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

NCT02831933 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: Pro00014976
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Lung Squamous Cell Carcinoma Stage IV; Nonsquamous Nonsmall Cell Neoplasm of Lung; Metastatic Uveal Melanoma

Keywords

lung cancer; metastatic; gene therapy; immunotherapy; melanoma; uveal

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Overall Survival (OS) Rate

  30 days after the last dose of nivolumab, up to 6 months

• Progression Free Survival (PFS) Rate

  30 days after the last dose of nivolumab, up to 6 months

• Clinical Benefit Rate (CBR)

  30 days after the last dose of nivolumab, up to 6 months

Study Arms (1)

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; Drug: Valacyclovir; Radiation: SBRT; Drug: nivolumab

Interventions

ADV/HSV-tk BIOLOGICAL

Replication-defective recombinant adenovirus vector

Experimental

Valacyclovir DRUG

Prodrug of the antiviral drug acyclovir

Also known as: valacyclovir hydrochloride

Experimental

SBRT RADIATION

Low-dose SBRT

Experimental

nivolumab DRUG

Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody

Also known as: Opdivo

Experimental

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Eric Bernicker, MD: lead

Study Sites (1)

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Uveal Melanoma; Lung Neoplasms; Neoplasm Metastasis; Melanoma

Interventions

Valacyclovir; Nivolumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Uveal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Eric Bernicker
• Organization: Houston Methodist Neal Cancer Center

ccresearch@houstonmethodist.org

713.790.3333

Study Officials

• Eric Bernicker, M.D.

  Houston Methodist Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator/Principal Investigator

Study Record Dates

• First Submitted: July 1, 2016
• First Posted: July 13, 2016
• Study Start: February 15, 2017
• Primary Completion: November 5, 2020
• Study Completion: November 5, 2020
• Last Updated: September 21, 2023
• Results First Posted: September 21, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

US (1)