 
throughout treatment. 

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7.2.1.5 Modified Barium Swallow 
 
Modified barium swallow (MBS) will be performed at the time points specified in the Study 
Flow Chart. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) will be used to assess 
dysphagia 34. 
 
7.2.1.6 Patient-reported outcomes (PROs) 
 
Symptom burden will be assessed by the validated MDASI-HN35 at multiple time points, as 
outlined in the Study Flow Chart. 
 
7.2.1.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
Available tissue will be mandatory for participation in the study. A biopsy will be mandatory 
prior to cycle 5 of treatment for patients who do not progress after 2 cycles of systemic 
therapy. Blood for future biomarker analysis will be drawn prior to cycle 1 (baseline), at the 
two re-staging image time-points (after 2 and 4 cycles of systemic therapy), and 
approximately 1 year after completion of curative intent treatment. For patients who achieve 
a pCR after 4 cycles of systemic therapy, an additional blood drawn will occur at the first 
follow-up visit (after 6 cycles of treatment). At each timepoint, blood will be collected for 
cfDNA (20 mL), EDTA plasma (10 mL) and PBMCs (40 mL) and will be processed and 
stored according to our department’s approved laboratory standard operating procedure by 
Dr. Hai Tran’s laboratory staff. 
 
Biospecimens collected (including archival and newly obtained tissue and blood) will be 
used for correlative studies. As part of the study, a biospecimen repository will be created. 
The objective of this repository will be to provide material for future evaluations of relevant 
biomarkers that may be associated with clinical outcomes. 
 
Tumor biomarker included in this proposal is PD-L1 expression by immunohistochemistry 
(clone 22C3). Additional tumor and blood biomarkers such as profiling of the tumor immune 
microenvironment by IHC including quantitative assessment of CD8 T cells, immune gene 
expression signatures by NanoString, multiplex measurement of cytokines and other soluble 
immune mediators, and other biomarkers that may emerge to be important for the use of 
checkpoint inhibitors might be evaluated according to the relevance in the literature, pending 
additional funding (grant submission once clinical trial is near completion/specimen are 
available). 
 
 
 
 
7.2.1.8 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 8. 

 
 
MDACC Protocol 2018-0876 
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Table 8 Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
Calcium 
 
Chloride 
 
Glucose 
 
Blood for correlative studies 
Phosphorus 
 
Potassium 
 
Sodium 
 
Magnesium 
 
Total Bilirubin 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
Total protein 
 
Blood Urea Nitrogen 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
‡ If considered standard of care in your region. 
 
 
 
 
 
 
 
 
 
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Laboratory tests for screening can be used for treatment if performed within 28 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. 
 
7.3 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 Merck’s product, is also an adverse event. All AEs will be recorded in a database 
(DMI) created specifically for this protocol. The investigator (or physician designee) is 
responsible for verifying and providing source documentation for all adverse events and 
assigning the attribution for all the adverse events for subjects enrolled. 
 
Adverse events may occur during the course of the use of Merck 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 first protocol specific 
intervention must be reported by the investigator. For the purpose of this study, adverse 
events that in the opinion of the treating investigator are related to planned procedures (e.g., 
usual pain, usual bleeding, and other clinically insignificant laboratory abnormalities) will 
not be captured and/or reported. 
 
● All AEs will be followed/reported through 90 days following cessation of study treatment.. 
For patients who initiate a new anticancer therapy before 90 days following cessation of study 
treatment, AEs will be reported through 30 days following cessation of study treatment or 
until the day the new anticancer treatment is initiated, whichever is longer. 
 
● All pregnancies and exposure during breastfeeding, from the time of treatment initiation 
through 150 days following cessation of study treatment must be reported by the investigator. 
For patients who initiate a new anticancer therapy before 150 days following cessation of 
study treatment, pregnancies and exposure during breastfeeding will be reported until 30 days 
following cessation of study treatment or until the day the new anticancer treatment is 
initiated, whichever is longer. 
 
● 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 

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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 Merck. 
 
