SBRT +/- Pembrolizumab in Patients With Local-Regionally Recurrent or Second Primary Head and Neck Carcinoma

Safety Run-In:

To evaluate the safety of the addition of pembrolizumab (anti PD-1 immunotherapy) to
re-irradiation with SBRT for patients with recurrent or new second primary head and neck
squamous cell carcinoma (HNSCC).

Phase II:

To compare progression-free survival (PFS) for patients with recurrent or new second primary
head and neck squamous cell carcinoma with SBRT re-irradiation with or without pembrolizumab.

OUTLINE:

Safety Run-In: Patients receive SBRT over 2 weeks and then receive pembrolizumab every 3
weeks for up to 2 years.

Phase II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive SBRT over 2 weeks and then receive pembrolizumab every 3 weeks for up
to 2 years.

ARM II: Patients receive SBRT over 2 weeks. Arm II patients who experience progressive
disease within 2 years after the start of SBRT will be allowed to cross over to receive
pembrolizumab for up to 2 years.

After the completion of study treatment, patients are followed up every 6 months for 3 years.

Inclusion Criteria:

- Histologically or cytologically-confirmed diagnosis of locoregional recurrent or any
new primary squamous cell carcinoma of the head and neck that is not amenable to
curative resection. A new primary HNSCC is defined where any one of the following
criteria are met:

- Metachronous invasive SCC developing ≥ 6 months after an index HNSCC, more than 3
cm from the index lesion;

- SCC developing in the same region as the index SCC if ≥ 36 months after the index
diagnosis and if within 3 cm of a site where disease was completely resected or
complete response was documented;

- New SCC that is cytologically or molecularly distinct from index SCC (eg new HPV
negative SCC with prior index SCC that was HPV positive).

- Tumor tissue testing for p16 status is required for base of tongue, soft palate, and
tonsil cancer. If a p16 testing has been previously performed on an oropharynx cancer
that has recurred, then repeat testing for p16 status is not required. Participants
whose first cancer was an unknown primary must have p16 testing from either the new
primary tumor or the recurrent cancer.

- Prior radiotherapy (RT) to the head and neck (30 Gy minimum)

- Disease must be limited to a single site or adjacent sites that can be treated in a
single contiguous target volume for which the maximum total tumor dimension (GTV) must
be <7.5cm. Examples of eligible patients include:

1. A primary site recurrence in the oropharynx with a concurrent level 2 nodal mass,
or a laryngeal recurrence with a level 3 nodal mass

2. Multiple nodes in the same (level 2) or adjacent nodal levels (levels 2 and 3)

3. Skull base recurrence with a lateral pharyngeal or high level 2 node

Note: These cases will be eligible provided that the maximum total tumor dimension is
<7.5cm. For cases in which a tumor biopsy was performed and there is a biopsy/tumor
debulking bed adjacent to the gross residual disease, all of the preoperative radiographic
abnormalities must be included in the GTV and meet the <7.5cm maximal dimension criteria to
meet eligibility.

Note: Patients who meet these criteria only after surgical removal of a portion of the
patient's disease (e.g. removal of level 4 nodal mass in a patient with a tongue base
primary; or of a contralateral nodal mass in an N2c patient) are ineligible.

- Patients who have undergone a recent biopsy (e.g. incisional) are eligible. Any
preceding surgical procedure beyond a biopsy (e.g. debulking) must be reviewed as
follows:

- Patients rendered free of gross disease are not eligible.

- Patients with gross residual disease postoperatively, must be reviewed by the
Surgical Co-PI for determination of eligibility.

- Patients eligible for study must have cutaneous wounds healed for 4-6 weeks prior
to the initiation of SBRT.

- History/physical examination within 56 days prior to entry

- Examination by a Radiation Oncologist and Medical Oncologist within 56 days prior to
entry; [Note: Baseline dental assessment is strongly recommended prior to start of
therapy but is not required for eligibility]

- Contrast enhanced CT or MRI, of the tumor and neck within 56 days prior to entry.

