Trial of Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma and Uveal Melanoma

This is a Phase II trial to determine the efficacy and safety of in situ gene therapy and
stereotactic body radiation therapy (SBRT) used as a window of opportunity treatment before
nivolumab in patients with metastatic squamous or non-squamous non-small cell lung carcinoma
(NSCLC) and metastatic uveal melanoma. In situ gene therapy will consist of
adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus
Valacyclovir therapy. Male or female patients aged ≥18 years with histologically or
cytologically confirmed metastatic squamous or non-squamous NSCLC whose disease has
progressed after a platinum-based chemotherapy and a single-agent immunotherapy OR
histologically or cytologically confirmed metastatic uveal melanoma that is immunotherapy
naive are eligible to participate in the study. NSCLC patients with EGFR or ALK genomic tumor
aberrations are eligible only if they have had disease progression on FDA-approved therapy
for these aberrations. ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be
injected intratumorally on day 0 of the study. Valacyclovir will be orally administered at a
dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24
hours after the gene vector injection from day 1 to day 15 of the study. SBRT of 30 gray (Gy;
6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting
on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up
to 12 months in patients without disease progression. The primary endpoint will be the
objective response rate (ORR) of ADV/HSV-tk + Valacyclovir therapy in combination with SBRT
used as a window of opportunity treatment before nivolumab in patients with metastatic
squamous or non-squamous NSCLC. Both RECIST 1.1 and modified immune-related response criteria
(irRC; derived from RECIST 1.1) will be used to assess treatment response. Secondary
endpoints will include a) clinical benefit rate (CBR); b) duration of response (DoR); c)
overall survival (OS) and progression-free survival (PFS) rates; d) safety and toxicity
(toxicity will be defined as any treatment-related death or any ≥ grade 3 toxicity excluding
alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03); and e)
immune-mediated antitumor activity (assessed by RECIST 1.1 and modified irRC) of ADV/HSV-tk
plus Valacyclovir therapy in combination with SBRT used as a window of opportunity treatment
before nivolumab.

Inclusion Criteria:

- Male or female ≥18 years of age.

- Histologically or cytologically confirmed stage IV, metastatic squamous or
non-squamous NSCLC that has progressed after a platinum-based chemotherapy and after a
single-agent immunotherapy OR histologically or cytologically confirmed metastatic
uveal melanoma that is immunotherapy naive

- Evaluable or measurable disease as per RECIST 1:1, a target lesion of suitable
diameter (at least 1 cm) for SBRT, and a non-target lesion of at least 1 cm in
diameter for abscopal effect evaluation.

- ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of
all prior systemic anticancer therapy (adequately recovered from the acute toxicities
of any prior therapy).

- Life expectancy greater than or equal to 6 months.

- Eastern Cooperative Oncology Group performance status of 0-1.

- Adequate bone marrow function:

- Absolute neutrophil count ≥ 1.5 x 10^9/L (without granulocyte colony stimulating
factor support within 2 weeks of laboratory test used to determine eligibility)

- Platelets ≥ 100 x 10^9/L (without transfusion within 2 weeks of laboratory test
used to determine eligibility)

- Hemoglobin ≥ 8 g/dL (without blood transfusion)

- White blood cell count > 2,500/uL and < 15,000/uL

- Lymphocyte count ≥ 500/uL

- Adequate liver function:

- Serum bilirubin less than or equal to 1.0 X upper limit of normal (ULN; patients
with known Gilbert's disease who have serum bilirubin level less than or equal to
3 X ULN may be enrolled)

- Serum transaminases (aspartate transaminase [AST] or alanine transaminase [ALT])
activity less than or equal to 2.5 X ULN with normal alkaline phosphatase
(patients with liver metastases less than or equal to 5 x ULN) OR AST and ALT
less than or equal to 1.5 X ULN with an alkaline phosphatase greater than 2.5 X
ULN

- International normalized ratio and activated partial thromboplastin time (aPTT) less
than or equal to 1.5 X ULN (unless patient is receiving anticoagulant therapy as long
as PT or aPTT is within therapeutic range of intended use of anticoagulants)

- Adequate renal function: serum creatinine less than 2 X ULN.

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
within 7 days prior to the administration of the first study treatment. Women must not
be lactating.

- WOCBP and men must practice an effective method of birth control

- Signed informed consent to participate in the study must be obtained from patients
after they have been fully informed of the nature and potential risks of the study by
the investigator (or his/her designee) with the aid of written information.

- Willing to provide biopsies as required by the study.

Exclusion Criteria:

- Prior treatment with gene therapy.

- Any cytotoxic chemotherapy, RT, or any investigational drug within 3 weeks of study
treatment start.

- Any immunotherapy within 3 weeks of study treatment start (NSCLC cohort only)

- Prior treatment with immunotherapy (uveal melanoma cohort only)

- Patients with EGFR or ALK genomic tumor aberrations that have not received any
FDA-approved therapy for these aberrations (NSCLC cohort only).

- Oxygen-dependent chronic obstructive pulmonary disease (NSCLC cohort only).

- Patients requiring oral prednisone for emphysema management (NSCLC cohort only).

- History of liver disease, such as cirrhosis or active/chronic hepatitis B or C.

- History of or current alcohol misuse/abuse within the past 12 months.

- Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or
chronic pancreatitis.

- Major surgery within 4 weeks prior to study enrollment.

- Uncontrolled brain or leptomeningeal metastases or brain or leptomeningeal metastases
requiring continued glucocorticoid treatment. Patients who have been treated at least
4 weeks prior to enrollment and have a CT or magnetic resonance imaging scan of the
brain showing no evidence of disease progression within 4 weeks of enrollment are
eligible.

- Congestive heart failure: New York Heart Association class III or IV heart failure or
unstable angina.

- History of syncope or family history of idiopathic sudden death.

- Sustained or clinically significant cardiac arrhythmias including sustained
ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia,
advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged
heart rate-corrected QT interval (longer than 470 milliseconds), or history of acute
myocardial infarction. (The QT interval is the time between the start of the Q wave
and the end of the T wave in the cardiac electrical cycle)

- Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by
diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis,
uncontrolled hypothyroidism, or cardiac failure.

- Presence of active or suspected acute or chronic uncontrolled infection or history of
immunocompromise, including a positive HIV test result.

- Any severe and/or uncontrolled medical conditions or other conditions that could
affect patient participation in the study such as severely impaired lung function, any
active (acute or chronic) or uncontrolled infection/disorders, and nonmalignant
medical illnesses that are uncontrolled or whose control may be jeopardized by the
study therapy.

- Known or suspected allergy or hypersensitivity to any component of nivolumab or its
analogues or any component of the proposed regimen (gene vector/Valacyclovir).

- Inability to swallow food or any condition of the upper gastrointestinal tract that
precludes administration of oral medications (Valacyclovir).

- Any active malignancy except for non-melanoma skin cancer or in situ cervical cancer
or treated cancer from which the patient has been continuously disease free for more
than 5 years.

- Pregnant or breastfeeding women or women/men able to conceive and unwilling to
practice an effective method of birth control.

- Unwilling or unable to comply with the study protocol.