Ph I/II Trial of Systemic VSV-IFNβ-NIS in Combination With Checkpoint Inhibitor Therapy in Patients With Select Solid Tumors

NCT03647163 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: VYR-VSV2-202
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 2

Brief Summary

The safety run-in portion of this study is designed to identify the optimal dose of VSV-IFNβ-NIS in combination with pembrolizumab in patients with solid tumors and follows the 3+3 design. The expansion portion will use one-sample binomial designs to assess the efficacy of the combination in patients with refractory NSCLC or NEC. The optimal dose (RP2D) determined in the dose escalation portion of the trial will be used for the expansion portion. The study has been conducted with a dose of 1.7 × 1010 as the recommended phase II dose in an expansion cohort of 10 patients with NSCLC. However, current data suggests that VSV-IFNβ-NIS doses of up to 1.7 × 1011 is safe and likely more efficacious. Thus, this study will test a second VSV-IFNβ-NIS dose level, 1.0x1011 TCID50. A safety assessment will be carried out after 3 patients are enrolled. If this dose schedule is well tolerated and virus PK are not negatively impacted, both the NSCLC and NEC expansion cohorts will open using this dose schedule. If 2 of the first 3 patients or 2 of the first 6 patients experience a DLT, the dose will be de-escalated to 5 x 1010. The safety run-in/dose escalation portion of this study is expected to require a minimum of 3 patients and a maximum of 18 patients (6 patients per dose level). The expansion portion of this study is expected to require a minimum of 10 per cohort. The NSCLC and NEC patients enrolled at the identified optimal dose in the dose escalation cohort would be included in the dose expansion cohort if they are evaluable for the primary endpoint in the expansion portion (4 dose escalation patients at the optimal dose are expected to roll over to the expansion). Additionally, up to 16 Renal Cell Carcinoma (RCC) patients will be treated in the expansion cohort. This will permit up to 86 treated patients.

Conditions

Solid Tumor; Non Small Cell Lung Cancer; Neuroendocrine Carcinoma; Renal Cell Carcinoma (RCC)

Keywords

NSCLC; NEC; RCC; Non-small cell lung cancer; Neuroendocrine; Renal Cell

Outcome Measures

Primary Outcomes (2)

• Expansion arms: Overall response rate (ORR)

  proportion of patients in the analysis population who have complete response (CR) or partial response (PR) based on RECIST 1.1 imaging

  43 days - 6 months

• Safety run-in arm: Number of participants with treatment related adverse events (NCI CTCAE; Version 4.03)

  Assessment of safety and toxicity of intravenous VSV-IFNβ-NIS in combination with pembrolizumab therapy

  21 days

Secondary Outcomes (5)

• Overall Survival (OS)

  6 months

• Progression Free Survival (PFS)

  6 months

• Duration of response

  6 months

• Disease Control Rate (DCR)

  6 months

• Adverse events

  6 months

Study Arms (6)

Safety Run-in Dose Level 1

EXPERIMENTAL

Patients with pembrolizumab refractory solid tumors will receive a single IV dose of 5e10 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 1, then every 21 days, up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: Pembrolizumab

Safety Run-in Dose Level 2

EXPERIMENTAL

Patients with pembrolizumab refractory Neuroendocrine Carcinoma (NEC) or non small cell lung cancer (NSCLC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: Pembrolizumab

Expansion NEC

EXPERIMENTAL

Patients with pembrolizumab refractory Neuroendocrine Carcinoma (NEC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: Pembrolizumab

Expansion NSCLC arm

EXPERIMENTAL

Patients with pembrolizumab refractory non small cell lung cancer (NSCLC) will receive a single IV dose of 1.0e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 8, then every 21 days, up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: Pembrolizumab

Expansion Part D

EXPERIMENTAL

Patients with non small cell lung cancer (NSCLC) or Neuroendocrine Carcinoma (NEC) will receive a single IV dose of VSV-IFNβ-NIS on Day 4 in combination with ipilumumab + nivolumab at standard labeled dose administered on Day 1 then every 21 days up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: ipilimumab + nivolumab

Expansion Renal Cell Carcinoma (RCC) Part E

EXPERIMENTAL

Arm Description: Renal Cell Carcinoma (RCC) will receive a single IV dose of VSV-IFNβ-NIS on Day 4 in combination with ipilumumab + nivolumab at standard labeled dose administered on Day 1 then every 21 days for a total of 4 Cycles. Nivo Single agent will be administered every 28 days starting with Cycle 5 for a total treatment period of up to 2 years.

