Priming Immunotherapy in Advanced Disease With Radiation

Subjects with front-line or relapsed NSCLC or relapsed HNSCC who are intended to receive
standard of care immune checkpoint inhibitors without a contraindication to Stereotactic Body
Radiation Therapy (SBRT) to a single cancer deposit greater than 1 cm (metastasis or primary
cancer) will be enrolled. Subjects will receive standard of care (SOC) immune checkpoint
inhibitors and within 2 weeks of initiation, and will receive either:

- SBRT to target to achieve Biological Equivalent Dose (BED) > 100 Gy OR

- 30 Gy fractionated radiation therapy (RT) delivered as a 3 dimensional (3-D) dose.

The lesion choice will be made by the treating radiation oncologist and will be directed to a
single malignant focus (non-CNS) that measures ≥ 1 cm. Essentially, the goals of both
techniques are the same but SBRT is reserved for lesions that are readily encompassed by a
single field with large RT fractions in which dose-limiting organs are within safe limits.

Inclusion Criteria:

1. Histologically proven advanced or metastatic non-small cell lung cancer or squamous
cell carcinoma head and neck with tumor at least 1 cm in size.

2. Eligible for treatment with radiation therapy.

3. Prior treatment: chemotherapy or radiotherapy or surgery.

1. Prior chemotherapy or radiation must have concluded ≥ 21 days prior to the start
of study treatment.

2. No limit is placed on prior systemic treatment, but subjects must be eligible for
immune checkpoint inhibitors therapy, for an FDA approved indication.

3. No major surgery within 14 days of start of study treatment.

4. No previous or concurrent malignancy is allowed except for adequately treated basal
cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which
the patient has been disease free for the past 3 years.

5. Age ≥ 18 years.

6. Life expectancy ≥ 3 months.

7. Required initial laboratory values:

1. Absolute neutrophil count ≥ 1,000/mm3

2. Platelets ≥ 100,000/mm3

3. Total bilirubin ≤ 1.5 x ULN

4. AST and ALT if no hepatic metastasis ≤ 2.5 times x ULN

5. AST and ALT with hepatic metastasis ≤ 5 x ULN

6. Creatinine ≤ 1.5 x ULN and Requires CrCl ≥ 60ml/min (per 24-hour urine collection
or calculated according to the Cockcroft-Gault formula)

8. Non pregnant and non-nursing women. Women of childbearing potential must have a
negative serum pregnancy test performed within 7 days prior to the start of treatment.
Women of childbearing potential and men must agree to use adequate contraception
(barrier method of birth control) prior to study entry and for the duration of study
participation. Subjects should use adequate birth control for at least 3 months after
the last administration of immune checkpoint inhibitors.

9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Active clinically serious infection > CTCAE Grade 2.

2. Serious non-healing wound, ulcer or bone fracture.

3. Prior treatment with immune checkpoint inhibitors.

4. Ineligible for immune checkpoint inhibitors based on package insert of the chosen
immune checkpoint inhibitor (e.g., uncontrolled immunologic disorders, active
hepatitis, active colitis, active pneumonitis, uncontrolled/active hormone gland
problems - including thyroid, pituitary, adrenal glands and pancreas).

5. Major surgical procedure (including craniotomy and open brain biopsy) or significant
traumatic injury within 14 days prior to registration or those patients who receive a
non-CNS minor surgical procedures (e.g. core biopsy or fine needle aspiration) within
3 days prior to registration. There is no waiting period for central line placement.
There is a 7-day window for recovery prior to registration for patients who underwent
stereotactic biopsy of the brain.

6. Participants may not have uncontrolled inter-current illness. This includes, but is
not limited to: ongoing or active infection; symptomatic congestive heart failure
(NYHA class III or IV); unstable angina pectoris or new onset angina that began within
the last 3 months; cardiac ventricular arrhythmias requiring anti-arrhythmic therapy;
or thrombotic/embolic events such as cerebrovascular accident, including transient
ischemic attacks within the past 6 months. Uncontrolled hypertension defined as
systolic blood pressure >150 mmHg or diastolic pressure > 90 mmHg, despite optimal
medical management. Known human immunodeficiency virus (HIV) infection or chronic
Hepatitis B or C. Known Grade 3 or 4 neurotoxicity.