IPI Biochemotherapy for Chemonaive Patients With Metastatic Melanoma

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 6 groups of 3 participants will be enrolled
in the Phase I portion of the study, and up to 46 participants will be enrolled in Phase II.

If you are enrolled in the Phase I portion, the dose of ipilimumab you receive will depend
on when you joined this study. The first group of participants will receive the lowest dose
level of ipilimumab. Each new group will receive a higher dose of ipilimumab than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of ipilimumab is found.

If you are enrolled in the Phase II portion, you will receive ipilimumab at the highest dose
that was tolerated in the Phase I portion.

All participants will receive the same dose level of cisplatin, temozolomide, interferon
alfa-2b and IL-2.

If you develop intolerable side effects while on study, your dose of IL-2 may be lowered 1-2
times until the side effects get better.

Catheter:

If you are found to be eligible to take part in this study, you will have a central venous
catheter (CVC) inserted, if you do not already have one. A CVC is a sterile flexible tube
that will be placed into a large vein while you are under local anesthesia. Your doctor will
explain this procedure to you in more detail, and you will be required to sign a separate
consent form.

Study Drug Administration:

The study drugs will be given in 3 stages: induction, consolidation, and maintenance.

Induction:

Induction will last 12 weeks. You will receive the study drugs in up to four 3-week cycles:

- You will receive ipilimumab by vein over 90 minutes on Day 1 of each cycle.

- You will take temozolomide by mouth 1 time a day on Days 2-5 of each cycle. You should
take temozolomide on an empty stomach at least 2 hours before or after a meal. Do not
open the capsule, mix it with food, or chew it.

- You will receive cisplatin by vein over 1 hour on Days 2-4 of each cycle.

- You will receive aldesleukin by vein as a continuous infusion on Days 2-5 of each
cycle.

- You will receive interferon alfa-2b as an injection under your skin on Days 2-6 of each
cycle.

Consolidation:

Consolidation will last 12 weeks. You will receive the study drugs in three 4-week cycles.

- You will receive ipilimumab by vein over 90 minutes on Day 1 of consolidation.

- You will receive interferon alfa-2b as an injection under your skin on Days 1-5 of each
cycle.

- You will receive aldesleukin by vein as a continuous infusion on Days 2-5 of each
cycle.

Maintenance:

Maintenance will last about 1½ years. You will receive ipilimumab by vein over 90 minutes on
Day 1 of up to six 12-week cycles.

Other Drugs:

You will be given other drugs to help decrease the risk of side effects. The study staff
will tell you about these drugs, how they will be given, and the possible risks.

Study Visits:

Before each cycle (+/- 3 days):

- You will be asked about any drugs you may be taking and any side effects you may have
had.

- Your performance status will be recorded.

- Your vital signs will be measured.

- If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test.

Every week, blood (about 1 teaspoon) will be drawn for routine tests. Before each cycle,
some of this blood will be used to check your liver and kidney function.

At the end of each cycle, you will have a physical exam, including measurement of your
weight. Any tumor that can be felt with the hands will be measured during the physical exam
to see if it has changed size.

Every 2 cycles (+/- 7 days), you will have a chest x-ray and CT or MRI scans to check the
status of the disease.

Anytime the doctor thinks it is needed, photos of the skin lesions will be taken. Your
private areas will be covered (as much as possible), and a picture of your face will not be
taken unless there are lesions on your face.

Length of Study:

You may continue taking the study drugs for up to 2 years. You will no longer be able to
take the study drugs if the disease gets worse, if intolerable side effects occur, or if you
are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-treatment
visit and follow-up.

End-of-Treatment Visit:

Within 14 days after you stop the study therapy, the following tests and procedures will be
performed:

- You will have a physical exam, including measurement of your vital signs and weight.

- Your performance status will be recorded.

- You will be asked about any drugs you may be taking and any side effects you may have
had.

- Blood (about 2 tablespoons) will be drawn for routine tests.

- If the doctor thinks it is needed, you will have a CT or MRI scan.

