Clinical Trials /

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

NCT02831933

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Uveal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Stereotactic Body Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma
  • Official Title: ENSIGN: Phase II Window of Opportunity Trial of Stereotactic Body Radiation Therapy and In Situ Gene Therapy Followed by Nivolumab in Metastatic Squamous or Non-Squamous Non-Small Cell Lung Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: Pro00014976
  • NCT ID: NCT02831933

Conditions

  • Lung Squamous Cell Carcinoma Stage IV
  • Nonsquamous Nonsmall Cell Neoplasm of Lung

Interventions

DrugSynonymsArms
ADV/HSV-tkExperimental
Valacyclovirvalacyclovir hydrochlorideExperimental
nivolumabOpdivoExperimental

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ExperimentalExperimentalADV/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.
  • Valacyclovir
  • nivolumab

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 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
                  ULN

          -  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.

        Exclusion Criteria:

          -  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
             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. 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
             study.

          -  Unwilling or unable to comply with the study protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:ORR
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Determine the ORR of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before nivolumab

Secondary Outcome Measures

Measure:DoR
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Determine the DoR
Measure:OS rate
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Determine the OS rate
Measure:PFS rate
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Determine the PFS rate
Measure:Number of participants with treatment-related adverse events as assessed by the NCI CTCAE v4.03
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by the NCI CTCAE v4.03
Measure:Antitumor activity
Time Frame:30 days after the last dose of nivolumab
Safety Issue:
Description:Document the antitumor activity as assessed by RECIST 1.1 and modified immune-related criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Eric Bernicker, MD

Trial Keywords

  • lung cancer
  • metastatic
  • gene therapy
  • immunotherapy

Last Updated

February 15, 2017