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

PRIMARY OBJECTIVES:

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 OBJECTIVES:

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 (IM) 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 IM 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.

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of unresectable stage III or
metastatic (stage IV) melanoma, including metastatic ocular melanoma, with estimated
largest tumor diameter =< 5cm and =< 2 tumors >= 3 to =< 5 cm diameter

- 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

- At least one safely accessible liver metastasis for patients with metastatic
ocular melanoma

- Patients with metastatic ocular melanoma must meet all of the additional inclusion
criteria:

- No more than 25% overall tumor involvement of the liver by magnetic resonance
imaging (MRI) imaging

- Child Pugh Score A

- Absence of ascites

- No portal vein thrombosis

- Have resolution of all previous treatment-related toxicities to grade 1 severity or
lower

- Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to
registration)

- Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)

- Hemoglobin >= 9.0 g/dL (without need for hematopoietic growth factor or transfusion
support) (obtained =< 14 days prior to registration)

- Alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (obtained =< 14
days prior to registration)

- Aspartate transaminase (AST) =< 2.5 x ULN (obtained =< 14 days prior to registration)

- Total bilirubin =< 1.5 x ULN (obtained =< 14 days prior to registration)

- Prothrombin time (PT) =< 1.5 x ULN (or international normalization ratio [INR] =< 1.4)
or partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) =<
ULN (obtained =< 14 days prior to registration)

- Serum creatinine within institutional limits of normal (=< ULN) (obtained =< 14 days
prior to registration)

- Life expectancy of >= 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Willing and have the ability to comply with scheduled visits (including geographical
proximity), treatment plans, laboratory tests, and other study procedures

- Willing to provide all biological specimens as required by the protocol including
fresh tissue for biomarker analysis (metastatic melanoma cohort with accessible
injectable lesions only)

- NOTE: patients with cutaneous melanoma and accessible cutaneous/subcutaneous
lesions will have one lesion biopsied prior to the subject receiving the first
dose of study treatment on day 1 of cycle 1 and the biopsy will be repeated on
the injected target lesion and an uninjected lesion where possible post-virus
treatment on day 3

- NOTE: repeat samples may be required if adequate tissue is not obtained

- Negative pregnancy test done =< 7 days prior to registration, for persons of
childbearing potential only

- NOTE: if the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required

- Willing to use an adequate method of contraception from the first dose of study
medication through 120 days after the last dose of study medication, for persons of
childbearing potential or persons able to father a child only

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

- History of or plan for splenectomy or splenic irradiation

- History or evidence of central nervous system (CNS) metastases

- Active skin lesions (open wounds, severe rash, herpetic lesions, etc.)

- Prior non-oncology vaccine therapies used for the prevention of infectious disease =<
28 days prior to registration

- Requires concomitant treatment with therapeutic anticoagulants

- Known history of active tuberculosis

- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Known acute or chronic hepatitis B or hepatitis C infection (requires negative test)

- Metastatic ocular melanoma patients only: liver radioembolization =< 90 days prior to
registration

- No other active second malignancy other than non-melanoma skin cancers and in situ
cervical cancers within 35 years of registration

- NOTE: a second malignancy is not considered active if all treatment for that
malignancy is completed and the patient has been disease-free for at least 3
years prior to registration

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled symptomatic cardiac arrhythmia

- Uncontrolled hypertension (defined as blood pressure > 160/90)

- 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

- Active CNS disorder or seizure disorder or known CNS disease or neurologic
symptomatology

- Pregnant or breast-feeding, or planning to become pregnant during study treatment and
through 3 months after the last dose of study treatment

- Person of childbearing potential who is unwilling to use two (2) highly effective
methods of contraception during study treatment and through 120 days after the last
dose of study treatment

- Person able to father a child who is unwilling to use a highly effective method of
contraception during study treatment and through 120 days after the last dose of study
treatment