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10.9 common terminology criteria for

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html)  
| Study #1: Specimen Collection for PD-L1 Expression   |                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                          |          |      |    |    |
|------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|----------|------|----|----|
| -                                                    | All patients will have slides cut from FFPE tissue blocks for analysis of PD-L1  expression by IHC staining                                                                                                                                                                                                                                                                       |                                                                                          |          |      |    |    |
| -                                                    | FFPE tissue will be obtained from the Tissue Procurement and/or pathology department  (CCF) or Biorepository and/or pathology department (UH) and assigned a unique  identification number. All other PHI will be redacted from the pathology report.                                                                                                                             |                                                                                          |          |      |    |    |
| -                                                    | Five slides will be cut from each FFPE block for PD-L1 and H&E staining.  o One slide each for H&E, PD-L1, and Isotype and two for repeat staining if needed                                                                                                                                                                                                                      |                                                                                          |          |      |    |    |
| -                                                    | Results: QualTek Molecular Laboratories Clinical Laboratories will report to Merck and  study investigators.                                                                                                                                                                                                                                                                      |                                                                                          |          |      |    |    |
| -                                                    | Residual Material: FFPE specimens will be retained by Cleveland Clinic and University  Hospitals in anatomic pathology per their routine, and made available for future use as  indicated.  Study #1 Specimens shipped to:  QualTekMolecularLaboratories  MISP Receiving  300 Pheasant Run  Newtown, PA USA 18940  Phone: 215-504-7402  Fax: 805-830-6379  MISPsamples@qmlabs.com |                                                                                          |          |      |    |    |
| Specimen Type                                        | Collection Time                                                                                                                                                                                                                                                                                                                                                                   | Collection                                                                               |          |      |    |    |
| Points                                               | Information and  Requirements                                                                                                                                                                                                                                                                                                                                                     | Shipping                                                                                 |          |      |    |    |
| Five                                                 | slides                                                                                                                                                                                                                                                                                                                                                                            | from                                                                                     |          |      |    |    |
| primary                                              | tumor                                                                                                                                                                                                                                                                                                                                                                             |                                                                                          |          |      |    |    |
| FFPE blocks                                          | Baseline                                                                                                                                                                                                                                                                                                                                                                          | Tumor                                                                                    | Sections | will | be | 4  |
| specimen                                             | micron thickness onto  Fisher ProbeOn Plus  Slides, Cat Number 22- 230-900.  Tissue sections must be  placed on the painted/  textured side of the  slide.                                                                                                                                                                                                                        | Slides shipped cold (2-8oC)  and in the dark using  QualTek-supplied packing  materials. |          |      |    |    |  
Study \#2: Blood Collection for Immune Biomarker Analysis
- **All patients will have blood collected at specific time points (pre-treatment and weeks 7,**
20, and 52). +/- 4 weeks is allowed on follow up visits.  
- **At each time point, up to 50cc of blood will be collected and processed by research**
laboratory personnel (Dr. Gastman, PI) to isolate lymphocytes and freeze for further analysis.  
- **Specimens will be assigned the same unique identification number used for Study \#1 and**
any other personal health information (PHI) will be redacted from the pathology report.  
- **Results: Research laboratory personnel will report to Merck and study investigators.**
- **Residual Material: cryopreserved specimens will be retained by the research laboratory**
until the study conclusion.
For CC**: Samples will typically be collected by CRA. Gastman lab will then be contacted**
as follows: Please call Ye Tian (Field) (Gastman Lab) at 773-226-2782 for pickup. If there is no response, please page Dr. Brian Gastman at 216-401-4776. The samples will be picked up by Gastman lab personnel and transported to: 9500 Euclid Avenue Gastman Laboratory Lerner Research institute, NE4-217 Cleveland, Ohio 44195 Phone: (216) 444-0202 For UH**: Samples will be collected by research nurse. These samples should be collected** by the research nurse *before 12PM***, to allow sufficient time for the TRPC (translational**
research and pharmacology core) to courier the samples to CC before 5pm. Generally, samples cannot be received at CC after 5PM. In the event that samples are late, they should still be sent to CC. The research nurse will then contact the Translational Research and Pharmacology Core of UH (Attn: Erin Hohler) at 216-286-3889 or 216-286-3890, pager 33471, emh14@case.edu. The tissue will then be picked up by the TRPC staff and they will arrange for courier of the tissue to Cleveland Clinic.
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the trpc should then courier

