A Study of Glembatumumab Vedotin as Monotherapy or in Combination With Immunotherapies in Patients With Advanced Melanoma

Glembatumumab vedotin consists of an antibody attached to a drug, monomethyl auristatin E
(MMAE), that can kill cancer cells. The fully human antibody is designed to deliver the drug
to cancer cells by attaching to a protein called glycoprotein NMB (gpNMB) that is expressed
on the cancer cell. The MMAE is then released inside of the cell, where it interferes with
cell growth and can lead to cell death of the targeted cell, as well as neighboring cells.
Varlilumab is a fully human antibody that binds to CD27. This antibody allows the body's
immune system to work against cancer cells. Nivolumab is a fully human antibody and
pembrolizumab is a humanized antibody. Both bind to PD-1. CDX-301 is a fully human protein
that helps boost production of certain white blood cells. This protein allows the body's
immune system to work against tumor cells.

Eligible patients who enroll in the study will receive treatment with one of the following:
glembatumumab vedotin, glembatumumab vedotin and varlilumab, glembatumumab vedotin and
CDX-301 or glembatumumab vedotin and either nivolumab OR pembrolizumab.

All patients enrolled in the study will be closely monitored to determine if their cancer is
responding to treatment and for any side effects that may occur.

Inclusion Criteria:

Among other criteria, patients must meet all of the following conditions to be eligible for
the study:

- Unresectable, histologically-confirmed advanced (Stage III or Stage IV) melanoma

- Disease progression during or after the last anticancer therapy received. For Cohort
3, progression must have occurred during the PD-1 targeted CPI (checkpoint inhibitor)
treatment and the investigator has deemed it appropriate to continue treatment with
the PD-1 targeted CPI beyond confirmed disease progression

- No more than one prior chemotherapy-containing regimen for advanced disease.

- Prior treatments received must include at least one CPI inhibitor (e.g., anti-CTLA-4,
PD-1-, PD-L1-targeted immunotherapy) and for patients with a BRAF mutation at least
one BRAF- or MEK-targeted therapy, unless patients are not candidates for, or refused,
these therapies. For cohort 3, prior treatment received must include a PD-1 targeted
CPI administered during the most recent disease progression and for patients with BRAF
mutation at least one BRAF- or MEK-targeted therapy when appropriate

- The study site will submit paraffin-embedded tumor tissue obtained from the patient
for gpNMB analysis. Patients may require a biopsy if recent tumor tissue is not
available. Patients in cohort 2 and 3 must submit a recently obtained biopsy of the
skin fold for gpNMB analysis. Patients in Cohort 4 will submit a tumor tissue sample
while on study.

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1

- Adequate bone marrow, liver and renal function.

Exclusion Criteria:

Among other criteria, patients who meet any of the following conditions are NOT eligible
for the study:

- Previously received glembatumumab vedotin (CR011-vcMMAE, CDX-011) or other
MMAE-containing agents

- Treatment with the following therapies before the planned start of study treatment:

1. BRAF or MEK inhibitors within 2 weeks

2. Monoclonal based therapies within 4 weeks except for the PD-1 targeted checkpoint
inhibitor in cohort 3

3. Immunotherapy (tumor vaccine, cytokine, or growth factor given to control the
cancer) within 2 weeks

4. Chemotherapy within 21 days or at least 5 half-lives (whichever is longer)

5. Investigational therapy within 2 weeks (or at least 5 half-lives, whichever is
longer)

- Patients with ocular melanoma

- Neuropathy that is moderate (Grade 2) or worse.

- Cancer that has spread to the brain or spine will be discussed with the study sponsor
and may exclude patients from the trial.

- History of another cancer except:

1. Patients with adequately treated and cured non-melanoma skin cancer or in situ
cancer

2. Patients with any other cancer from which the patient has been disease-free for ≥
3 years

- Significant cardiovascular disease

- Previously received varlilumab or any other anti-CD27 mAb (Cohort 2 only)

- Active systemic infection requiring treatment

- Treatment with immunosuppressive medications within 4 weeks or corticosteroids within
two weeks

- Patients with interstitial lung disease (Cohort 3 only)

- Patients with active diverticulitis (Cohort 3 only)

- Any non-study vaccination within 4 weeks, or influenza vaccine within 2 weeks, prior
to CDX-301 dosing (Cohort 4 only)