PEmbrolizumab Combined With Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck

Phase I Dose-escalation Study of PEmbrolizumab (MK3475) Anti-PD1 Immune Checkpoint Inhibitor Combined With Radical Chemoradiotherapy in Patients With Stage IV Squamous Cell Carcinoma of the Head and Neck

This study aims to establish whether the combination of pembrolizumab (MK-3475) and conventional cisplatin-based chemoradiotherapy is tolerable and results in acceptable levels of acute and late toxicity in patients with stage IV LA-SCCHN. In particular, the study will provide data on the levels of mucosal and cutaneous toxicity within the radiation fields, as these are the primary acute toxicities associated with this treatment regimen. In addition, toxicity outside the radiation portals (which may theoretically be exacerbated by radiation) will be studied. However, all toxicity will be monitored. This study will also give an indication of the activity of pembrolizumab in LA-SCCHN because we are deliberately selecting a group of patients with high- and intermediate-risk disease who have a significant chance of experiencing loco-regional or systemic failure.

This will be a single centre phase 1 dose-escalation study to confirm the safety of combining pembrolizumab with standard platin-based chemoradiotherapy in patients with stage IV high- and intermediate-risk locally-advanced squamous cell carcinoma of the head and neck (LA-SCCHN). 6-36 patients (18 HPV+ve and 18 HPV-ve) will be recruited in a standard 3+3 dose-escalation trial design with an expansion cohort at the maximum tolerated dose (or 200 mg, if no DLT is defined). A pre-loading dose of 100 or 200mg (dependent on dosing level) of pembrolizumab will be given once the patient has completed the screening period. Patients will then return 2 weeks later to begin cycle 1 of a regimen of pembrolizumab 3 weekly at a dose of 100 or 200mg (dependent on dosing level) for a total of 7 cycles (3 during chemoradiotherapy and 4 after chemoradiotherapy).

Parallel studies in HPV-ve and HPV +ve disease will be conducted (note these patients may have different patterns of co-morbidity and, hence, different treatment-related toxicities). The primary endpoint of the study will be safety and tolerability. Dose-limiting acute toxicity will be assessed during administration of study drug according to CTCAEv4.0. The maximum tolerated dose of study drug (or 200 mg in the absence of DLT) will be used in a subsequent randomised phase 2 study comparing standard-of-care therapy with standard-of-care therapy plus study drug.

Inclusion Criteria:

1. Have treatment naive and histologically confirmed high-/intermediate-risk LA-SCCHN
2. Be willing and able to provide written informed consent for the trial.
3. Be > or = 18 years of age on day of signing informed consent.
4. Have measurable disease based on RECIST 1.1.
5. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumour lesion.
6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
7. Be fit for definitive platin-based chemoradiation therapy.
8. Demonstrate adequate organ function as defined in table 1, all screening labs should be performed within 10 days of confirmation of study eligibility.
9. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to confirmation of study eligibility. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female patient s of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 6.7.2). Patient s of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
11. Male patient s should 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. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
2. Has received prior radiotherapy to the head and neck region.
3. 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.
4. Has had a prior monoclonal antibody, chemotherapy, targeted small molecule therapy, or radiation therapy.
5. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patient s with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
7. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patient s with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patient s with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has active tuberculosis.
11. Has known hypersensitivity to pembrolizumab or any of its excipients.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. 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.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days prior to the first dose of trial treatment.