Follow-Up:

Every 2 months for up to 3 years, you will be contacted by phone or during a clinic visit to
see how you are doing.

This is an investigational study. Temozolomide, cisplatin, ipilimumab, interferon alfa-2b,
and aldesleukin are FDA approved and commercially available to treat metastatic cancer.
However, it is investigational to give temozolomide to patients with metastatic melanoma.

Up to 64 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients with histologically documented diagnosis of advanced stage IV or
unresectable stage III melanoma are eligible for Phase I and Phase II

2. They must have recurrent melanoma with measurable or evaluable sites of disease, 1.0
cm or larger, in order to assess the response to treatment by the immune-related
response criteria

3. Phase I: Patients with prior therapy who do not have alternative treatment of higher
priority will be eligible. Phase II: patients should not have been previously treated
with cytotoxic drugs or drugs included in IPI-Biochemotherapy or regional therapy for
metastatic malignant melanoma. Prior adjuvant interferon is permitted. Prior adjuvant
Ipilimumab therapy is not permitted. Prior therapy with targeted therapy including
but not limited to B-RAF, MEK inhibitors etc. is allowed. At least three weeks should
have passed since the last dose of prior adjuvant interferon therapy and prior
targeted therapies and patient has fully recovered from toxicities of drugs. Prior
radiation therapy for metastatic melanoma is permitted provided the patient has
unirradiated metastatic sites for response evaluation and has fully recovered from
its toxicity.

4. Patients between 18 years of age and 65 years of age with an ECOG performance status
of 0, 1 or 2 will be eligible.

5. They should have normal blood counts with a WBC count of more than or equal to
3000/mm^3 an absolute neutrophil count of more than or equal to 1500/mm^3 and a
platelet count of more than 100,000/mm^3 and have no impairment of renal function
(serum creatinine less than 1.1 mg/dl for females and less than 1.4 mg/dl for males),
hepatic function (serum bilirubin level of less than 1.2 mg/dl) and no evidence of
significant cardiac or pulmonary dysfunction.

6. They should have no significant intercurrent illness such as an active infection
associated with fever lasting more than 24 hours requiring antibiotics, uncontrolled
psychiatric illness, hypercalcemia (calcium greater than 11 mg), or active GI
bleeding.

7. Females of child-bearing potential (non-childbearing is defined as greater than one
year post-menopausal or surgically sterilized) must use acceptable contraceptive
methods( abstinence, intrauterine device, oral contraceptive or double barrier
devices) and must have a negative serum or urine pregnancy test within 72 hours prior
to beginning treatment on this trial. Sexually active men must also use acceptable
contraceptive methods for the duration of time on study.

Exclusion Criteria:

1. Patients with bone metastases only.

2. Patients with brain metastases unless all of their metastatic brain lesions have been
resected or treated with stereotactic radiotherapy with gamma rays and they are off
corticosteroids. Patient should not have significant brain edema. Patients with
spinal cord compression and leptomeningeal disease are not eligible. Patients with
treated CNS metastases are not eligible for the neoadjuvant treatment cohort in Phase
II. No major surgery or radiation therapy within 21 days before starting treatment.

3. Patients with significant cardiac illness such as symptomatic coronary artery disease
or previous history of myocardial infarction, impaired left ventricle function
(Ejection Fraction less than 50%) on account of any organic disease such as
hypertension or valvular heart disease or serious cardiac arrhythmia requiring
therapy. Patients will be evaluated by the investigator or his designee.

4. Patients with significant impairment of pulmonary function on account of chronic
bronchitis or chronic obstructive pulmonary disease (COPD) which has resulted in
impairment of vital capacity of FEV1 to less than 75% of predicted normal values.

5. Patients with symptomatic effusions on account of pleural, pericardial or peritoneal
metastases of melanoma.

6. Patients who are unable to return for follow-up visits as required by this study.

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

8. Patients with a history of second malignant tumor, other than the common skin cancers
- basal and squamous carcinomas, within the past 3 years and uncertainty about the
histological nature of the metastatic lesions. Cases with other types of malignancies
should be reviewed and decided by the PI of the study.