Cleveland Clinic Central Biorepository Pathology and Lab Medicine Institute- L15 Surgical Pathology- Tissue Procurement 2119 East 93rd **St**
Cleveland, Ohio 44106 Phone (216)444-0047 When specimens arrive at L15, please call Ye Tian (Fields) (Gastman Lab) at 773-2262782 for pickup. If there is no response, please page Dr. Brian Gastman at 216-401-4776. Also, please email the following personnel notifying them that a sample was collected: samsaj@ccf.org; robinss@ccf.org; koyfmas@ccf.org;tisscenterap@ccf.org;THOMPSS9@ccf.org; tainy2@ccf.org gastmab@ccf.org  
| Specimen Type                                                                                                                         | Collection Time                                                                                                                                                     | Collection   |          |
|---------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|----------|
| Points                                                                                                                                | Information and  Requirements                                                                                                                                       | Shipping     |          |
| Up                                                                                                                                    | to                                                                                                                                                                  | 50cc         | of       |
| peripheral                                                                                                                            | whole                                                                                                                                                               |              |          |
| blood                                                                                                                                 | in                                                                                                                                                                  | heparin      |          |
| (green                                                                                                                                | top)                                                                                                                                                                | or           |          |
| EDTA  (lavender/purple  top) tubes                                                                                                    | Pre-treatment,  weeks 7, 20, and  52                                                                                                                                | Lymphocytes  | isolated |
| by centrifugation over  Ficoll gradient and  stored frozen in  FBS/10% DMSO in 1.8  mL cryovials.  Samples should be  stored at -80oC | CCF: After collection, blood  tubes will be delivered to  Gastman Lab.  UH: After collection, blood  tubes will be sent to  anatomic pathology via  courier (L-15). |              |          |  
Study \#3 and \#4: Fresh or FFPE Tissue for Immune Biomarker Analysis and Tumor Gene Expression Analysis (Optional)
- **For patients who consent to other IRB-approved tissue banking protocols:**
o **Fresh tumor tissue will have been received, de-identified, processed and stored**
(frozen). RNA isolation may have also taken place for gene expression analysis o **This tissue may be sent to the Gastman lab for experimentation.**
- **FFPE tissue may be obtained in patients for whom fresh tissue is not available:**
o **FFPE tissue will be obtained from the Tissue Procurement (CC) or Biorepository**
(UH) tissue bank and assigned a unique identification number. All other PHI will be redacted from the pathology report.  
o **Up to 10 slides will be cut from each tissue block for immune biomarker staining**
o **A small punch will be taken for RNA isolation for subsequent gene expression**
analysis
- **Results: Research laboratory personnel will report to Merck and study investigators.**
- **Residual Material: cryopreserved specimens, tissue slides, and genetic material will be**
retained by the research laboratory until the study conclusion.
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for university hospitals

