Trial of Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma and Uveal Melanoma
Condition: Lung Squamous Cell Carcinoma Stage IV; Nonsquamous Nonsmall Cell Neoplasm of Lung; Metastatic Uveal Melanoma
MeSH terms: Carcinoma; Melanoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Uveal Neoplasms
Intervention: ADV/HSV-tk; Valacyclovir; SBRT; nivolumab
Intervention description: Replication-defective recombinant adenovirus vector; Prodrug of the antiviral drug acyclovir; Low-dose SBRT; Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
Intervention MeSH terms: Valacyclovir; Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: lung cancer; metastatic; gene therapy; immunotherapy; melanoma; uveal

Summary:

      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.
    

Eligibility criteria:

        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 5 mm) for SBRT, and a non-target lesion of at least 1 cm in
             diameter for abscopal effect evaluation.

          -  ≥ 4 weeks since any major surgery.

          -  A 2-week washout period post any prior systemic anticancer therapy, RT, and/or
             investigational therapy is required prior to trial entry. Subject should be 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 (NSLC Cohort):

               -  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

          -  Adequate liver function (uveal melanoma cohort):

               -  Serum bilirubin less than 1.5 ULN (patients with known Gilbert's disease who have
                  serum bilirubin level 3 ULN may be enrolled)

               -  Serum transaminases (AST or ALT) activity less than or equal to 4 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 ULN with an alkaline phosphatase
                  greater than or equal to 2.5 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 immunotherapy within 2 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.