PRIMARY OBJECTIVE:
I. To compare the overall survival (OS) of nivolumab/ipilimumab/sargramostim (GM-CSF) versus
nivolumab/ipilimumab.
SECONDARY OBJECTIVES:
I. To evaluate progression free survival (PFS) of patients treated with
nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.
II. To assess for differences in tolerability, specifically the rate of grade III or higher
adverse events, between nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.
III. To evaluate immune-related response rate (based on immune-related response criteria) and
response rate (based on Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and
to compare them.
EXPLORATORY TOBACCO USE OBJECTIVES:
I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other
forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported
cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose
modifications).
II. To determine the effects of tobacco on patient-reported physical symptoms and
psychological symptoms.
III. To examine quitting behaviors and behavioral counseling/support and cessation medication
utilization.
IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose
intensity, and therapeutic benefit.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 30 minutes on
day 1, ipilimumab IV over 30 minutes on day 1, and sargramostim subcutaneously (SC) on days
1-14. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or
unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in induction therapy.
Patients with partial response (PR), stable disease (SD), or complete response (CR) at 24
weeks may continue maintenance therapy for up to 2 years in the absence of disease
progression or unacceptable toxicity.
ARM B: INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment
repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable
toxicity.
MAINTENANCE THERAPY: Patients receive nivolumab as in induction therapy. Patients with PR,
SD, or CR at 24 weeks may continue maintenance therapy for up to 2 years in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.
Inclusion Criteria:
- 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
- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception or to abstain from sexual
intercourse for at least one week prior to the start of the research study, and
continuing for 5 months for women of childbearing potential and 7 months for sexually
active males after the last dose of the study drugs
- Patients must have unresectable stage III or stage IV melanoma; 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 mitogen-activated protein kinase [MEK] agents); patients may have had prior
anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) 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 programmed cell death (PD)-1/PD-ligand (PD-L)1 agent in the
adjuvant 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
- 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 subjects with normal direct bilirubin or those
with known Gilbert's syndrome (obtained within 4 weeks prior to randomization)
- Serum lactate dehydrogenase (LDH) =< 10 X ULN (obtained within 4 weeks prior to
randomization)
- Patients with autoimmune hypothyroid disease or type I diabetes on replacement
treatment are eligible
Exclusion Criteria:
- Women must not be pregnant or breast-feeding due to use of cytotoxic immunotherapy and
risk of teratogenic side effects; all females of childbearing potential must have a
blood test or urine study within 2 weeks prior to randomization to rule out pregnancy;
a female of childbearing potential is any woman, 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 may not have had any prior ipilimumab and/or anti-PD-1/PD-L1 agent in the
metastatic setting
- Patients must not receive any other investigational agents while on study or within
four weeks prior to randomization
- Patients are excluded for receiving any non-oncology vaccine therapy used for
prevention of infectious diseases for up to four weeks (28 days) prior to or after any
dose of ipilimumab; NOTE: Patients are permitted to receive inactivated vaccines and
any non live vaccines including those for the seasonal influenza and coronavirus
disease 19 (COVID-19)
- 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
- 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 subject'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 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
