Randomized Phase II/III Study of Nivolumab plus Ipilimumab plus Sargramostim versus Nivolumab plus Ipilimumab in Patients with Unresectable Stage III or Stage IV Melanoma (EA6141)

This phase II/III trial studies the side effects of nivolumab and ipilimumab when given
together with or without sargramostim and to see how well they work in treating patients with
stage III-IV melanoma that cannot be removed by surgery (unresectable) and that may have
spread from where it first started to nearby tissue, lymph nodes, or distant parts of the
body (advanced). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab,
may help the body's immune system attack the cancer, and may interfere with the ability of
tumor cells to grow and spread. Colony-stimulating factors, such as sargramostim, may
increase the production of white blood cells. It is not yet known whether nivolumab and
ipilimumab are more effective with or without sargramostim in treating patients with
melanoma.

Inclusion Criteria:

- All patients must be >= 18 years of age

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

- Patients must have known BRAF mutational status of tumor; wild-type (WT) or mutated,
prior to randomization

- Patients must not be pregnant or breast-feeding due to use of cytotoxic immunotherapy
and risk of teratogenic side effects; all patients of childbearing potential must have
a blood test or urine study within 2 weeks prior to randomization to rule out
pregnancy; a patient of childbearing potential is anyone, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- Patients must not conceive or father children by using accepted and effective
method(s) of contraception or by abstaining from sexual intercourse from the time of
study registration and continuing (for patients of child bearing potential) for at
least 5 months after the last dose of protocol treatment; patients of childbearing
potential must also not donate eggs during this same time period

- Patients must have unresectable stage III or stage IV melanoma according to American
Joint Committee on Cancer (AJCC) version (v)7; patients must have histological or
cytological confirmation of melanoma that is metastatic or unresectable and clearly
progressive

- Patients must have measurable disease per RECIST 1.1 criteria; all sites of disease
must be evaluated within 4 weeks prior to randomization

- Patients may have had prior systemic therapy in the adjuvant setting (e.g. interferon,
BRAF, or MEK agents). Patients may have had prior anti-CTLA-4 in the adjuvant setting,
if at least one year from last dose of treatment has passed prior to beginning
treatment. Patients may have had any prior anti-PD-1 or anti-PD-L1 agent in the
adjuvant setting, if at least one year from last dose of treatment has passed prior to
beginning treatment

- Patients may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the
metastatic setting

- Patients must have discontinued chemotherapy, immunotherapy or other investigational
agents used in the adjuvant setting >= 4 weeks prior to randomization and recovered
from adverse events due to those agents; mitomycin and nitrosoureas must have been
discontinued at least 6 weeks prior to entering the study; patients must have
discontinued radiation therapy >= 2 weeks prior to entering the study and recovered
from any adverse events associated with treatment; prior surgery must be >= 4 weeks
from randomization and patients must be fully recovered from post-surgical
complications

- Patients must not receive any other investigational agents while on study or within
four weeks prior to randomization

- Patient must not have received any live vaccine within 30 days prior to randomization,
while participating in the study, and for 4 weeks (28 days) after the last dose of
protocol treatment; live vaccines include, but are not limited to, the following:
measles, mumps, rubella, chicken pox, yellow fever, rabies, bacillus Calmette-Guerin
(BCG), and typhoid (oral) vaccine; patients are permitted to receive inactivated
vaccines and any non-live vaccines including those for the seasonal influenza and
coronavirus disease 19 (COVID-19) (Note: intranasal influenza vaccines, such as
Flu-Mist (registered trademark) are live attenuated vaccines and are not allowed); if
possible, it is recommended to separate study drug administration from vaccine
administration by about a week (primarily, in order to minimize an overlap of adverse
events)

- Patients are ineligible if they have any currently active central nervous system (CNS)
metastases; patients who have treated brain metastases (with either surgical resection
or stereotactic radiosurgery) that have been stable on head magnetic resonance imaging
(MRI) or contrast computed tomography (CT) scan for at least 4 weeks following
treatment and within 4 weeks prior to randomization are eligible; patients must not
have taken any steroids =< 14 days prior to randomization for the purpose of managing
their brain metastases; patients with only whole brain irradiation for treatment of
CNS metastases will be ineligible

- Patients must not have other current malignancies, other than basal cell skin cancer,
squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in
situ of the breast; patients with other malignancies are eligible if they have been
continuously disease-free for > 3 years prior to the time of randomization

- White blood count >= 3,000/uL (obtained within 4 weeks prior to randomization)

- Absolute neutrophil count (ANC) >= 1,500/uL (obtained within 4 weeks prior to
randomization)

- Platelet count >= 100,000/uL (obtained within 4 weeks prior to randomization)

- Hemoglobin >= 9 g/dL (obtained within 4 weeks prior to randomization)

- Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance
(CrCl) >= 40 ml/min (obtained within 4 weeks prior to randomization)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5 x
ULN for patients with documented liver metastases) (obtained within 4 weeks prior to
randomization)

- Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement
and =< 7 x ULN for patients with known bone involvement) (obtained within 4 weeks
prior to randomization)

- Total bilirubin =< 1.5 x ULN except patients with normal direct bilirubin; those
patients with known Gilbert's syndrome must have total bilirubin < 3 x ULN (obtained
within 4 weeks prior to randomization)

- Serum lactate dehydrogenase (LDH) =< 10 X ULN (obtained within 4 weeks prior to
randomization)

- Patients must not have any serious or unstable pre-existing medical conditions (aside
from malignancy exceptions specified above), including but not limited to, ongoing or
active infection requiring parenteral antibiotics on day 1, history of bleeding
diathesis or need for concurrent anticoagulation (international normalized ratio [INR]
=< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), or psychiatric
illness/social situations that would limit compliance with study requirements,
interfere with patient's safety, or obtaining informed consent

- Patients with human immunodeficiency virus (HIV) infection are ineligible; due to the
mechanism of action of ipilimumab and GM-CSF, activity and side effects in an immune
compromised patient are unknown

- Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV)
infection are not eligible; patients with cleared HBV and HCV (0 viral load) infection
will be allowed

- Patients must not have autoimmune disorders or conditions of immunosuppression that
require current ongoing treatment with systemic corticosteroids (or other systemic
immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or
continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
history of occasional (but not continuous) use of steroid inhalers is allowed;
replacement doses of steroids for patients with adrenal insufficiency are allowed;
patients who discontinue use of these classes of medication for at least 2 weeks prior
to randomization are eligible if, in the judgment of the treating physician
investigator, the patient is not likely to require resumption of treatment with these
classes of drugs during the study

- Exclusion from this study also includes patients with a history of symptomatic
autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
[scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune vasculitis
[e.g., Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin
(e.g., Guillain-Barre syndrome and myasthenia gravis); other CNS autoimmune disease
(e.g., multiple sclerosis)

- Patients with autoimmune hypothyroid disease or type I diabetes on replacement
treatment are eligible

- Patients must not have a history of inflammatory bowel disease or diverticulitis
(history of diverticulosis is allowed)

- Patients must not have other significant medical, surgical, or psychiatric conditions
or require any medication or treatment that in the opinion of the investigator may
interfere with compliance, make the administration of the study drugs hazardous or
obscure the interpretation of adverse events (AEs), such as a condition associated
with frequent diarrhea; patients must not have an active infection requiring current
treatment with parenteral antibiotics