This pilot phase I trial studies how well VX15/2503 (pepinemab) with or without ipilimumab
and/or nivolumab work in treating participants with stage IIIB-D melanoma that can be removed
by surgery. Monoclonal antibodies, such as VX15/2503, ipilimumab, and nivolumab may interfere
with the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVE:
I. Evaluate the effect of VX15/2503 (pepinemab) in combination with immune checkpoint
inhibitors on T cell infiltrate into the tumor microenvironment in involved and uninvolved
lymph nodes and peripheral blood.
SECONDARY OBJECTIVES:
I. Evaluate the effect of VX15/2503 in combination with immune checkpoint inhibitors on the
immune profile of involved and uninvolved lymph nodes and peripheral blood.
II. Assess safety and tolerability of profile and tolerability of single agent VX15/2503 to
the combination of VX15/2503 and immune checkpoint inhibitors in patients with resectable
metastatic melanoma.
III. Document pathologic response rates of single agent VX15/2503 and combination VX15/2503
and immune checkpoint inhibitors in patients with resectable melanoma.
IV. Compare pathologic response to radiographic response using Response Evaluation Criteria
in Solid Tumors (RECIST) criteria in patients receiving single agent VX15/2503 and
combination VX15/2503 and immune checkpoint inhibitors in patients with resectable melanoma.
OUTLINE: Participants are assigned to 1 of 5 arms.
ARM I: Participants receive VX15/2503 intravenously (IV) over 60 minutes and nivolumab IV
over 30 minutes on days 1 and 21 and undergo surgery between days 35-49.
ARM II: Participants receive VX15/2503 IV over 60 minutes and ipilimumab IV over 30 minutes
on days 1 and 21 and undergo surgery between days 35-49.
ARM III: Participants receive VX15/2503 IV over 60 minutes, nivolumab IV over 30 minutes, and
ipilimumab IV over 30 minutes on days 1 and 21 and undergo between days 35-49.
ARM IV: Participants nivolumab IV over 30 minutes on days 1 and 21 and undergo between days
35-49.
ARM V: Participants undergo surgery.
After completion of study treatment, participants are followed up at 90 days, every 12 weeks
for 2 years, every 6 months for 3 years, then annually up to 10 years.
Inclusion Criteria:
- Stage IIIB, IIIC, IIID histologically-proven melanoma.
- Cancer confirmed to be surgically resectable, with surgery evaluation with
planned prior to resection.
- No prior immunotherapy with cytotoxic T-lymphocyte associated protein-4 (CTLA-4),
anti programmed cell death-1 (PD-1) or VX15/2503. Prior interferon (at least 1
year prior to consent) will be allowed.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Absolute neutrophil count ≥ 1,500 cells/µL.
- Platelets ≥ 100,000/µL.
- Hemoglobin ≥ 9.0g/dL (may receive packed red blood cells [PRBC] transfusion).
- Total bilirubin ≤ 1.5 x the upper limit of normal (ULN).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN.
- Albumin ≥ 3.0 g/dL.
- Serum creatinine ≤ 1.5 x ULN OR calculated creatinine clearance of ≥ 50 mL/min using
Cockcroft-Gault formula.
- International normalized ration (INR) ≤ 1.5. Anticoagulation is allowed only with low
molecular weight heparin (LMWH). Patient receiving LMW heparin on stable therapeutic
dose for more than 2 weeks or with factor Xa level < 1.1 U/mL are allowed on the
trial.
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.
- Ability to understand and willingness to sign a written informed consent document.
- Female subjects of childbearing potential must agree to use adequate contraception (at
least one highly effective method and one additional method of birth control at the
same time or complete abstinence) prior to study entry, for the duration of study
treatment and 5 months after last dose of study treatment.
- Male subjects must agree to use adequate contraception (at least one highly effective
method and one additional method of birth control at the same time or complete
abstinence) prior to study entry, for the duration of study treatment and 7 months
after last dose of study treatment.
- Female subjects of childbearing age must have a negative serum pregnancy test at study
entry.
Exclusion Criteria:
- Determined not to be a surgical candidate due to medical co-morbidities.
- Treatment with chronic immunosuppressants (e.g., cyclosporine following
transplantation).
- Prior organ allograft or allogeneic bone marrow transplantation.
- Subjects with active or history of immune mediated pneumonitis, colitis, hepatitis,
endocrinopathy, nephritis, or skin reactions as these patients may be at increased
risk for developing immune therapy-induced exacerbation or recurrence of their immune
mediated disease, potentially delaying surgery.
- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in the absence of active
autoimmune disease.
- Women who are pregnant or lactating.
- Uncontrolled intercurrent illness including, but not limited to, human
immunodeficiency virus (HIV)-positive subjects receiving combination antiretroviral
therapy, ongoing or active infection, symptomatic congestive heart failure (NYHA class
III or IV), unstable angina pectoris, ventricular arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.
- Other medications, or severe acute/chronic medical or psychiatric condition, or
laboratory abnormality that may increase the risk associated with study participation
or study drug administration, or may interfere with the interpretation of study
results, and in the judgment of the investigator would make the subject inappropriate
for entry into this study.
- Clinical evidence of bleeding diathesis or coagulopathy.
- Patients with prior malignancies, including pelvic cancer, are eligible if they have
been disease free for > 5 years. Patients with prior non-melanoma skin cancers and in
situ carcinomas are eligible provided there was complete removal.
- Active bacterial or fungal infections requiring systemic treatment within 7 days of
treatment.
- Use of other investigational drugs (drugs not marked for any indication) within 28
days or at least 5 half-lives (whichever is longer) before study drug administration.
- History of severe hypersensitivity reactions to other monoclonal antibodies.
- Non-oncology vaccines within 28 days prior to or after any dose of ipilimumab.
- Prisoners and subjects who are compulsory detained.
- Patients with rapidly progressive disease.
