Clinical Trials /

Combination Therapy With Intravenous VSV-IFNβ-NIS and Pembrolizumab in Refractory NSCLC and HNSCC

NCT03647163

Description:

This is a Phase I safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with pembrolizumab, followed by expansion to examine efficacy of combination therapy in patients with refractory NSCLC or HNSCC.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Combination Therapy With Intravenous VSV-IFNβ-NIS and Pembrolizumab in Refractory NSCLC and HCC
  • Official Title: Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon (VSV-IFNβ-NIS), in Combination With Pembrolizumab, With Expansion Cohorts in Patients With Refractory Non-Small Cell Lung Cancer or Hepatocellular Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: VYR-VSV2-202
  • NCT ID: NCT03647163

Conditions

  • Solid Tumor
  • Hepatocellular Carcinoma
  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
VSV-IFNβ-NISVoyager-V1Safety Run-in Dose Level 1
PembrolizumabSafety Run-in Dose Level 1

Purpose

This is a Phase I safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with pembrolizumab, followed by expansion to examine efficacy of combination therapy in patients with refractory NSCLC or HCC.

Detailed Description

      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 pateints with refractory NSCLC or HCC. The optimal dose determined in
      the dose escalation portion of the trial will be used as the starting dose for the expansion
      portion. The primary endpoint of the dose escalation portion of this trial is to find the
      optimal dose of VSV-IFNβ-NIS+pembrolizumab. For the expansion portion of the trial, the
      primary endpoint is RECIST 1.1 confirmed response.
    

Trial Arms

NameTypeDescriptionInterventions
Safety Run-in Dose Level 1ExperimentalPatients 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.
  • VSV-IFNβ-NIS
  • Pembrolizumab
Safety Run-in Dose Level 2ExperimentalPatients with pembrolizumab refractory hepatocellular carcinoma (HCC) or non small cell lung cancer (NSCLC) will receive a single IV dose of 1.7e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 1, then every 21 days, up to 2 years.
  • VSV-IFNβ-NIS
  • Pembrolizumab
Expansion HCC armExperimentalPatients with pembrolizumab refractory hepatocellular carcinoma (HCC) will receive a single IV dose of 1.7e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 1, then every 21 days, up to 2 years.
  • VSV-IFNβ-NIS
  • Pembrolizumab
Expansion NSCLC armExperimentalPatients with pembrolizumab refractory non small cell lung cancer (NSCLC) will receive a single IV dose of 1.7e11 TCID50 VSV-IFNβ-NIS in combination with Pembrolizumab at standard labeled dose administered on day 1, then every 21 days, up to 2 years.
  • VSV-IFNβ-NIS
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  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 HCC 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 HCC 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.

        Arm4: 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.

          -  Measurable disease based on RECIST 1.1. The first 3 patients in the safety run-in
             phase do not need measurable disease. HCC lesions that have been previously embolized
             (bland embolization, chemo- or radio-embolization) or have undergone percutaneous
             thermoablation are not eligible as target lesions.

          -  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 (See Section 14.0).

          -  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.

        Exclusion Criteria:

          -  Availability of and patient acceptance of curative therapy.

          -  Recent or ongoing serious infection, including:

               1. Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial,
                  or fungal infection within 2 weeks of registration.

               2. Known seropositivity for or active infection by the human immunodeficiency virus
                  (HIV).

               3. 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

               4. 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)

          -  New York Heart Association classification III or IV, known symptomatic coronary artery
             disease, or symptoms of coronary artery disease on systems review, or known cardiac
             arrhythmias (atrial fibrillation or SVT) (Appendix II).

          -  Any known or suspected active organ-threatening autoimmune disease, such as
             inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis, with the
             exception of hypothyroidism and type 1 diabetes that are controlled with treatment.

          -  Immunodeficiency or immunosuppression, including systemic corticosteroids at >10mg/day
             prednisone or equivalent within 1 week prior to planned start of study treatment

          -  History of severe immune-mediated adverse reaction to immune checkpoint inhibitors.

          -  Toxicities from previous therapies that have not resolved to a grade 1 or less.

          -  History of non-infectious pneumonitis that required steroids, or current pneumonitis.

          -  High volume disease, as assessed clinically via parameters such as radiologic
             impression and tumor markers or LDH.

          -  Portal vein thrombosis involving more than intrahepatic portal vein branches:
             thrombosis of the right or left portal vein branch or the bifurcation, partial or
             complete obstruction of the portal vein trunk.

          -  Known concurrent malignancy that is progressing or requires active treatment.
             EXCEPTIONS: basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
             in-situ cervical cancer that has been treated with curative intent, prostate cancer
             confined to the prostate gland with Gleason score <6 or PSA <1, as well as any stage I
             cancer treated with curative intent or any prior cancer with a disease-free interval
             of ≥3 years.

          -  Other concurrent anti-cancer therapy (chemotherapy, immunotherapy, radiotherapy, or
             any ancillary therapy considered investigational (used for a non-FDA approved
             indication and in the context of a research investigation)).

          -  Has received a live vaccine within 30 days of planned start of study treatment.
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
             are allowed; intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated
             vaccines and are NOT allowed.

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant women or women of reproductive ability who are unwilling to use highly
                  effective contraception

               -  Nursing women

               -  Men who are unwilling to use a condom (even if they have undergone a prior
                  vasectomy) while having intercourse with any woman, while taking the drug and for
                  4 weeks after stopping treatment.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Expansion arms: Overall response rate (ORR)
Time Frame:43 days - 6 months
Safety Issue:
Description:proportion of patients in the analysis population who have complete response (CR) or partial response (PR) based on RECIST 1.1 imaging

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:6 months
Safety Issue:
Description:Survival time is defined as the time from registration to death due to any cause.
Measure:Progression Free Survival (PFS)
Time Frame:6 months
Safety Issue:
Description:Progression-free survival is defined as the time from registration to the earliest date documentation of disease progression or death due to any cause
Measure:Duration of response
Time Frame:6 months
Safety Issue:
Description:defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented.
Measure:Disease Control Rate (DCR)
Time Frame:6 months
Safety Issue:
Description:proportion of patients in the analysis population who have complete response (CR), partial response (PR) or stable disease (SD) based on RECIST 1.1 imaging on day 43.
Measure:Adverse events
Time Frame:6 months
Safety Issue:
Description:All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each patient.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vyriad, Inc.

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