Phase I Trial to Evaluate the Safety and Efficacy of Intratumoral and Intravenous Injection of Vesicular Stomatitis Virus Expressing Human Interferon Beta and Tyrosinase Related Protein 1 (VSV-IFNb-TYRP1) in Patients With Metastatic Ocular Melanoma and Previously Treated Patients With Unresectable Stage III/IV Cutaneous Melanoma
Overview
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Mayo Clinic
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Incidence of adverse events
Overview
Brief Summary
This phase I trial studies the side effects and best dose of a modified virus called VSV-IFNbetaTYRP1 in treating patients with stage III-IV melanoma. The vesicular stomatitis virus (VSV) has been altered to include two extra genes: human interferon beta (hIFNbeta), which may protect normal healthy cells from becoming infected with the virus, and TYRP1, which is expressed mainly in melanocytes (specialized skin cell that produces the protective skin-darkening pigment melanin) and melanoma tumor cells, and may trigger a strong immune response to kill the melanoma tumor cells.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the safety profile and maximum tolerated dose (MTD) of recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 (VSV-IFNbeta-TYRP1) therapy when administered by intravenous (IV) and intratumoral (IT) injection in patients with previously treated metastatic melanoma.
SECONDARY OBJECTIVE:
I. To gather preliminary data on tumor response rate and progression-free survival time of VSV-IFNbeta-TYRP1 intravenous and intratumoral therapy among patients with metastatic malignant melanoma.
CORRELATIVE OBJECTIVES:
I. To determine the pharmacokinetic (PK) profile of VSV-IFNbeta-TYRP1 in patients by measurement of viremia in the blood using reverse transcriptase polymerase chain reaction (RT-PCR) for VSV-N ribonucleic acid (RNA).
II. To characterize the pharmacodynamics (PD) of VSV-IFNbeta-TYRP1 by measuring serum interferon-beta.
III. To determine if there is viral shedding (mouthwash, buccal swab, and urine) before and after viral treatment at different time points.
IV. Assess fresh pre- and post-treatment tumor biopsy samples for viral RNA, viral protein by immunohistochemistry (IHC), infectious virus recovery, infiltrating immune cells.
V. Assess transcriptome of fresh pre- and post-treatment tumor biopsy samples. VI. Assess exome of fresh peripheral blood lymphocytes (PBL) and fresh tumor samples pre-VSV treatment for neoantigen profiling.
VII. Assess changes in cytokine levels and immune cell profile in peripheral blood and tumor samples, pre and post viral treatment.
VIII. Assess if there is an increase in the amount of VSV and melanoma antigen, specifically TYRP1, reactive IFN-gamma secreting T cells by intracellular staining intracellular cytokine (ICS) and enzyme-linked immunosorbent spot (ELISpot) assays.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups.
GROUP A: Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 intratumorally (IT) and intravenously (IV) over 30-60 minutes 2-4 hours later on day 1.
GROUP B: Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1. Cycle 1 continues for 28 days, with subsequent cycles repeating every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients in Group A are followed up at 42 days. Patients in Group B are followed up at 28 days, every 3 months until progressive disease, and then every 6 months for a maximum of 5 years after study registration.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age \>= 18 years
- •Histologically or cytologically confirmed diagnosis of unresectable stage III or metastatic (stage IV) melanoma, including metastatic ocular melanoma
- •Cutaneous melanoma patients only:
- •At least one prior Food and Drug Administration (FDA) approved systemic therapy in the metastatic setting; and disease progression after immune checkpoint inhibitors
- •If tumor is BRAF-mutated, previous BRAF- and/or MEK-targeted therapies are required
- •NOTE: for ocular melanoma patients no current standard of care exists, so patients are permitted to be treated in 1st line setting
- •Measurable disease by any imaging modality as defined by Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1)
- •NOTE: disease that is measurable by physical examination only is not eligible
- •Injectable disease (i.e., suitable for direct injection or through the use of ultrasound guidance) defined as:
- •At least 1 injectable and safely accessible cutaneous, subcutaneous, or nodal melanoma lesion \>= 5 mm in longest diameter for metastatic cutaneous or mucosal melanoma
Exclusion Criteria
- •Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy
- •Any of the following prior therapies:
- •Prior chemotherapy =\< 2 weeks prior to registration
- •Prior immunotherapy (monoclonal antibodies) =\< 3 weeks prior to registration
- •Prior experimental agent =\< 2 weeks prior to registration
- •Prior radiation therapy =\< 2 weeks prior to registration
- •Need for concurrent chemotherapy, immunotherapy, radiotherapy, ablation therapy or any ancillary therapy considered investigational (used for a non-FDA approved indication or in the context of a research investigation)
- •Minor surgical or interventional procedure =\< 7 days prior to registration
- •Major surgical procedure =\< 21 days prior to registration
- •History or evidence of melanoma associated with immunodeficiency states (e.g., hereditary immune deficiency, organ transplant, or leukemia, requires concomitant treatment with immunosuppressive agents, including CTLA-4 agonists, or chronic oral or systemic steroid medication including physiological replacement doses for adrenal insufficiency
Arms & Interventions
Group A (VSV-IFNbetaTYRP1)
Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1.
Intervention: Recombinant Vesicular Stomatitis Virus-expressing Interferon-beta and Tyrosinase Related Protein 1 (Drug)
Group B (VSV-IFNbetaTYRP1)
Patients receive recombinant vesicular stomatitis virus-expressing interferon-beta and tyrosinase related protein 1 IT and IV over 30-60 minutes 2-4 hours later on day 1. Cycle 1 continues for 28 days, with subsequent cycles repeating every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Recombinant Vesicular Stomatitis Virus-expressing Interferon-beta and Tyrosinase Related Protein 1 (Drug)
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 42 days after treatment for Group A and 28 days after treatment for Group B
Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed by dose level to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Maximum-tolerated dose
Time Frame: Up to 28 days
The maximum tolerated dose is defined as the highest dose level among those tested where at most 1 out of 6 patients develops a dose-limiting toxicity (DLT) prior to the start of their second cycle of treatment and the next highest dose level is such that 2 of the 3 to 6 patients treated at this dose level develop a DLT prior to the start of their second cycle of treatment.
Secondary Outcomes
- Tumor response rate(Up to 1 year)
- Overall survival(From registration to death due to any cause, assessed up to 1 year)