Anti-SEMA4D Monoclonal Antibody VX15/2503 With Nivolumab or Ipilimumab in Treating Patients With Stage III or IV Melanoma

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of the combination of anti-SEMA4D monoclonal
antibody VX15/2503 (anti-SEMA4D VX15/2503) with nivolumab, or ipilimumab, in melanoma
patients who have progressed on anti-PD1/L1 based checkpoint inhibitors.

II. To determine the recommended phase II dose and schedule of the combination of anti-SEMA4D
VX15/2503 with nivolumab, or ipilimumab, in melanoma patients who have progressed on
anti-PD1/L1 based checkpoint inhibitors.

SECONDARY OBJECTIVES:

I. Define the adverse event profile for the agent combinations and determine attribution
(i.e. drug related adverse events [AEs]); II. To evaluate clinical response of patients
treated with maximum tolerated dose (MTD) or maximum administered dose (MAD) of the
combination of anti-SEMA4D with nivolumab, or ipilimumab.

III. To evaluate whether adding anti-SEMA4D to PD1 or CTLA-4 blockade can increase T-cell
infiltration into tumors and whether change in T-cell infiltration is associated with
response.

OUTLINE: This is a dose-escalation study of anti-SEMA4D monoclonal antibody VX15/2503.
Patients are randomized to 1 of 2 arms.

ARM A: Patients receive anti-SEMA4D monoclonal antibody VX15/2503 intravenously (IV) over 60
minutes and nivolumab IV over 30 minutes every 28 days for up to 12 months in the absence of
disease progression or unacceptable toxicity.

ARM B: Patients receive anti-SEMA4D monoclonal antibody VX15/2503 IV over 60 minutes and
ipilimumab IV over 30 minutes every 21 days for courses 1-4, then receive anti-SEMA4D
monoclonal antibody VX15/2503 every 28 days for subsequent courses for up to 12 months in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 2 years,
every 6 months for 3 years, then annually thereafter.

Inclusion Criteria:

- Patients with histologically confirmed unresectable stage III or stage IV metastatic
melanoma, who have not been previously treated with a SEMA4D antibody and have had
prior anti-PD1/PDL1 inhibitors with documented progression; patient may have or not
have prior anti-CTLA4 treatments

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version
(v.) 1.1 criteria

- Patients must have non-target lesion accessible for sequential biopsy (core needle
biopsy or excision preferred, fine needle aspiration not eligible)

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

- Women of child-bearing potential must have a negative serum pregnancy test within 24
hour of initiation of dosing and must agree to use an effective form of contraception
during the study from the time of the negative pregnancy test up to 6 months after the
last dose of study drug; effective forms of contraception include abstinence, hormonal
contraceptive in conjunction with a barrier method, or a double barrier method; women
of non-childbearing potential may be included if they are either surgically sterile or
have been postmenopausal for >= 1 year; fertile men must also agree to use an
effective method of birth control while on study drug and up to 6 months after the
last dose of study drug

- Patients must have fully recovered from the effects of any major surgery or
significant traumatic injury within 14 days of course 1 day 1 (C1D1)

- Absolute neutrophil count >= 1 X 10^9/L

- Hemoglobin (Hgb) > 8 g/dL

- Platelet count >= 75 X 10^9/L

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 X upper limit of
normal (ULN) or < 5 X ULN in the presence of liver metastases

- Bilirubin =< 3 X ULN or < 5 X ULN in the presence of liver metastases

- Creatinine =< 3 X ULN or calculated creatinine clearance (CrCl) > 30 mL/min using
Cockcroft- Gault formula

- Willing and able to provide written informed consent prior to any study related
procedures and to comply with all study requirements

Exclusion Criteria:

- Active secondary malignancy, unless the malignancy is not expected to interfere with
the evaluation of safety and is approved by the Medical Monitor; examples include
basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and
isolated elevation of prostate-specific antigen; patients with a completely treated
prior malignancy with no evidence of disease for >= 2 years are eligible

- Investigational drug use within 28 days of C1D1

- Chemotherapy, targeted therapy, growth factors or radiation therapy within 14 days of
C1D1

- Systemic steroid therapy or any other form of immunosuppressive therapy within 14 days
prior to registration

- History of any of the following toxicities associated with a prior immunotherapy:

- Grade > 3 immune mediated adverse event that was considered related to previous
immunotherapy and required immune suppressive therapy

- Immune mediated adverse event that was considered related to previous
immunotherapy and is still > grade 1 with immune suppressive therapy

- Patients with active central nervous system (CNS) lesions are excluded (i.e., those
with radiographically unstable, symptomatic lesions); however, patients treated with
stereotactic therapy or surgery are eligible if they remain without evidence of
disease progression in the brain for >= 3 weeks

- Major surgery within 28 days of registration

- Has received a live vaccine within 28 days prior to registration

- Active and clinically significant bacterial, fungal or viral infection including
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or
acquired immunodeficiency syndrome (AIDS) related illness (human immunodeficiency
virus [HIV] testing is not required), including patients who have an active infection
requiring systemic therapy

- Any of the following within the 12 months prior to registration: myocardial
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident or transient ischemic attack

- Uncontrolled intercurrent illness

- History of active ethanol abuse

- Patients who are imprisoned or under legal guardianship

- The presence of a medical or psychiatric condition that, in the opinion of the
principal investigator, makes the patient inappropriate for inclusion in this study