- Chest CT scan or full body PET/CT within 56 days prior to entry; patients with
equivocal pulmonary nodules that are < 1.5 cm, that cannot be safely biopsied, or that
are negative on PET/CT imaging are eligible.

- Zubrod Performance Status of 0-1 within 28 days prior to entry.

- Age ≥ 18

- Trial is open to all genders

- Hematologic: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3, Platelets ≥ 100,000
cells/mm3, Hemoglobin ≥ 9 g/dL

- Hepatic: Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 x ULN, AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x ULN, OR measured or calculated creatinine clearance > 60 mL/min for
subject with creatinine levels > 1.5 x institutional ULN [NOTE: Calculated creatinine
per institutional standard; GFR may be used in place of creatinine or CrCl]

- Negative serum pregnancy test within 14 days prior to entry for women of childbearing
potential. (Note: A pregnancy test must be repeated within 3 days prior to the
administration of the first dose of pembrolizumab)

- The patient or legally authorized representative must provide study-specific informed
consent prior to study entry.

Exclusion Criteria:

- Distant metastases.

- Tumors that involve more than 180 degrees of the carotid artery on diagnostic CT or
MRI of the neck within 56 days prior to entry. Investigators are encouraged to review
the CT simulation imaging and ensure that tumor progression has not occurred whereby
patients who were initially eligible based on diagnostic imaging, would be rendered
ineligible based on CT simulation imaging (e.g. tumor size >7.5cm, skin involvement,
>180 degrees of carotid encasement by tumor). If this does occur, the patient should
be removed from the study and the Radiation Oncology Co-PIs should be notified via
email. Note: It is strongly recommended that CT simulation be performed prior to
entry.

- Patients with gross skin involvement (i.e. tumor ulceration through the skin) are
excluded. Patients with tumor approaching the skin but in which the overlying skin
remains intact are eligible, providing that planning constraints can be achieved
without the use of bolus.

- Disease that requires two or more discontiguous target volumes will be ineligible.
Examples of such cases include:

- Bilateral nodal targets

- Level 2 and level 4 nodes

- An oropharyngeal recurrence with a low level 4 node;

- Patients for whom the maximal total tumor dimension (GTV) is >7.5cm

- Prior radiation to primary tumor within 6 months of entry

- Prior systemic therapy, investigational agent or investigational device within 28 days
of start of study treatment.

- Surgical resection of the qualifying cancer is not permitted. (Patients who have
undergone biopsies are eligible). Patients without radiographically apparent gross
tumor are ineligible. For cases where an operation more extensive than a biopsy was
performed but radiographically apparent gross residual tumor remains, will be reviewed
by the Surgical Co-PI for determination of eligibility.

- No concurrent treatment with other investigational agent or investigational device.

- Prior therapy with a checkpoint inhibitor (eg anti-CTLA-4, anti-PD-1 or anti-PD-L1
therapy).

- Patients with immunodeficiency, or receiving systemic steroid, or any form of
immunosuppressive therapy at the time of registration (e.g. history of human
immunodeficiency virus - HIV). Use of physiologic doses corticosteroids may be
approved with consultation with study chairs.

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

- Known active hepatitis B (positive test for virus surface antigen - HBsAg) or
hepatitis C virus (e.g. positive HCV RNA qualitative test).

- History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

- Treatment with a live vaccine within 30 days of entry.

- Unstable angina and or congestive heart failure requiring hospitalization in the last
6 months.

- Myocardial infarction within the last 6 months.

- Active bacterial or fungal infection requiring intravenous antibiotic at the time of
entry

- Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days of entry.

- Other significant medical, surgical or psychiatric conditions or requirements for any
medication or treatment that in the opinion of the investigator may interfere with
compliance, make administration of anti-PD-L1 therapy hazardous, or obscure
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea.

- Pregnancy, nursing females, or women of childbearing potential and men who are
sexually active and not willing/able to use medically acceptable forms of
contraception; this exclusion is necessary because the treatment involved in this
study may be significantly teratogenic.