Postoperative aRCH With Cisplatin Versus aRCH With Cisplatin and Pembrolizumab in Locally Advanced Head and Neck Squamous Cell Carcinoma

Postoperative Adjuvant Radiochemotherapy (aRCH) With Cisplatin (C) Versus aRCH With C and Pembrolizumab (P) in Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC); Multicenter Randomized Phase II Study Within the German Interdisciplinary Study Group of German Cancer Society (IAG KHT); Pembro-Adjuvant-highRisk

This trial evaluates the addition of pembrolizumab to standard postoperative adjuvant radiochemotherapy in the treatment of patients with locally advanced intermediate and high risk head and neck squamous cell carcinoma (HNSCC).

Inclusion Criteria:

1. Macroscopically complete resection of newly diagnosed (not recurrent, not secondary primary) advanced squamous-cell carcinoma arising in the oral cavity, oropharynx, larynx, or hypopharynx

2. Advanced stage III, IVA/B HNSCC according to the TNM classification version 7th edition (Note! The 8th edition will not be used, please adhere to the national cancer institute guidelines)

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; performance status allows adjuvant chemo radiation with cisplatin.

4. Had either intermediate or high-risk characteristics, i.e. any or all of the following:

   • histologic evidence of invasion of two or more regional lymph nodes
   • extracapsular extension of nodal disease,
   • microscopically involved mucosal margins of resection (R1) or margins of resection < 5mm (R0)

5. Had pathological histologic assessment of p16 (only oropharyngeal carcinoma)

6. Be > 18 years of age

7. Written informed consent

8. Demonstrate adequate organ function

9. Female subject of childbearing potential should have a negative pregnancy test within 3 days prior to receiving the first dose of study medication.

10. Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication.

11. Reproductive male subjects must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria:

1. Concurrent participation in any other interventional clinical trial or participation in any other interventional trial within one month before enrolment into this trial.

2. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before enrolment into this trial.

3. Known history of active TB (Bacillus Tuberculosis)

4. Hypersensitivity to Pembrolizumab or comparable medicinal products or any of its excipients.

5. Prior anti-cancer monoclonal antibody (mAb) therapy within one month before enrolment into this trial or who has not recovered (i.e., ≤ Grade 1 (NCI CTCAE Grade) at baseline) from adverse events due to agents administered more than one month earlier.

6. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within one month before enrolment into this trial or who has not recovered (i.e., ≤ grade 1 (NCI CTCAE Grade) at baseline) from adverse events due to a previously administered agent.

   1. Note: Subjects with ≤ Grade 2 (NCI CTCAE Grade) neuropathy are an exception to this criterion and may qualify for the study.
   2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

7. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

8. Active autoimmune disease that has required systemic treatment in the past 2 years prior to enrolment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

9. Evidence of interstitial lung disease or history of (non-infectious) pneumonitis that required steroids within the last 6 months before enrolment into this trial, or current pneumonitis.

10. Active infection requiring systemic therapy.

11. Suspected lack of compliance

12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the baseline visit through 120 days after the last dose of trial treatment.

13. HIV, HBV or HCV infection

14. Application of a live vaccine within one month of enrolment.

15. Hypersensitivity to cisplatin or any of its excipients

16. Any potential relationship to the investigator/his deputy or to medical staff of the study team, to the coordinating investigator or is an employee of the study sit