Subjects with Stage III resectable melanoma will receive one dose of nivolumab 480 mg IV,
then undergo standard definitive surgery approximately 4 weeks after the initial dose of
nivolumab. Post-operatively, subjects will receive open-label treatment with up to 1 year of
adjuvant nivolumab 480 mg IV every 4 weeks or ipilimumab plus nivolumab, as determined by
pathologic response at the time of resection. Subjects with pathologic complete response or
near pathologic complete response (PathCR/nearCR) (Arm A) receive adjuvant nivolumab for up
to one year. Subjects with <PathCR/nearCR are randomized 1:2 to either adjuvant nivolumab
(480 mg) for up to one year (Arm B) or adjuvant ipilimumab (1mg/kg) plus nivolumab (3mg/kg)
for 4 doses and then nivolumab (480 mg) alone for a total of one year (Arm C).
- The subject must have clinical stage III resectable melanoma per investigator.
Subjects may not have a diagnosis of uveal or mucosal melanoma.
- Either the subject or the subject's legally authorized representative must be willing
and able to provide written informed consent before the performance of any
- The subject must be ≥18 years of age on day of signing informed consent.
- The subject must have a performance status of 0 or 1 on the ECOG Performance Scale.
- The subject must demonstrate adequate organ function as defined in Table 1; all
screening labs must be performed within 28 days of treatment initiation.
- Hematologic System: Absolute neutrophil count (ANC) ≥1500/mcL; Platelets
≥100,000/mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
- Renal System: Serum creatinine OR measured or calculated creatinine clearance
(GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of
normal (ULN) OR ≥50 mL/min for subject with creatinine levels >1.5 X
- Hepatic System: Serum total bilirubin ≤1.5 X ULN OR Direct bilirubin ≤ ULN for
subjects with total bilirubin levels >1.5 ULN; AST (SGOT) and ALT (SPGT) ≤2.5 X
ULN OR ≤5 X ULN for subjects with liver metastases
- A female participant is eligible to participate if she is not pregnant (see Appendix
3), not breastfeeding, and at least one of the following conditions applies: A.) Not a
woman of childbearing potential (WOCBP) as defined in Appendix 3 OR B.) A WOCBP who
agrees to follow the contraceptive guidance in Appendix 3 during the treatment period
and is willing to use a highly effective method of contraception or abstain from
heterosexual intercourse for at least 2 weeks prior to the time of first dose of study
medication through 5 months after the last dose of study medication.
- Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
- Male subjects must agree to follow the contraceptive guidance in Appendix 3 starting
with the first dose of study medication, while on study, through 7 months after the
last dose of study medication.
- Subject has unresectable disease; i.e. in the opinion of the surgical oncologist, all
of the subject's melanoma cannot be completely removed with a clear margin.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX 40, CD137), interferon, high dose IL-2 or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways.
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to the first dose of study drug. Note: Participants must have
recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants
with ≤Grade 2 neuropathy are an exception to this criterion.
- If participant received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting study treatment.
- Subject has received transfusion of blood products (including platelets or red blood
cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or
recombinant erythropoietin) within 4 weeks to the first dose of study drug.
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has a known additional malignancy that is progressing or requires active treatment.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of
the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that
have undergone potentially curative therapy are not excluded.
- Has active autoimmune disease that has required systemic treatment in the past 3
months (i.e. with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment.
- Has evidence of active interstitial lung disease or a history of (non-infectious)
pneumonitis that required steroids or has current pneumonitis.
- Has an active infection requiring systemic therapy.
- Patients known to be positive for Human Immunodeficiency Virus (HIV) if they have a
CD4 count of less than 350 mm3 and a serum HIV viral load > 25,000 IU/mL
- Has active Hepatitis B infection or active Hepatitis C virus infection as determined
by medical record review.
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 5 months,
if female, or 7 months, if male, after the last dose of investigational drug.
- Prisoners or subjects who are involuntarily incarcerated.
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.