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

PRIMARY OBJECTIVES:

I. To compare overall survival for patients receiving ipilimumab plus bevacizumab versus
ipilimumab alone.

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival, response rate and safety in patients receiving
ipilimumab plus bevacizumab versus ipilimumab alone.

II. To evaluate the utility of immune related response criteria (irRC) in patients receiving
ipilimumab plus bevacizumab versus ipilimumab alone.

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

ARM A:

INDUCTION THERAPY: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1.
Treatment repeats every 21 days for 4 courses in the absence of disease progression or
unacceptable toxicity.

MAINTENANCE THERAPY: Beginning course 8, patients receive ipilimumab IV over 90 minutes on
day 1. Courses repeat every 12 weeks in the absence of disease progression or unacceptable
toxicity.

ARM B:

INDUCTION THERAPY: Patients receive ipilimumab IV over 90 minutes and bevacizumab IV over
30-90 minutes on day 1. Treatment repeats every 21 days for 4 courses in the absence of
disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive bevacizumab as in Induction Therapy. Beginning course
8, patients also receive ipilimumab IV over 90 minutes on day 1. Courses repeat every 12
weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Inclusion Criteria:

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

- Untreated or previously received one treatment regimen for measurable unresectable
stage III or stage IV melanoma (American Joint Committee on Cancer [AJCC] 2010) (for
BRAF wild-type, and regardless of human leukocyte antigen [HLA] type); untreated or
previously received up to two treatment regimens for measurable unresectable stage III
or stage IV melanoma (AJCC 2010) (for BRAF mutant, and regardless of HLA type; If 2
prior regimens, one should be a BRAF inhibitor); this does not include any therapies
given in the adjuvant setting

- Prior treatment (chemotherapy [chemo], radiation, hormone, and immune therapies) must
be completed > 4 weeks prior to randomization (> 6 weeks prior to randomization for
nitrosoureas, mitomycin C, and checkpoint inhibitors)

- Patients who received prior therapy with anthracyclines should have a baseline
multigated acquisition scan (MUGA) or echocardiogram (echo) with a normal ejection
fraction within 28 days prior to randomization

- Patients must have recovered from any acute toxicity associated with prior therapy by
the start of study treatment

- Women must not be pregnant or breast-feeding; 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)

- All sites of disease must be evaluated within 4 weeks prior to randomization; patients
must have measurable disease

- White blood cell (WBC) >= 2000/uL (obtained within 4 weeks prior to randomization)

- Absolute neutrophil count (ANC) >= 1000/uL (obtained within 4 weeks prior to
randomization)

- Platelets >= 75 x 10^3/uL (obtained within 4 weeks prior to randomization)

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

- Creatinine =< 2.0 x upper limit of normal (ULN) (obtained within 4 weeks prior to
randomization)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN for
patients without liver metastases and =< 5 x ULN for patients with liver metastases
(obtained within 4 weeks prior to randomization)

- Serum bilirubin =< 2.0 x ULN (except patients with Gilbert's syndrome, who must have a
total bilirubin less than 3.0 mg/dL) (obtained within 4 weeks prior to randomization)

- Patients BRAF mutation status must be known

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

- No infection with human immunodeficiency virus (HIV)

- No active infection with hepatitis B

- No active or chronic infection with hepatitis C

- Patients are ineligible if they have any history of central nervous system (CNS)
metastases

- Patients are ineligible 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 ineligible if they have a history of autoimmune disease, as follows:
patients with a history of inflammatory bowel disease are excluded from this study as
are patients with a history of symptomatic disease (e.g., rheumatoid arthritis,
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
vasculitis [e.g., Wegener's granulomatosis]); patients with motor neuropathy
considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis)
are excluded; 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 ineligible if they have an active infection

- Patients are ineligible if they have a history of prior treatment with ipilimumab,
bevacizumab, or prior tumor CD137 agonist or CTLA-4 inhibitor or agonist; patients may
be treatment naive or have had one prior systemic therapy for metastatic disease as
outlined in the eligibility criteria; patients may have received PD-1 or PD-L1 as per
current protocol eligibility, although they are not currently commercially approved in
the front line setting

- Patients are ineligible if they have a history of any underlying medical or
psychiatric conditions or require any medications or treatment that in the opinion of
the principal investigator may interfere with compliance, make the administration of
study drug hazardous or obscure the interpretation of adverse events, such as a
condition associated with frequent diarrhea

- Patients are ineligible if they have any concurrent medical condition requiring the
use of systemic steroids; (use of inhaled or topical steroids is acceptable)

- Patients are ineligible if they have inadequately controlled hypertension (defined as
systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on
antihypertensive medications)

- Patients are excluded if they have any prior history of hypertensive crisis or
hypertensive encephalopathy

- Patients are excluded if they have New York Heart Association (NYHA) grade II or
greater congestive heart failure

- Patients are excluded if they have a history of myocardial infarction or unstable
angina within 6 months prior to randomization

- Patients are excluded if they have a history of stroke or transient ischemic attack
within 6 months prior to randomization

- Patients are excluded if they have known significant vascular disease (e.g., aortic
aneurysm, aortic dissection)

- Patients are excluded if they have symptomatic peripheral vascular disease

- Patients are excluded if they have evidence of bleeding diathesis or coagulopathy

- Patients are excluded if they have had a surgical procedure or a significant traumatic
injury within 28 days prior to randomization

- Patients are excluded if they have had a biopsy or other minor surgical procedure,
excluding placement of a vascular access device, within 7 days prior to randomization

- Patients are excluded if they have history of abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 6 months prior to randomization

- Patients are excluded if they have a non-healing wound or ulcer

- Patients are excluded if they have proteinuria at screening as demonstrated by either:

- Urine dipstick for proteinuria >= 2+ (patients discovered to have >= 2+
proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine
collection and must demonstrate =< 1 g of protein in 24 hours to be eligible) OR

- Urine protein: creatinine (UPC) ratio >= 1.0 at screening; for UPC ratio > 1, a
24 hour urine protein should be obtained and the level should be < 1000mg; NOTE:
urine protein should be screened by urine analysis for UPC ratio; a UPC ratio of
1 is roughly equivalent to a 24-hour urine protein of 1 g

- Patients must not have known hypersensitivity to Chinese hamster ovary cell products
or other recombinant human antibodies

- Patients are excluded if they have a history of hemoptysis (bright red blood of 1/2
teaspoon or more per episode) within 3 months prior to randomization

- Patients are excluded if they have current, ongoing treatment with full-dose warfarin
or its equivalent (i.e., unfractionated and/or low molecular weight heparin); subjects
should have not taken full-dose warfarin or equivalent for at least 2 weeks prior to
randomization

- Patients are excluded if they have current or recent (within 10 days of enrollment)
use of aspirin (> 325 mg/day) or chronic use of other non-steroidal anti-inflammatory
drugs (NSAID)

- Patients are excluded if they use medications that inhibit platelet function (e.g.,
dipyridamole, epoprostenol, eptifibatide, clopidogrel, cilostazol, abciximab,
ticlopidine, and ibuprofen and related compounds) unless subject has been off
treatment for at least 2 weeks prior to randomization

- Patients are excluded if they have known involvement of melanoma within the
gastrointestinal tract

- Patients are excluded for any non-oncology vaccine therapy used for prevention of
infectious diseases (for up to 1 month before or after any dose of ipilimumab)

- Women of childbearing potential and sexually active males must agree to practice
abstinence or use an accepted and effective method of contraception