Intratumoral CAVATAK (CVA21) and Ipilimumab in Patients With Advanced Melanoma (VLA-013 MITCI)

Primary Objective:

To evaluate the safety and efficacy of CAVATAK (CVA21) administered intratumorally in
combination with the approved dose and schedule of ipilimumab. Of particular interest is to
estimate the overall response rate (ORR) in the subgroup of subjects with unresectable or
metastatic stage III B/C or IV melanoma who have progressed on a single prior anti-PD-1
therapy.

Secondary Objectives:

1. Assess the clinical efficacy of ipilimumab in combination with intratumoral CVA21 in
terms of:

- Immune-related progression-free survival (irPFS) at 6 and 12 months,

- Durable response rate (DRR),

- 1-year survival,

- Overall survival (OS), and

- Quality of life.

2. Assess the response of injected and non-injected melanoma lesions after CVA21 and
ipilimumab.

3. Assess the time to initial response.

Inclusion Criteria:

1. Patients with unresectable or metastatic stage III B/C or IV melanoma. Patients
enrolled under this version of the protocol must also have progressed on prior
anti-PD-1 therapy, according to RECIST 1.1 criteria. Patients who progressed within 3
months of treatment start are excluded.

2. Patients must have at least one cutaneous or subcutaneous tumor, measuring 0.5 to 5.0
cm in the longest diameter, or a palpable lymph node. At least one tumor must qualify
as an index lesion that can be accurately and reproducibly measured in two dimensions
for which the longest diameter is .10 mm (.15 mm in short axis diameter [SAD] for
lymph nodes), and be amenable to intratumoral injection.

3. Histological confirmation of melanoma will be required by previous biopsy or cytology.

4. Patients who have received prior ipilimumab treatment for metastatic melanoma are not
eligible.

5. Patients with ≤ 3 visceral metastases (excluding pulmonary lesions), with no lesions
>3.0 cm. Patients with substantial tumor burden of non-measurable disease may not be
good candidates for an immunotherapy and should be discussed with the Medical Monitor.

7. ECOG performance status of 0-1.

Key Exclusion Criteria:

1. Patients with tumors to be injected lying close to an airway, major blood vessel or
spinal cord that, in the opinion of the Investigator, could cause occlusion or
compression in the case of tumor swelling or erosion into a major vessel in the case
of necrosis. Patients with lesions in mucosal areas (vulvar, anus, oral cavity, etc.),
are eligible, as long as the subject has at least one lesion suitable for injection;
consult Medical Monitor for confirmation.

2. Patients with active, known or suspected autoimmune disease except for autoimmune
thyroiditis or vitiligo. Thyroiditis patients must be asymptomatic, on adequate
thyroid replacement and have normal thyroid function tests.

3. Patients with active colitis or immune-mediated colitis that has not resolved to grade
1 or less.

4. Patients with untreated brain metastases. Patients with treated brain metastases who
are off corticosteroids for at least two weeks and who demonstrate control of brain
metastases with follow-up imaging 4 or more weeks after initial therapy are eligible.

5. Patients previously treated with CVA21.