Cleveland Clinic Central Biorepository Pathology and Lab Medicine Institute- L15 Surgical Pathology- Tissue Procurement 2119 East 93rd **St**
Cleveland, Ohio 44106 Phone (216)444-0047 When specimens arrive at L15, please call Ye Tian (Field) (Gastman Lab) at 773-226-2782 for pickup. If there is no response, please page Dr. Brian Gastman at 216-401-4776. Also, please email the following personnel notifying them that a sample was collected: samsaj@ccf.org; robinss@ccf.org; koyfmas@ccf.org; tisscenterap@ccf.org; THOMPSS9@ccf.org; tiany2@ccf.org gastmab@ccf.org  
| Specimen Type                                                                                                                                                                                               | Collection Time                                 | Collection   |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|--------------|---------|
| Points                                                                                                                                                                                                      | Information and  Requirements                   | Shipping     |         |
| Fresh primary tumor  tissue or up to 10  slides cut from FFPE  tissue blocks and  3mm punches taken  from FFPE tumor  blocks.                                                                               | Time                                            | of           | primary |
| surgical                                                                                                                                                                                                    | resection                                       |              |         |
| or                                                                                                                                                                                                          | from                                            | baseline     |         |
| tumor specimen                                                                                                                                                                                              | Tumors                                          | dissociated  | by      |
| enzymatic                                                                                                                                                                                                   | digestion                                       |              |         |
| followed by freezing in  FBS/10% DMSO for  subsequent analysis.  Samples should be stored  at -80oC.  RNA isolation from fresh  tissue or FFPE punches by  organic extraction/ silica  column purification. | Tumor tissue will be delivered  to Gastman lab. |              |         |
| Protocol v 12/04/2019                                                                                                                                                                                       | 72                                              |              |         |
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11.0 references

1. Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. Journal of the American Academy of Dermatology 2013;68:957-66. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Squamous Cell Skin Cancer. 2015. (Accessed 3/8, 2015, at http://www.nccn.org/professionals/physician_gls/pdf/squamous.pdf.) 3. Kwan W, Wilson D, Moravan V. Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the skin. Int J Radiat Oncol Biol Phys 2004;60:406-11. 4. Lin C, Tripcony L, Keller J, et al. Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features. International journal of radiation oncology, biology, physics 2012;82:334-40. 5. Mendenhall WM, Amdur RJ, Hinerman RW, Cognetta AB, Mendenhall NP. Radiotherapy for cutaneous squamous and basal cell carcinomas of the head and neck. The Laryngoscope 2009;119:1994-9. 6. Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY, Veness MJ. Predictors of outcome in patients with metastatic cutaneous head and neck squamous cell carcinoma involving cervical lymph nodes: Improved survival with the addition of adjuvant radiotherapy. Head & neck 2012;34:1524-8. 7. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nature reviews Immunology 2008;8:467-77.  
8. Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of PDL1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral oncology 2011;47:1148-53. 9. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer research 2013;73:1733-41. 10. Seiwert TY ea. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)- associated and non-HPV–associated head and neck (H/N) cancer. . Journal Clinical Oncology;(suppl; abstr 6011). :32:5s. 11. Ferris RL, Whiteside TL, Ferrone S. Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2006;12:3890-5.  
12. Whiteside TL. Immunobiology of head and neck cancer. Cancer metastasis reviews 2005;24:95-105. 13. Belai EB, de Oliveira CE, Gasparoto TH, et al. PD-1 blockage delays murine squamous cell carcinoma development. Carcinogenesis 2014;35:424-31. 14. Madeleine MM, Carter JJ, Johnson LG, et al. Risk of squamous cell skin cancer after organ transplant associated with antibodies to cutaneous papillomaviruses, polyomaviruses, and TMC6/8 (EVER1/2) variants. Cancer medicine 2014;3:1440-7. 15. Hodge JW, Guha C, Neefjes J, Gulley JL. Synergizing radiation therapy and immunotherapy for curing incurable cancers. Opportunities and challenges. Oncology 2008;22:1064-70; discussion 75, 80-1, 84. 16. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. The Journal of clinical investigation 2014;124:687-95. 17. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71. 18. Powell SF GM, Sumey CJ, et al. Safety of pembrolizumab with chemoradiation (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). J Clin Oncol 35, 2017 (suppl; abstr 6011).
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12.0 summary of changes v08/03/2017