 
 
7.3.1 
Serious Adverse Event (SAE) Reporting 
 
 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or the sponsor, it results in any 
of the following outcomes: 
 
 
x 
Death 
x 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the view of the initial reporter, at 
immediate risk of death from the adverse experience as it occurred. It does not include an adverse experience that, had it 
x 
occurred in a more severe form, might have caused death. 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
x 
A congenital anomaly/birth defect. 
x 
 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
 
x 
Important medical events as defined above, may also be considered serious adverse events. Any important medical event can and 
should be reported as an SAE if deemed appropriate by the Principal Investigator 
x 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be reported to the IRB in accordance 
with the timeframes and procedures outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
x 
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. Unless stated 
otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IRB, regardless of attribution (within 5 working 
days of knowledge of the event). 
x 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a written report submitted within 
24 hours (next working day) of knowledge of the event to the IRB.  
x 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the MDACC IRB. 
x 
Serious adverse events will be captured from the time of the first protocol-specific intervention, until 90 days after the last dose of drug, 
unless the participant withdraws consent. Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable resolution of the event. 
 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 

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7.3.1 Definition and Reporting of an Overdose for This Protocol 
 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
 
7.3.2 Reporting of Pregnancy and Lactation 
 
Although pregnancy and infant exposure during breastfeeding 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 initiation 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, or a procedure. 
 
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. 
 
Such events must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) 
 
7.3.3 Immediate Reporting of Adverse Events 
 
7.3.3.1 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 
7.3.3.1.1 Results in death; 

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7.3.3.1.2 Is life threatening; 
7.3.3.1.3 Results in persistent or significant disability/incapacity; 
7.3.3.1.4 Results in or prolongs an existing inpatient hospitalization; 
7.3.3.1.5 Is a congenital anomaly/birth defect; 
7.3.3.1.6 Is an other important medical event 
 
7.3.3.1.7 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 Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these 
events are considered serious by Merck for collection purposes. 
 
7.3.3.1.8 Is a new cancer (that is not a condition of the study); 
7.3.3.1.9 Is associated with an overdose. 
 
 
Refer to Table 9 for additional details regarding each of the above criteria. 
 
7.3.3.2 
Merck Serious Adverse Events Reporting 
 
For the time period beginning when the consent form is signed until treatment allocation, 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 2 working days to Merck Global 
Safety. 
 
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause whether or not related to the Merck product, must be reported within 2 
working days to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
 
All participants with serious adverse events must be followed up for outcome. 
 
 
It is the responsibility of the PI to ensure serious adverse events are reported according to the 
Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the Merck’s 
guidelines, and Institutional Review Board policy. Selected non-serious and serious adverse 
events are also known as Events of Clinical Interest (ECI) and must be reported within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661- 
6229). 

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Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
 
7.3.3.3 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 the Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215-661-6229). 
 
For the time period beginning at treatment initiation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck 
product, must be reported within 2 working days to Merck Global Safety. 
 
Events of clinical interest for this trial include: 
 
1. an overdose of Merck product, as defined in Section 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 5X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 3X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 3X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
 
 
 
7.3.4 Evaluating Adverse Events 
 
The principal investigator will evaluate all adverse events according to the NCI Common 
Terminology for Adverse Events (CTCAE), version 5. 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 9 Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V5 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 Merck 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 Merck 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  Merck within 2 working days to meet certain local 
requirements); or 
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 
Merck within 2 working days.. 

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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 Merck product to be discontinued? 
Relationship to 
Merck Product 
Did Merck product cause the adverse event? The determination of the likelihood that Merck 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 Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to 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 
to Merck 
Product 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the 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 Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK 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 Merck 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product. The temporal sequence of the AE onset relative to the administration of Merck product is reasonable. 
The AE is more likely explained by Merck product than by another cause. 

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No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
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8.1 STATISTICAL ANALYSIS PLAN 
 
8.2 
Sample Size Calculation 
 
The study two co-primary endpoints are: 
 
- Disease Control Rate (DCR) after two cycle of Pembrolizumab, Cisplatin and Docetaxel 
(PCD), AND 
 
- Pathologic Complete Response rate (pCR) after 4 cycles of PCD. 
 
