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Interferon-beta

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Immunologic Factors

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.

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.

Recombinant Vesicular Stomatitis Virus-expressing Interferon-beta and Tyrosinase Related Protein 1

Roxana S. Dronca, M.D.

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.

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.

Modified Virus VSV-IFNbetaTYRP1 in Treating Patients With Stage III-IV Melanoma

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

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.

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.

A tumor response is defined as either a complete response or partial response on two consecutive evaluations at least 6 weeks apart. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by dose level).

The distribution of survival time will be estimated using the method of Kaplan-Meier.

Mayo Clinic

Spots Global Cancer Trial Database for metastatic choroid melanoma