| Protocol  Date   | Section   | Change                                                                                                                                                                                                                                                                  |
|------------------|-----------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 08/03/17         | 2.1       | Safety run in period and Phase II portion was deleted from this section  The following was added to this section:   A pilot study that investigated the safety of adding Pembrolizumab to  head and neck IMRT in addition to weekly cisplatin was recently  presented at ASCO 2017. Powell, et al reported excellent safety profile  of 27 patients with locally advanced head and neck cancer treated with  chemoradiation with weekly cisplatin, and 70Gy in 35 fractions of  IMRT along ith Pembrolizumab 200mg fixed dose IV every 3 weeks  beginning 4-7 days prior to the initiation of radiation 2 doses  concomitant with IMRT and 5 additional doses post IMRT. 21 patients  (78%) completed all planned doses of Pembrolizumab. 3 discontinued  due to irAEs (G2 peripheral motor neuropathy, G3 AST elevation, G1  Lhermitte-like syndrome). 3 discontinued due to protocol reasons (early  neck dissection -2 pts, prolonged hospitalization-1 pt). All pts  completed the full radiation dose (70 Gy) without significant delay  (defined as > 5 days). 23 (85%) received the goal target dose of cisplatin  (200 mg/m2). There was one patient death due to concurrent illness,  unrelated to treatment.18 Based on these results, the NRG Oncology  HN-003 study which was designed as a phase I safety study of the  addition of Pembrolizumab to postoperative head and neck IMRT and  weekly cisplatin discontinued their planned phase I safety study and  converted to an open label efficacy signal study. We therefore feel quite  confident in the safety of our proposed regimen as our study involves  less extensive IMRT fields and does not include any concurrent  chemotherapy. We will however monitor DLTs very carefully and  include that as a co-primary endpoint of the study.                                                                                                                                                                                                                                                                         |
| 08/03/17         | 4.2.2     |                                                                                                                                                                                                                                                                         |
| 08/03/17         | 4.2.3.2   | Initial safety run in information deleted from this section  4) Lymphoid malignancies deleted. Patients with a history of chronic  lymphoid or leukemic malignancies which are not under active  therapy (no active therapy within the last 3 months) will be eligible. |
| 08/03/17         | 5.1.1     | 4) Lymphoid malignancies deleted  Patients with chronic lymphoid/leukemic malignancies that have  undergone treatment in the last 3 months will be ineligible.                                                                                                          |
| 08/03/17         | 5.1.2     |                                                                                                                                                                                                                                                                         |
| 08/03/17         | 5.4       | Safety run in period and Phase II portion was deleted from this section                                                                                                                                                                                                 |
| 08/03/17         | 8.0       | Initial safety run in period deleted from this section                                                                                                                                                                                                                  |  
| Protocol  Date   | Section                                                     | Change  One year PFS outcomes will be assessed overall and also separately for  immunocompetent patients vs. immunosuppressed patients (e.g. CLL).  These outcomes will be compared to our historical dataset for both  subsets respectively. Added to this section   |
|------------------|-------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 08/03/17         | Table 1                                                     | Removed coagulation section                                                                                                                                                                                                                                           |
| 08/03/17         | 8.3                                                         |                                                                                                                                                                                                                                                                       |
| 08/03/17         | 7.1.5.3                                                     | Changed 2nd paragraph "visits performed within 3 weeks…" to within  4 weeks…                                                                                                                                                                                          |
| 08/03/17         | Appendix                                                    | Study #2, 3 and 4 lab address change for Cleveland Clinic from NE6-                                                                                                                                                                                                   |
| 10.10            | 251 to NE4-217                                              |                                                                                                                                                                                                                                                                       |
|                  | Protocol date change to 08/03/2017 on page 1 and the footer |                                                                                                                                                                                                                                                                       |
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summary of changes v08/29/2017

| Protocol  Date   | Section                                                     | Change  Patients with chronic lymphoid or leukemic malignancies are eligible                                              |
|------------------|-------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|
| 08/29/17         | 5.0 #7                                                      | with or without active disease as long as they have not had treatment  within the past three months Added to this section |
| 08/29/17         | Protocol date change to 08/29/2017 on page 1 and the footer |                                                                                                                           |
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summary of changes v09/27/2017

| Protocol  Date   | Section                                                     | Change  Patients with chronic lymphoid or leukemic malignancies are eligible                                                                                                                    |
|------------------|-------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 09/27/17         | 5.1.1#4                                                     | with or without active disease as long as they have not had treatment  within the past three months Added to this section  Patients with chronic lymphoid or leukemic malignancies are eligible |
| 09/27/17         | 5.1.2 #7                                                    | with or without active disease as long as they have not had treatment  within the past three months Added to this section                                                                       |
| 09/27/17         | Protocol date change to 09/27/2017 on page 1 and the footer |                                                                                                                                                                                                 |
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summary of changes v08/30/2018