We simultaneously monitor two co-primary efficacy endpoints using the Bayesian optimal 
phase 2 (BOP2) design (Zhou, Lee and Yuan, 2017). The null hypothesis assumes a DCR of 
65% and a pCR rate of 15%. The alternative hypothesis assume a DCR of 85% and a pCR rate 
of 30%. There will be an interim monitoring after 10, 15, and 20 patients are enrolled. The 
study will be stopped early if both endpoints do not meet efficacy criteria. The design has 
10% type I error and 88% power. If the treatment works, the average N=24.6. If the 
treatment does not work, the averaged N=17.6. Since pCR is evaluated at a later time, we 
will have some patients enrolled with the DCR information but not pCR. Only the cases with 
complete information will be used in the interim analysis.  
 
Specifically, let ݊ denote the interim sample size and ܰ denote the maximum sample size. Let 
ܻଵ and ܻଶ denote the two co-primary endpoints, with ܻଵൌͳ and ܻଶൌͳ indicating that 
patients experienced favorable treatment responses in the two respective endpoints. We 
assume that the joint distribution of ሺܻଵǡ ܻଶሻ follows a multinomial distribution with 4 
elementary outcomes: ሺܻଵǡ ܻଶሻ = (1, 1), (1, 0), (0, 1) and (0, 0). Let ݌ଵൌܲݎሺܻଵൌͳሻ, ݌ଶൌ
ܲݎሺܻଶൌͳሻ, and define the null hypothesis ܪ଴ǣ ݌ଵ൑ͲǤ͸ͷ and ݌ଶ൑ͲǤͳͷ, representing that 
the treatment is inefficacious in both co-primary endpoints. We will stop enrolling patients 
and claim the treatment is not promising if 
ܲݎሺ݌ଵ൐ͲǤ͸ͷȁ݀ܽݐܽሻ൏ߣሺ݊
ܰሻఈǡ 
AND 
ܲݎሺ݌ଶ൐ͲǤͳͷȁ݀ܽݐܽሻ൏ߣሺ݊
ܰሻఈǡ 
where ߣ=0.95 and ߙ=0.8 are design parameters optimized to minimize the chance of 
incorrectly claiming that an efficacious treatment is not promising (i.e., type II error) under the 
alternative hypothesis ܪଵǣ ݌ଵൌͲǤͺͷ and ݌ଶൌͲǤ͵, while controlling the type I error rate at 
0.1 (i.e., the chance of incorrectly claiming that an inefficacious treatment is promising is no 
more than 10%). Assuming a Dirichlet prior distribution ܦ݅ݎሺͲǤͳͶͻǡͲǤͷͲͳǡͲǤͲͲͳǡͲǤ͵Ͷͻሻ for the 
treatment effect, the above decision rule corresponds to the following stopping boundaries 
and yields a statistical power of 0.8785 under ܪଵ: 

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Table 10: Optimized stopping boundaries 
 
# patients treated Stop if # Eff1 <= AND # Eff2 <= 
10 
6 
1 
15 
10 
2 
20 
14 
4 
25 
19 
7 
Based on Table 1, we perform the interim analysis when the number of enrolled patients 
reaches 10, 15, 20. When the total number of patients reaches the maximum sample size of 
25, we reject the null hypothesis and conclude that the treatment is promising if the number 
of responses in first endpoint are greater than 19, or the number of responses in second 
endpoint are greater than 7; otherwise we conclude that the treatment is not promising. 
Below (Table 11) are the operating characteristics of the design based on 10000 simulations 
using the BOP2 web application, which is available at http://www.trialdesign.org. 
Table 11: Operating characteristics for monitoring treatment efficacy 
 
Pr(Eff1 & 
Pr(Eff1) Pr(Eff2) 
Eff2) 
Early stopping (%) Claim promising (%) Sample size 
0.65 
0.15 
0.149 
68.73 
9.80 
17.6 
0.85 
0.30 
0.299 
4.49 
87.85 
24.5 
 
