Ipilimumab With or Without Sargramostim in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To evaluate the overall survival for the combination of GM-CSF (sargramostim) plus
ipilimumab and ipilimumab alone in patients with advanced melanoma.

SECONDARY OBJECTIVES:

I. To evaluate the progression-free survival, response rate, safety and tolerability for the
combination of GM-CSF plus ipilimumab and ipilimumab alone in patients with advanced
melanoma.

II. To explore the utility of immune related response criteria (irRC) prospectively in
patients receiving ipilimumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive induction therapy comprising ipilimumab intravenously (IV) over 90
minutes on day 1 and sargramostim subcutaneously (SC) once daily on days 1-14. Treatment
repeats every 21 days for 4 courses. After 12 weeks of induction treatment, anti-tumor
response is assessed and patients then receive maintenance therapy comprising ipilimumab IV
over 90 minutes on day 1 and sargramostim SC once daily on days 1-14. Treatment with
ipilimumab repeats every 12 weeks and treatment with sargramostim repeats every 21 days.
After 12 weeks of maintenance therapy, anti-tumor response is reassessed and patients with
responsive or stable disease then continue maintenance therapy until disease progression or
unacceptable toxicity.

ARM B: Patients receive induction therapy comprising ipilimumab IV over 90 minutes on day 1.
Treatment repeats every 21 days for 4 courses. After 12 weeks of induction treatment,
anti-tumor response is assessed and patients then receive maintenance therapy of ipilimumab
IV over 90 minutes on day 1. Treatment with ipilimumab repeats every 12 weeks. After 12 weeks
of maintenance therapy, anti-tumor response is reassessed and courses repeat every 12 weeks
in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- All sites of disease must be evaluated within 4 weeks prior to randomization; patients
must have measurable disease as defined by Response Evaluation Criteria in Solid
Tumors (RECIST)

- No more than one prior systemic therapeutic regimen for unresectable stage III or
stage IV melanoma; this includes chemotherapy, biologic therapy, biochemotherapy, or
investigational treatment; this does not include any therapies given in the adjuvant
setting

- Histologic diagnosis of metastatic melanoma; for unknown primary disease, diagnosis of
metastatic disease by cytology fine needle aspiration (FNA) is not acceptable

- Women must not be pregnant or breast-feeding; all women of childbearing potential must
have a blood test within 72 hours prior to randomization to rule out pregnancy; women
of childbearing potential and sexually active males must be strongly advised to use an
accepted and effective method of contraception; women of childbearing potential
(WOCBP) must be using an adequate method of contraception to avoid pregnancy
throughout the study and for up to 12 weeks after the last dose of investigational
product, in such a manner that the risk of pregnancy is minimized; sexually mature
females who have not undergone a hysterectomy or who have not been postmenopausal
naturally for at least 24 consecutive months (i.e., who have had menses at some time
in the preceding 24 consecutive months) are considered to be of childbearing
potential; women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or mechanical
products such as an intrauterine device or barrier methods (diaphragm, condoms,
spermicides) to prevent pregnancy, or are practicing abstinence or where their partner
is sterile (e.g., vasectomy) should be considered to be of childbearing potential

- White blood cells (WBC) >= 2000/uL

- Absolute neutrophil count (ANC) >= 1500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8 g/dL

- Creatinine =< 3.0 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

- Bilirubin =< 3.0 x ULN, (except patients with Gilbert's syndrome, who must have a
total bilirubin less than 3.0 mg/dL)

- No concomitant therapy with any of the following: interleukin (IL) 2, interferon, or
other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive
agents; other investigation therapies; or chronic use of systemic corticosteroids;
must have been discontinued >= 4 weeks

- No infection with human immunodeficiency virus (HIV)

- No active infection with hepatitis B

- No active or chronic infection with hepatitis C

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

Exclusion Criteria:

- Patients with any history of central nervous system (CNS) metastases are excluded

- Patients are excluded if they have a history of any other malignancy from which the
patient has been disease-free for less than 2 years, with the exception of adequately
treated and cured basal or squamous cell skin cancer, superficial bladder cancer or
carcinoma in situ of the cervix

- Patients are excluded if they have a history of any autoimmune disease; patients with
a history of autoimmune thyroiditis are eligible if their current thyroid disorder is
treated and stable with replacement or other medical therapy

- Patients are excluded for any underlying medical or psychiatric condition, which in
the opinion of the investigator, will make the administration of study drug hazardous
or obscure the interpretation of adverse events, such as a condition associated with
frequent diarrhea

- 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

- Patients are excluded if they have a history of prior treatment with ipilimumab or
prior cluster of differentiation (CD)137 agonist or cytotoxic T-lymphocyte antigen 4
(CTLA-4) inhibitor or agonist

- Any concurrent medical condition requiring the use of systemic steroids is not
permitted (the use of inhaled or topical steroids is permitted)