This is a phase I/II safety run-in study designed to determine the safety of VSV-IFNβ-NIS in
combination with pembrolizumab, followed by dose expansion in patients with refractory NSCLC
or HNSCC. The safety run-in portion of this study is designed to identify the optimal dose of
VSV-IFNβ-NIS in combination with the approved dose of 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 HNSCC. The
optimal dose (recommended phase 2 dose, RP2D) determined in the dose escalation portion of
the trial will be used for the expansion portion.
Three patients will initially be treated at each dose level. The dose of each subsequent dose
level will be determined by the adverse event (AE) evaluations. The VSV-IFNβ-NIS starting
dose will be 1.7 x 10e10 TCID50 injected intravenously. If this dose level is tolerated (no
more than 1 out of 6 or 0 out of 3 patients experience DLT), a second dose level may be
tested (5 × 1010); if this dose is tolerated it will be the dose for parts B and C. If ≥ 2
DLTs are seen in 6 patients at a given dose level, the level below will be explored using the
- 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 HNSCC 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 HNSCC 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. HNSCC 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
- 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.
- 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
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
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
- Pregnant women or women of reproductive ability who are unwilling to use highly
- 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.