Regarding interim monitoring, we will suspend patient accrual if the observed efficacy  outcomes 
do not exceed the stopping boundaries. For example, when there are 10 patients treated, the 
stopping boundaries are if there are 6 or less disease control (DC) and 1 or less pathologic 
complete response (pCR). After treating 10 patients, if we see at least 7 patients with DC or at 
least 2 patients with pCR, we will proceed to enroll the next 5 patients even when the outcomes 
of some patients may still be pending. On the other hand, if we have not seen at least 7 DC’s or 2 
pCR’s, we will suspend the patient accrual until a decision can be rendered to proceed or stop the 
trial. 
 
 
8.3 Monitoring Plan for unacceptable level of toxicity 
A dose limiting toxicity (DLT) will be defined as Grade 4 neutropenia lasting ≥ 7 days, Grade 3 or 
4 febrile neutropenia, Grade 4 anemia, Grade 4 thrombocytopenia or any non-hematologic toxicity 
Grade 3 or greater that per Principal Investigator judgement is clinically significant and either 

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2018-0876 
11.9.2018 
 
possibly, probably or definitely attributable to study therapy. Exceptions include grade 3 infusion 
reactions that resolve within 24 hours, grade 3 diarrhea, nausea, and/or vomiting that responds to 
standard medical treatment within 48 hours, grade 3 electrolyte disturbances that respond to 
correction within 24 hours), and grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal 
insufficiency) that is managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the subject is asymptomatic. Bayesian toxicity monitoring will be applied 
to ensure patient safety. Unacceptable toxicity is defined as 30% or more of the patients 
experiencing DLT. When Probability (unacceptable toxicity) > 0.8, patient accrual will be 
suspended and the clinical team will review the safety data to determine whether and how to 
proceed, e.g., dose de-escalation or stopping the trial. Toxicity monitoring will start from 6 patients 
with a cohort size of 1. Toxicity monitoring will be done during first two cycle of chemo- 
immunotherapy combination. The toxicity boundaries for DLT in which the regimen is considered 
too toxic are at least: 3 in 6, 4 in 7-8, 5 in 9-11, 6 in 12-14, 7 in 15-17, 8 in 18-20, 9 in 21-23, and 
10 in 24-25 patients. The operating characteristics of the toxicity monitoring is shown in the 
Table12 in three scenarios when the true probabilities of toxicity are 0.1, 0.2, and 0.3, respectively. 
The calculation was based on the Shiny application “Bayesian Toxicity Monitoring v2.1.1” 
available at www.trialdesign.org. 
 
Table 12. Operating characteristics of toxicity monitoring 
 
Scenario 
Prob.Of.Tox Prob.Early.Sto Prob.Declare.T
Avg.N.Patient Avg.N.Tox 
1 
0.1 
0.018 
0.018 
24.67 
2.47 
2 
0.3 
0.434 
0.439 
18.23 
5.47 
3 
0.5 
0.943 
0.949 
9.14 
4.57 
 
 
 
 
8.3 Statistical Analysis Plan 
 
The co-primary endpoints of the study are the disease control rate (DCR) and the pathological 
complete response rate (pCR). The primary endpoints will be analyzed based on the BOP2 
design as described above. 
 
The secondary endpoints include the safety and tolerability, the laryngeal preservation rate at 2 
years, the relapse-free survival at 2 years in all patients and in patients achieved pCR, and the 
patient-reported outcomes in patients treated with PCD. Additional exploratory objective is to 
assess predictive tissue and blood-based biomarkers of benefit from PCD in larynx SCC. 
 
In general, for both the primary endpoint and secondary endpoints, exploratory data analysis 
and graphical methods will be applied as the first step to examine the distribution of the data, 
error checking, and outlier identification. Range check and consistency check will be applied to 
ensure the data quality. Descriptive statistics will be provided to summarize the data. Toxicity 
data will be summarized by frequency tables. Standard distribution plots such as the histogram 

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and box-plot will be applied for continuous data. The time-to-event endpoints will be estimated 
by the Kaplan-Meier method. Median survival, two-year rate, and the corresponding 95% 

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confidence intervals will be calculated. Standard statistical methods for analyzing continuous 
data, discrete data, and survival data will be applied whenever appropriate. 
 
