Phase II Trial of Pembrolizumab in Recurrent or Metastatic HNSCC (POPPY)

Inclusion Criteria

1. Histologically confirmed recurrent or metastatic squamous cell carcinoma of the head and neck that is considered incurable by local therapies.
2. Measurable disease evaluated by RECIST v1.1
3. WHO performance status of 2
4. Life expectancy of at least 12 weeks
5. Aged ≥ 18 years of age

6. Adequate Bone marrow function:

   • Absolute neutrophils grade 0 or 1 (using CTCAE v5)
   • Platelets grade 0 or 1
   • Haemoglobin grade 0 or 1

7. Adequate renal function:

   Creatinine grade 0 or 1 Calculated glomerular filtration rate (GFR) ≥ 50 mL/min estimated using validated creatinine clearance calculation (e.g. Cockcroft-Gault or Wright formula). If calculated GFR is < 50 mL/min then an isotope GFR assessment (Cr51-EDTA or 99mTc-DTPA) should be performed. If an isotope GFR test is unavailable an estimation from 24 hour urine collection may be used

8. Adequate liver function:

   Serum bilirubin grade 0 or 1 AST and ALT grade 0 or 1 (up to grade 2 for patients with liver metastases)

9. Willing to use contraception for the duration of trial treatment and for 120 days after completion of treatment
10. Willing to have a new biopsy, if site of disease is accessible and considered safe to biopsy by investigator If newly obtained samples cannot be obtained (e.g. inaccessible disease or patient safety concern) sites may submit archival tissue only upon agreement from the sponsor
11. Able to give informed consent, indicating that the patient has been informed of and understands the experimental nature of the study, possible risks and benefits, trial procedures, and alternative options
12. Willing and able to comply with the protocol for the duration of the study, including the treatment plan, investigations required and follow up visits

Exclusion Criteria:

1. Patients with undifferentiated nasopharyngeal or sino-nasal cancers
2. Disease suitable for treatment with curative intent
3. Prior therapy with an anti-PD-1, anti-PD-L1 or anti-PD-L2 agent
4. Any investigational agents within 4 weeks prior to registration
5. Anti-cancer monoclonal antibody therapy within 4 weeks prior to registration
6. Chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks prior to registration
7. Patients with concurrent or previous malignancy that could compromise assessment of the primary or secondary endpoints of the trial
8. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
9. Grade 3 or 4 peripheral neuropathy
10. Any serious and/or unstable pre-existing medical, psychiatric or other condition that, in the treating clinician's judgment, could interfere with patient safety or obtaining informed consent

11. Active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they:

    Are stable, without evidence of progression for at least four weeks prior to the first dose of trial treatment Have no evidence of new or enlarging brain metastases Have no evidence of leptomeningeal disease Are not using steroids for at least 7 days prior to trial treatment

12. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is detected) NB: Without known history, testing is required to determine eligibility. Hepatitis C antibody testing is allowed for screening purposes in sites where HCV RNA is not part of standard of care
13. Immunocompromised patients (e.g. known HIV positive status)*
14. Prior organ transplantation including allogenic stem-cell transplantation
15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids, or current pneumonitis/interstitial lung disease
16. Active infection requiring systemic therapy
17. Has received a live vaccine within 30 days prior to registration (seasonal flu vaccines that do not contain live virus are permitted)
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (NB: the use of physiologic doses of corticosteroids may be approved after consultation with UCL CTC)

19. Active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent. Patients with the following are eligible:

    Autoimmune-related hyperthyroidism or autoimmune-related hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone Vitiligo Psoriasis

20. Current use of immunosuppressive medication, except for the following:

intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisolone or equivalent (after approval by UCL CTC) Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

*Testing for HIV for the POPPY trial is not mandatory, however if this test has been done the result should be known prior to registration.