Biological: VSV-IFNβ-NIS; Biological: ipilimumab + nivolumab

Interventions

VSV-IFNβ-NIS BIOLOGICAL

Intravenous oncolytic Vesicular stomatitis virus (VSV) expressing Interferon-beta (IFNβ) and the sodium iodide symporter (NIS)

Also known as: Voyager-V1, VSV, VSV2

Expansion NEC; Expansion NSCLC arm; Expansion Part D; Expansion Renal Cell Carcinoma (RCC) Part E; Safety Run-in Dose Level 1; Safety Run-in Dose Level 2

Pembrolizumab BIOLOGICAL

Pembrolizumab

Expansion NEC; Expansion NSCLC arm; Safety Run-in Dose Level 1; Safety Run-in Dose Level 2

ipilimumab + nivolumab BIOLOGICAL

Intravenous ipilimumab 1mg/kg in combination with nivolumab 360mg, or Intravenous ipilimumab 1mg/kg in combination with nivolumab 3mg/ kg for 4 cycles, followed by fixed dose nivolumab 480mg

Expansion Part D; Expansion Renal Cell Carcinoma (RCC) Part E

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed diagnosis of:
• Arm 1: dose level 1 and below: Advanced and/or metastatic solid tumors for which no existing options are felt to provide clinical benefit
• Arm 2: dose level 2: Advanced and/or metastatic NSCLC OR NEC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit.
• Arm 3: Advanced and/or metastatic NEC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit.
• Arm 4: Advanced and/or metastatic NSCLC in which radiological progression has been demonstrated during therapy with a PD-1/PD-L1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit.
• Arm 5: NEC: poorly differentiated NEC (large or small cell, or not further specified) with progressive disease following at least one prior line of systemic therapy.
• Arm 6: RCC: histologically confirmed diagnosis of advanced or metastatic RCC, including all IMDC risk categories (favorable, intermediate, and poor risk).
• Measurable disease based on RECIST 1.1. The first 3 patients in the safety run-in phase do not need measurable disease. Part C: advanced NEC (neuroendocrine carcinoma based on histopathology according to WHO criteria. Patients with small cell carcinoma, large cell neuroendocrine carcinoma, and neuroendocrine carcinoma not otherwise specified, of any primary organ are eligible in which radiological progression has been demonstrated during therapy with a PD-(L)1 immune checkpoint inhibitor, and for which no existing options are felt to provide clinical benefit.
• Performance status of 0 or 1 on the ECOG Performance Scale.
• Life expectancy of \>3 months if not on active anti-cancer therapy
• Willingness to provide biological samples required for the duration of the study including a fresh tumor biopsy sample.
• Adequate organ function using predefined laboratory values obtained ≤14 days prior to registration.
• Negative pregnancy test for female patients of childbearing potential
• Absence of active CNS involvement. NOTE: Pre-enrollment imaging of asymptomatic patients not mandatory
• Ability to provide written informed consent.

You may not qualify if:

• Availability of and patient acceptance of curative therapy.
• a. For NSCLC cohort: i. Known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 \[L858R\] substitution mutations). All patients with non-squamous histology must have been tested for EGFR mutation status; use of an FDA-approved test is strongly encouraged. ii. Non-squamous histology and unknown or indeterminate EGFR status. b. Part D NSCLC cohort: Known ALK translocations which are sensitive to available targeted inhibitor therapy. If tested, use of an FDA-approved test is strongly encouraged. Patients with unknown or indeterminate ALK status may be enrolled.
• Recent or ongoing serious infection, including:
• Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial, or fungal infection within 2 weeks of registration.
• Known seropositivity for or active infection by the human immunodeficiency virus (HIV).
• Acute hepatitis B or acute hepatitis C. Patients with chronic hepatitis B or hepatitis C may be enrolled provided their liver function is adequate as per section 3.17
• Known history of active TB (Bacillus tuberculosis).
• Any serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months)
• Prior therapy within the following timeframe before the planned start of study treatment as follows:
• Chemotherapy, small molecule inhibitors, radiation, interventional radiology procedure, and/or other investigational agent: ≤3 weeks or 5 half-lives, whichever is shorter
• Other monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or experimental therapies: ≤4 weeks (≤3 weeks with documented disease progression)
• Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to randomization. Subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of randomization are strongly encouraged to receive palliative radiotherapy prior to randomization.
• NSCLC patients only: prior chemotherapy or immunotherapy or a combination of chemotherapy and immunotherapy for stage IV NSCLC.
• RCC patients:
• i. Previously received a CTLA-4 inhibitor in the first-line setting. ii. Relapsed/progressed during adjuvant immunotherapy with a PD-(L)1 inhibitor or relapse within 12 months after completion of adjuvant immunotherapy

Sponsors & Collaborators

• Vyriad, Inc.: lead
• Mayo Clinic: collaborator

Study Sites (2)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Cleveland Clinic Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Neuroendocrine; Carcinoma, Renal Cell

Interventions

pembrolizumab; Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Alex Adjei, MD, PhD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

• Patrick McGarrah, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Safety run-in with dose escalation to be used to identify the optimum dose for expansion. Dose expansion will recruit patients in parallel into 3 groups, NSCLC, NEC and RCC.

Study Record Dates

• First Submitted: August 23, 2018
• First Posted: August 27, 2018
• Study Start: April 9, 2019
• Primary Completion: July 31, 2025
• Study Completion: September 30, 2025
• Last Updated: September 16, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)