REirradiation and Programmed Cell Death Protein 1 (PD-1) Blockade On Recurrent Squamous Cell Head and Neck Tumors
REirradiation and Programmed Cell Death Protein 1 (PD-1) Blockade On Recurrent Squamous Cell Head and Neck Tumors
Each subject will participate in the trial until death, drop out, or loss-to follow-up from
 the time the subject signs the Informed Consent Form (ICF) through the final contact. After a
 screening phase of up to 28 days, each eligible subject will receive nivolumab. Two weeks
 after start of nivolumab the patients will receive radiotherapy (RT) to a total dose of 60
 Gy, given as 1.5 Gy fractions twice daily for a total period of 4 weeks. Treatment with
 nivolumab will continue until disease progression, unacceptable adverse event(s),
 intercurrent illness that prevents further administration of treatment, Investigator's
 decision to withdraw the subject, noncompliance with trial treatment or procedures
 requirements, subject receives nivolumab for 12 months, pregnancy, or administrative reasons.

 After the end of treatment, each subject will be followed for 30 days for adverse event
 monitoring serious adverse events (SAEs) will be collected for 90 days after the end of
 treatment. Patients without disease progression will have follow-up visits for 4 years after
 end of study therapy.
In this study, the aim is to release the brake on the immune response by use of nivolumab, an
 inhibitory antibody against Programmed cell death protein 1 (PD-1). Nivolumab has shown
 efficacy and mild toxicity when given as monotherapy for HNSCC at a dose of 3.0 mg/kg every 2
 weeks, which is the target dose in the present trial.

 Radiotherapy is a powerful inducer of inflammation, and the expression of Programmed
 death-ligand 1 (PD-L1) is known to be enhanced by inflammatory cytokines, including
 interferon-gamma (IFNg). Experimental evidence from mice models have shown that radiotherapy
 induces increased PD-L1 expression in tumor tissue. Moreover, there is evidence suggesting
 that HNSCC with T-cell infiltration is more sensitive to radiotherapy. There is thus a strong
 rationale for combing PD-1 inhibitors with radiotherapy. However, this potential remains
 largely unexplored in humans. The investigators consider that head-and-neck cancer is a
 particularly attractive entity for investigating this therapeutic combination, because of i)
 the high radiosensitivity of this cancer form ii) the clinical efficacy of Programmed cell
 death protein 1 (PD-1) inhibitors as monotherapy in early clinical trials iii) the
 availability of tumor biopsies for translational/biomarker research.The RT given in the
 present study gives considerable side effects, related to inflammation that may be enhanced
 by Programmed cell death protein 1 (PD-1) blockade.
Inclusion Criteria:

 -  Age 18 years or older

 -  Recurrent or secondary primary squamous cell carcinoma originating from the oral
 cavity, oro/hypo-pharynx or larynx

 -  Prior radiotherapy (46-70Gy)

 -  Adequate newly obtained core or excisional biopsy of a recurrent tumor lesion

 -  Measurable disease

 -  Lesion available for biopsy during study treatment

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Life expectancy of more than 12 months

 -  A minimum of 6 months since prior radiotherapy in the same area or minimum 4 weeks (28
 days) since previous other cancer treatment

 -  Human papillomavirus positive and negative disease allowed

 -  Distant metastases allowed

 -  Adequate organ function based on clinical examination and lab values

 -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
 test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
 the start of study drug

 -  Women must not be breastfeeding

 -  WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the
 time required for nivolumab to undergo five half-lives) after the last dose of
 investigational drug

 -  Males who are sexually active with WOCBP must agree to follow instructions for
 method(s) of contraception for a period of 90 days (duration of sperm turnover) plus
 the time required for the investigational drug to undergo five half-lives. The
 terminal half-life of nivolumab is up to 25 days

 Exclusion Criteria:

 -  History of other prior malignancy, with the exception of curatively treated basal cell
 or squamous cell carcinoma of the skin, cervical cancer stage IB and stage I prostate
 cancer considered not necessary to treat

 -  Disease suitable for curative salvage surgery

 -  Treatment with any investigational medicinal product (IMP) that may interfere with the
 study treatment, within 4 weeks prior to first administration of study drug.

 -  Significant cardiac, pulmonary or other medical illness that would limit activity or
 survival

 -  Pregnancy or lactation.

 -  Known hypersensitivity to any of the components of the investigational product

 -  Patients who test positive for hepatitis B, C or HIV.

 -  Diagnosis of immunodeficiency or medical condition requiring systemic steroids or
 other forms of immunosuppressive therapy

 -  Autoimmune disease that has required systemic therapy within the past 2 years

 -  Any reason why, in the opinion of the investigator, the patient should not participate