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

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 and Metastatic 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.

Study Overview

• Status: Terminated
• Conditions: Nonsquamous Nonsmall Cell Neoplasm of Lung; Metastatic Uveal Melanoma; Lung Squamous Cell Carcinoma Stage IV
• Intervention / Treatment: Biological: ADV/HSV-tk; Drug: Valacyclovir; Radiation: SBRT; Drug: nivolumab

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 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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental; 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.

Biological: ADV/HSV-tk; Replication-defective recombinant adenovirus vector; Drug: Valacyclovir; Prodrug of the antiviral drug acyclovir; Other Names: valacyclovir hydrochloride; Radiation: SBRT; Low-dose SBRT; Drug: nivolumab; Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody; Other Names: Opdivo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Determine the ORR of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before nivolumab. Administration of ADV/HSV-tk + Valacyclovir in combination with SBRT before nivolumab represents a novel window of opportunity to enhance nivolumab efficacy by boosting endogenous immune-mediated antitumor activity and neoantigen expression. The concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC, which uses unidimensional measurements. For modified irRC, only target and measurable lesions are taken into account. The same assessment method and technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at EOT. All measurements should be recorded in metric notation.	30 days after the last dose of nivolumab, up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) Rate	Determine the OS rate. Months from start of treatment till date of death.	30 days after the last dose of nivolumab, up to 6 months
Progression Free Survival (PFS) Rate	Determine the Progression Free Survival (PFS) rate. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, using the smallest sum on study (includes the baseline sum) as the reference. In addition to the relative 20% increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) Overall irPD: ≥ 20% increase in the sum of the longest diameters of target and new measurable lesions increases (compared to nadir), confirmed by a repeat, consecutive observation at least 6 weeks (normally it should be done at 8 weeks) from the date first documented. Documentation of immune-related PD (based on modified irRC) does not mandate discontinuation of the study treatment even after irPD is confirmed with CT scan 6 weeks after the initial observation of irPD.	30 days after the last dose of nivolumab, up to 6 months
Clinical Benefit Rate (CBR)	Estimate the CBR as assessed by RECIST 1.1 and modified immune-related criteria	30 days after the last dose of nivolumab, up to 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abscopal effect of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT	Determine the abscopal effect of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT	Baseline and Day 17
Immune response to nivolumab	Measure the immune response to nivolumab	30 days after the last dose of nivolumab
T-helper1 (cellular-based) response	Assess the T-helper1 (cellular-based) response	Baseline and Day 17
Tumor-infiltrating lymphocytes before and after ADV/HSV-tk plus Valacyclovir therapy	Measure tumor-infiltrating lymphocytes before and after ADV/HSV-tk plus Valacyclovir therapy	Baseline and Day 17

Collaborators and Investigators

• Sponsor: Eric Bernicker, MD
• Investigators: Principal Investigator: Eric Bernicker, M.D., Houston Methodist Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2017
• Primary Completion (Actual): November 5, 2020
• Study Completion (Actual): November 5, 2020

Study Registration Dates

• First Submitted: July 1, 2016
• First Submitted That Met QC Criteria: July 11, 2016
• First Posted (Estimated): July 13, 2016

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; lung cancer; gene therapy; metastatic; melanoma; uveal
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Eye Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Melanoma; Uveal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Valacyclovir
• Other Study ID Numbers: Pro00014976

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No