Pilot Ipilimumab in Stage IV Melanoma Receiving Palliative Radiation Therapy

This is a single institution, open-label, pilot study of palliative radiation therapy (RT)
combined with ipilimumab in patients with stage IV melanoma. The primary objective of this
study is to assess the safety of combining ipilimumab with palliative RT in patients with
Stage IV melanoma. Secondary objectives are a) to assess the induction of anti-melanoma
immune responses using laboratory correlative studies of T cell responses to melanoma
antigens, and b) to compare tumor response rates and duration of response at unirradiated
sites with responses in patients with Stage IV disease treated with ipilimumab alone on
expanded access study CA184045. In this study, ipilimumab will be administered as recently
approved by the FDA (3 mg/kg iv every 3 weeks for a total of 4 treatments). Palliative RT
will start within 2 days of the first ipilimumab dose. Patients will be seen at least every
12 weeks for follow-up following completion of ipilimumab therapy until progression of
disease by imaging criteria or increased symptomatology that requires another therapy. A
total of 20 patients with previously treated unresectable metastatic melanoma requiring
palliative radiation therapy will be treated on this pilot study over approximately 18
months. All subjects who receive study drug will be monitored for safety. Relevant tumor
imaging studies will be obtained at baseline, 2-4 weeks following the 4th/last dose of
ipilimumab, and then every 12 weeks until disease progression. This study will provide the
safety data (and possibly early efficacy signals) needed to proceed with a randomized Phase
II study for proof of principle. If compelling data is obtained supporting this IT + RT
vaccine strategy, this approach will be extended to other solid tumor types.

Inclusion Criteria:

1. Signed Written Informed Consent

Before any study procedures are performed, subjects (or their legally acceptable
representatives) will have the details of the study described to them, and they will
be given a written informed consent document to read. Then, if subjects consent to
participate in the study, they will indicate that consent by signing and dating the
informed consent document in the presence of study personnel.

2. Target Population

- Histologically confirmed Stage IV melanoma.

- Must have failed at least one systemic therapy for malignant melanoma or be
intolerant to at least one prior systemic treatment.

- Subjects with asymptomatic brain metastases are eligible. (Systemic steroids
should be avoided if possible, or the subject should be stable on the lowest
clinically effective dose, as steroids as they may interfere with the activity of
ipilimumab if administered at the time of the first ipilimumab dose.)

- Primary ocular and mucosal melanomas are allowed.

- Must be at least 28 days since treatment with chemotherapy, biochemotherapy,
surgery, radiation, or immunotherapy, and recovered from any clinically
significant toxicity experienced during treatment.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

- Life expectancy of ≥ 16 weeks.

- Subjects must have baseline (screening/baseline) radiographic images, (e.g.
brain, chest, abdomen, pelvis, and bone scans with specific imaging tests to be
determined by the attending physician) within 6 weeks of initiation of
ipilimumab.

- Required values for initial laboratory tests:

- White blood cell (WBC) ≥ 2000/uL (~ 2 x 10^9/L)

- Absolute neutrophil count (ANC) ≥ 1000/uL (~ 1 x 10^9/L)

- Platelets ≥ 75 x 10^3/uL (~ 75 x 10^9/L)

- Hemoglobin ≥ 9 g/dL (~ 80 g/L; may be transfused)

- Creatinine ~ 2 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ~ 2.5 x
ULN for subjects without liver metastasis ~ 5 times for liver metastases

- Bilirubin: ~ 2.0 x ULN (except for subjects with Gilbert's Syndrome, who must
have a total bilirubin of < 3.0 mg/dL)

- No active or chronic infection with HIV, Hepatitis B, or Hepatitis C.

- Two or more measurable sites of disease (≥ 1.5 cm) which include the disease site
that requires palliative radiation therapy as well as ≥ 1 other disease site
outside of the planned radiation therapy field.

3. Age and Sex

- Men and women, at least 18 years of age.

- Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study [and for up to 26 weeks
after the last dose of investigational product] in such a manner that the risk of
pregnancy is minimized.

- WOCBP include any female who has experienced menarche and who has undergone
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal. Post-menopausal is defined as:

- Amenorrhea ≥ 12 consecutive months without another cause, or

- For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level >
35 mIU/mL

- 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 (eg, vasectomy) should be considered to be of childbearing
potential. WOCBP must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the
start of investigational product.

c) Men of fathering potential must be using an adequate method of contraception
to avoid conception throughout the study [and for up to 26 weeks after the last
dose of investigational product] in such a manner that the risk of pregnancy is
minimized.

Exclusion Criteria:

1. Sex and Reproductive Status

- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy
for the entire study and for up to 8 weeks after the last dose of investigational
product.

- WOCBP using a prohibited contraceptive method.

- Women who are pregnant or breastfeeding.

- Women with a positive pregnancy test on enrollment or before investigational
product administration.

2. Target Disease Exceptions

- Subjects on any other systemic therapy for cancer, including any other
experimental treatment.

- Prior treatment with an anti-CTLA-4 antibody if treatment failure was due to
adverse events (AEs). If a subject was discontinued from the prior anti-CTLA-4
treatment due to an AE or serious adverse event (SAE), regardless of the type of
event, that discontinuation constitutes an exclusion criterion. If AEs were
serious enough to require a subject's withdrawal from prior treatment, the
subject should be excluded from this study.

- A history of AEs with prior IL-2 or Interferon will not preclude subjects from
entering the current study.

- Subjects who relapsed in study MDX010-16 are not eligible for this study.

3. Medical History and Concurrent Diseases

- Autoimmune disease: subjects with a documented history of inflammatory bowel
disease, including ulcerative colitis and Crohn's disease are excluded from this
study as are subjects with a history of symptomatic disease (eg, rheumatoid
arthritis, systemic progressive sclerosis [scleroderma]; systemic lupus
erythematosus (SLE); autoimmune vasculitis [eg, Wegener's Granulomatosis]).
Subjects with motor neuropathy considered of autoimmune origin (eg,
Guillain-Barre Syndrome and Myasthenia Gravis) are excluded from this study.

- Any subject who has a life-threatening condition that requires high-dose
immunosuppressant(s)

- Presence of known Hepatitis B or Hepatitis C infection, regardless of control on
antiviral therapy

- Subjects with melanoma who have another active, concurrent, malignant disease are
not eligible for the CA184045 study, with the exception of subjects with
adequately treated basal or squamous cell skin cancer, superficial bladder
cancer, or carcinoma in situ of the cervix.

4. Medical History and Concurrent Diseases

- Prisoners or subjects who are involuntarily incarcerated.

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.

- Any underlying medical or psychiatric condition that, in the opinion of the
investigator, could make the administration of ipilimumab hazardous or could
obscure the interpretation of adverse events.

- Any non-oncology vaccine therapy used for prevention of infectious diseases for
up to 4 weeks before or after any dose of ipilimumab, with the exceptions of
amantadine and flumadine.

- Central nervous system (CNS) metastases that require palliative radiation
therapy; prior brain irradiation is allowed providing CNS disease is stable.

5. Additional Concomitant Treatments

- Any investigational agents

- Any other (non-CA184045 related) CTLA-4 inhibitors or agonists

- CD137 agonists

- Immunosuppressive agents (unless required for treating potential AEs)

- Chronic systemic corticosteroids (unless required for treating treatment emergent
AEs or required for management of signs or symptoms due to brain metastases, upon
discussion with BMS medical monitor).

Eligibility criteria for this study have been carefully considered to ensure the safety of
the study subjects and to ensure that the results of the study can be used. It is
imperative that subjects fully meet all eligibility criteria.