Patients’ demographic and clinical characteristics at baseline will be summarized using 
descriptive statistics such as frequency distribution, mean (± s.d.) and median (range) 
accompanied by graphical analysis. Student t-test/Wilcoxon test and ANOVA/Kruskal- Wallis  
test will be used to compare continuous variables between different groups. The chi-square test 
or the Fisher’s exact test will be applied to assess the association between two categorical 
variables. Log-rank test and Cox regression will be applied to time-to-event data whenever 
appropriate. 
8.1.1.1.1 
 
8.1.1.1.2  Reference 
 
Zhou, H., Lee, J. J., & Yuan, Y. (2017). BOP2: Bayesian optimal design for phase II clinical 
trials with simple and complex endpoints. Statistics in Medicine, 36(21):3302-3314. 
 
 
 
9.1 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
9.2 
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. Cisplatin, Carboplatin, and Docetaxel are standard of care therapeutic agents. 
 
Pembrolizumab will be provided by Merck as summarized in Table 13. 
Table 13 Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
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-assess location under the storage 
conditions specified on the label. 

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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.5 
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the 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 a r r a n g e f o r disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
 
 
 
10.0 APPENDICES 
 
10.1ECOG 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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10.2Common Terminology Criteria for Adverse Events V5 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5  will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
10.3Contraceptive 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 

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● 
Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 14 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant. 
○ 
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 14 
during the protocol-defined time frame in Section 5.1.1. 

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Table 14 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 
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). 
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 150 days 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. 

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Pregnancy Testing 
 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 
 
 
10.4 Larynx cancer TNM staging AJCC 8th Edition 
 
 
 
 
Primary tumor (T) 
 
Supraglottis 
 
T category 
 
T criteria 
 
TX 
 
Primary tumor cannot be assessed 
 
Tis 
 
Carcinoma in situ 
 
T1 
 
Tumor limited to one subsite of supraglottis with normal vocal cord mobility 
 
T2 
 
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or 
region outside the supraglottis (eg, mucosa of base of tongue, vallecula, medial wall of 
pyriform sinus) without fixation of the larynx 
T3 
Tumor limited to larynx with vocal cord fixation and/or invades any of the following: 
postcricoid area, preepiglottic space, paraglottic space, and/or inner cortex of thyroid 
cartilage 
T4 
Moderately advanced or very advanced 
 
T4a 
 
Moderately advanced local disease. 
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues 
beyond the larynx (eg, trachea, soft tissues of neck including deep extrinsic muscle of 
the tongue, strap muscles, thyroid, or esophagus). 
 
T4b 
 
Very advanced local disease. 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures. 
 
Glottis 
 
T category 
 
T criteria 

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TX 
 
Primary tumor cannot be assessed 
 
Tis 
 
Carcinoma in situ 
T1 
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with 
normal mobility 
T1a 
Tumor limited to one vocal cord 
T1b 
Tumor involves both vocal cords 
 
T2 
Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord 
mobility 
 
T3 
Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space 
and/or inner cortex of the thyroid cartilage 
 
T4 
 
Moderately advanced or very advanced 
 
T4a 
 
Moderately advanced local disease. 
Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues 
beyond the larynx (eg, trachea, cricoid cartilage, soft tissues of neck including deep 
extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus). 
 
T4b 
 
Very advanced local disease. 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures. 
Subglottis 
T category 
T criteria 
TX 
Primary tumor cannot be assessed 
 
Tis 
 
Carcinoma in situ 
 
T1 
 
Tumor limited to the subglottis 
 
T2 
 
Tumor extends to vocal cord(s) with normal or impaired mobility 
 
T3 
Tumor limited to larynx with vocal cord fixation and/or invasion of paraglottic space 
and/or inner cortex of the thyroid cartilage 
 
T4 
 
Moderately advanced or very advanced 

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T4a 
 
Moderately advanced local disease. 
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (eg, 
trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap 
muscles, thyroid, or esophagus). 
 
