Ipilimumab With or Without Talimogene Laherparepvec in Unresected Melanoma

The phase 1b part is an open-label, multicenter, single-arm study where all participants will
receive talimogene laherparepvec in combination with ipilimumab.

The phase 2 part of the study is an open-label, multicenter, randomized study to further
assess the safety and to evaluate the efficacy of talimogene laherparepvec in combination
with ipilimumab. Participants will be randomized 1:1 to receive talimogene laherparepvec plus
ipilimumab or ipilimumab alone.

Participants randomized before amendment 2 will be stratified by stage of disease (stage
IIIB/C, IVM1a, and stage IVM1b vs IVM1c) and v-raf murine sarcoma viral oncogene homolog B1
(BRAF) V600E (a mutation resulting in a substitution of glutamic acid for valine at codon
600) (mutation vs mutation not present). Participants randomized after amendment 2 will be
stratified by stage of disease (stage IIIB/C and IVM1a vs stage IVM1b and IVM1c) and prior
therapy (treatment naïve vs previously treated with systemic anticancer immunotherapy vs
previously treated with systemic anticancer treatment other than immunotherapy).

Inclusion Criteria:

- Histologically confirmed diagnosis of malignant melanoma.

- Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c disease that is not suitable for surgical
resection

- Phase1: Treatment naïve: Must not have received any prior systemic anticancer
treatment consisting of chemotherapy, immunotherapy, or targeted therapy for
unresected stage IIIB to IV melanoma.

- Phase 2:

- Either treatment naïve or received only one line of systemic anticancer therapy
if v-raf murine sarcoma viral oncogene homolog B1 (BRAF) wild-type or up to two
lines of systemic anticancer therapy including one BRAF inhibitor-containing
regimen if BRAF mutant. Treatments given in an adjuvant setting (eg, interferon,
radiotherapy, isolated limb perfusion, or investigational agents) are not
considered as prior lines of therapy. No prior talimogene laherparepvec, other
oncolytic virus therapies, or tumor vaccines are allowed, even if given in the
adjuvant setting.

- Subjects treated with prior ipilimumab must have had partial response (PR),
complete response (CR), or at least 6 months of stable disease followed by
disease progression.

- Subjects previously treated with anti-program death-1 (PD1) or anti-cytotoxic
T-lymphocyte associated antigen 4 (CTLA-4) antibodies must not have discontinued
therapy due to any treatment-related adverse events including immune-related
adverse events. Prior treatment-related adverse events should also be fully
resolved and not requiring treatment for at least 28 days prior to randomization.

- Measurable disease defined as one or both of the following

- at least 1 melanoma lesion that can be accurately and serially measured in at
least 2 dimensions and for which the longest diameter is ≥ 10 mm and with
perpendicular diameter ≥ 5 mm as measured by contrast-enhanced or spiral computed
tomography (CT) scan for visceral or nodal/soft tissue disease. Lymph nodes must
measure > 15 mm in their short axis to be considered measurable by CT scan.

- at least 1 superficial cutaneous or subcutaneous melanoma lesion that can be
accurately and serially measured in at least 2 dimensions and for which the short
axis is ≥ 5 mm as measured by calipers

- Injectable disease (ie, suitable for direct injection or through the use of ultrasound
[US] guidance) defined as follows:

- at least 1 injectable cutaneous, subcutaneous, or nodal melanoma lesion ≥ 5 mm in
longest diameter

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

- Adequate hematologic, hepatic, renal, and coagulation functions

Exclusion Criteria:

- Primary uveal or mucosal melanoma

- History or evidence of melanoma associated with immunodeficiency states (eg,
hereditary immune deficiency, organ transplant, or leukemia)

- Phase 1b: History or evidence of central nervous system (CNS) metastases

- Phase 2: Clinically active cerebral melanoma metastases. Subjects with up to 3
cerebral metastases, and neurological performance status of 0 may be enrolled,
provided that all lesions have been adequately treated with stereotactic radiation
therapy, craniotomy, or Gamma knife therapy, with no evidence of progression, and have
not required steroids, for at least 2 months prior to enrollment.

- History or evidence of symptomatic autoimmune disease (such as pneumonitis,
glomerulonephritis, vasculitis, rheumatoid arthritis, inflammatory bowel disease,
systemic lupus erythematosus, scleroderma, or other), or history of autoimmune disease
that required systemic treatment (ie, use of corticosteroids, immunosuppressive drugs
or biological agents used for treatment of autoimmune diseases) in past 2 months prior
to enrollment. Replacement therapy (eg, thyroxine for hypothyroidism, insulin for
diabetes mellitus) is not considered a form of systemic treatment for autoimmune
disease.

- History of or plan for splenectomy or splenic irradiation

- Active herpetic skin lesions or prior complications of herpes simplex type-1 virus
(HSV-1) infection (eg, herpetic keratitis or encephalitis).

- Requires intermittent or chronic systemic (intravenous or oral) treatment with an
antiherpetic drug (eg, acyclovir), other than intermittent topical use

- Known human immunodeficiency virus (HIV) disease

- Known acute or chronic hepatitis B or hepatitis C infection

- Phase 1b: Prior talimogene laherparepvec, ipilimumab, other CTLA-4 inhibitors, PD-1
inhibitors, or tumor vaccine

- Phase 2: Prior talimogene laherparepvec, other oncolytic virus therapies, or tumor
vaccines

- Currently receiving or less than 28 days since ending systemic anticancer treatment
for unresected stage IIIB to IV melanoma