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 and non-squamous non-small cell lung
carcinoma (NSCLC). 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 on or after platinum-based chemotherapy
or on or after immune checkpoint therapy are eligible to participate in the study. 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 (240 mg) will be administered
intravenously over 60 minutes every 2 weeks starting on day 17 of the study and continuing
until disease progression or unacceptable toxicity. 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) duration of response (DoR); b) overall survival (OS) and
progression-free survival (PFS) rates; c) 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 d) 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.
- Male or female ≥18 years of age.
- Histologically or cytologically confirmed stage IV, metastatic squamous or
non-squamous NSCLC that has progressed on or after platinum-based chemotherapy or on
or after immune checkpoint therapy.
- 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 ≥ 9 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
- International normalized ratio and activated partial thromboplastin time less than or
equal to 1.5 X ULN
- Adequate renal function: serum creatinine at or below the institutional normal value.
- 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.
- Prior treatment with gene therapy.
- Any cytotoxic chemotherapy, RT, or immunotherapy or any investigational drug within 3
weeks of study treatment start.
- Patients with EGFR or ALK genomic tumor aberrations that have not received any
FDA-approved therapy for these aberrations.
- Oxygen-dependent chronic obstructive pulmonary disease.
- Patients requiring oral prednisone for emphysema management.
- 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
- 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
- Congestive heart failure: New York Heart Association class III or IV heart failure or
- 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
- 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. WOCBP must have a negative serum
pregnancy test within 7 days prior to the administration of the first study
treatment. Oral, implantable, and injectable contraceptives may be affected by
cytochrome P450 interactions and therefore, are not considered effective for this
- Unwilling or unable to comply with the study protocol.