T4b 
 
Very advanced local disease. 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal 
structures. 
Regional lymph nodes (N) 
 
Clinical N (cN) 
 
N category 
 
N criteria 
 
NX 
 
Regional lymph nodes cannot be assessed 
 
N0 
 
No regional lymph node metastasis 
 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and 
ENE(–) 
 
N2 
 
Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE(–); or 
Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE(–); or 
Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
 
dimension and ENE(–) 
 
N2a 
Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in 
greatest dimension and ENE(–) 
 
N2b 
Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension 
and ENE(–) 
 
N2c 
Metastases in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE(–) 
 
N3 
 
Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(–); or 
 
Metastasis in any lymph node(s) with clinically overt ENE(+) 
 
N3a 
 
Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(–) 

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N3b 
 
Metastasis in any lymph node(s) with clinically overt ENE(+) 
 
NOTE: A designation of "U" or "L" may be used for any N category to indicate metastasis above the 
lower border of the cricoid (U) or below the lower border of the cricoid (L). 
Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+). 
Pathological N (pN) 
N category 
N criteria 
NX 
Regional lymph nodes cannot be assessed 
 
N0 
 
No regional lymph node metastasis 
 
N1 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and 
ENE(–) 
 
N2 
 
Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and 
ENE(+); or 
Larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–); or 
Metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest 
dimension and ENE(–); or 
In bilateral or contralateral lymph node(s), none larger than 6 cm in greatest dimension 
 
and ENE(–) 
 
N2a 
 
Metastasis in a single ipsilateral node, 3 cm or smaller in greatest dimension and 
ENE(+); or 
Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in 
 
greatest dimension and ENE(–) 
 
N2b 
Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension 
and ENE(–) 
 
N2c 
Metastases in bilateral or contralateral lymph node(s), none larger than 6 cm in 
greatest dimension and ENE(–) 
 
N3 
 
Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(–); or 
Metastasis in a single ipsilateral node, larger than 3 cm in greatest dimension and 
ENE(+); or 
Multiple ipsilateral, contralateral, or bilateral lymph nodes any with ENE(+); or 
 
A single contralateral node of any size and ENE(+) 

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N3a 
 
Metastasis in a lymph node, larger than 6 cm in greatest dimension and ENE(–) 
 
N3b 
 
Metastasis in a single ipsilateral node, larger than 3 cm in greatest dimension and 
ENE(+); or 
Multiple ipsilateral, contralateral, or bilateral lymph nodes any with ENE(+); or 
 
A single contralateral node of any size and ENE(+) 
NOTE: A designation of "U" or "L" may be used for any N category to indicate metastasis above the 
lower border of the cricoid (U) or below the lower border of the cricoid (L). 
Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+). 
Distant metastasis (M) 
 
M category 
 
M criteria 
 
M0 
 
No distant metastasis 
 
M1 
 
Distant metastasis 
 
Prognostic stage groups 
 
When T is... 
 
And N is... 
And M is... 
Then the stage group is... 
 
Tis 
 
N0 
M0 
0 
 
T1 
 
N0 
M0 
I 
T2 
N0 
M0 
II 
T3 
N0 
M0 
III 
 
T1, T2, T3 
 
N1 
M0 
III 
 
T4a 
 
N0, N1 
M0 
IVA 
 
T1, T2, T3, 
 
T4a 
 
N2 
M0 
IVA 
 
Any T 
 
N3 
M0 
IVB 
 
T4b 
 
Any N 
M0 
IVB 
 
Any T 
 
Any N 
M1 
IVC 
 
TNM: tumor, node, metastasis; AJCC: American Joint Committee on Cancer; UICC: Union for 
International Cancer Control; ENE: extranodal extension. 

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Used with permission of the American College of Surgeons, Chicago, Illinois. The original source 
for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by 
Springer International Publishing. Corrected at 4th printing, 2018. 
 
 
 
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