| Protocol  Date   | Section                     | Change  Removed Laboratory tests for screening or entry into the study should  be performed within 10 days prior to the first dose of treatment.  Added Laboratory tests for screening or entry into the study should be  performed within 4 weeks prior to the first dose of treatment.                         |
|------------------|-----------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 08/30/18         | 7.1.2.6  page 49            | Removed lab contact information for Lukas Pfannenstiel 443-622- 9736. Added contact information for Ye Tian (Field) 773-226-2782.  konczov@ccf.org was removed and tiany2@ccf.org was added.                                                                                                                     |
| 08/30/18         | Study #2  page 71  Study #3 |                                                                                                                                                                                                                                                                                                                  |
| 08/30/18         | & 4 page  73                | Removed lab contact information for Lukas Pfannenstiel 443-622- 9736. Added contact information for Ye Tian (Field) 773-226-2782.  konczov@ccf.org was removed and tiany2@ccf.org was added.                                                                                                                     |
| 08/30/18         | 7.2.1                       | Changed fax # to 215-661-6229                                                                                                                                                                                                                                                                                    |
| 08/30/18         | 7.2.2                       | Changed fax # to 215-661-6229                                                                                                                                                                                                                                                                                    |
| 08/30/18         | 7.2.3.1                     | Added a note further clarifying serious adverse events, Changed fax #  to 215-661-6229  Changed fax # to 215-661-6229, Removed, "this trial site guidance for  assessment and follow-up of these criteria can be found in the  investigator trial file binder (or equivalent)  Removed additional adverse events |
| 08/30/18         | 7.2.3.2                     |                                                                                                                                                                                                                                                                                                                  |  
| Protocol  Date   | Section                                                     | Change  Added: Invasion of the axial skeleton or skull base or skull base  foramina and Tumor greater that 2cm with any 1 additional feature  Removed: Note: Not all patients with T2N0 cancer with one  additional risk factor may be ideal candidates for this study, such as  patients with only focal perineural invasion without other adverse  features. Clinical judgment should be used by recurrence with  radiation alone.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|------------------|-------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 10/30/2018       | 5.1.1                                                       | Added: (CT chest preferred, CXR acceptable) and superscript c: CT  neck and chest CT will be acceptable if done within 12 weeks of trial  registration. PET/CT is optional and only recommended if there is  concern for gross residual disease. MRI brain and/or orbits may be  important for tumors near the skull base, especially those with  perineural invasion. In these cases, MRI is recommended to be  obtained at baseline, at wk 20 follow up, and at later follow up visits  as clinically indicated. While the routine surveillance images are  scheduled for weeks 20, 32 and 52, changes in patient symptoms or  persistent symptoms may prompt the clinician to order a CT at any  time, as per standard practice.  Removed: CT neck and chest will be acceptable if done within 12  weeks of trial registration. PET/CT is optional and only recommended  if there is concern for gross residual disease. MRI brain and/or orbits  may be important for tumors near the skull base, especially those with  perineural invasion. In these cases, MRI is recommended to be  obtained at baseline, at wk 20 follow up, and at later follow up visits as  clinically indicated. While the routine surveillance CT are scheduled  for weeks 20, 32 and 52, changes in patient symptoms or persistent  symptoms may prompt the clinician to order a CT at any time, as per  standard practice guidelines. |
| 10/30/2018       | 6.0                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| 10/30/2018       | Protocol date change to 10/30/2018 on page 1 and the footer |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
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summary of changes v12/04/2019

| Protocol  Date   | Section   | Change                                                                       |
|------------------|-----------|------------------------------------------------------------------------------|
| 12/04/19         | Page 1    | Updated protocol date to 12/04/2019 and footer protocol date to  12/04/2019. |
| 12/04/19         | Page 67   | Added registry integration information.                                      |