Ipilimumab + Temozolomide in Metastatic Melanoma

The ability to control melanoma depends on how well your immune system recognizes and then
attacks cancer cells. Researchers want to use ipilimumab to try to trigger your immune
system response, while temozolomide is designed to damage the cancer cells themselves.

Study Drugs:

Ipilimumab is designed to block the activity of cells that lower the immune system's ability
to fight cancer. Blocking these cells may help the body's immune system fight the cancer
cells better.

Temozolomide is designed to stop cancer cells from making new DNA (the genetic material of
cells). If they cannot make DNA, then they cannot divide into new cancer cells.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will begin to receive
treatment with ipilimumab plus temozolomide. You will have an intravenous (IV) catheter
placed into a large vein for the Ipilimumab.

There are 2 phases of study drug treatment: Induction and Maintenance.

During the Induction Phase, you will receive ipilimumab by vein over 90 minutes on Day 1 of
each 3-week Induction "course." You will take temozolomide by mouth in tablet form on Days
1-4 of each course. You will receive up to 4 courses of Induction therapy.

During the Maintenance Phase, you will receive ipilimumab by vein over 90 minutes on Day 1
every 12 weeks. You will also take temozolomide by mouth for 5 days in a row, every 4 weeks.

You may take the Temozolomide dose within 48 hours of receiving the Ipilimumab dose on Day 1
of both the Induction and the Maintenance Phase.

You will see your doctor before each new course (every 3 weeks) during the Induction Phase,
and once every 4 weeks during the Maintenance Phase. All treatments will be given in the
outpatient clinic. You will be given anti-nausea medication to decrease the risk of nausea
and vomiting, as needed.

Study Tests:

Before Each Course:

(Every 3 weeks during Induction, and every 4 weeks during Maintenance)

- Blood (about 1 teaspoon) will be drawn for routine tests and tests of your liver and
kidney function.

- You will be asked about any medication you are taking and any side effects you are
experiencing.

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

- Your performance status will be recorded.

- Your vital signs will be measured on Day 1.

Every week, blood (about 1 teaspoon) will be drawn for routine tests.

At the end of each course, any tumor that can be felt with the hands will be measured during
physical exam to see if it is shrinking.

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

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse or
intolerable side effects occur.

If you stop receiving the study drugs for any reason, you will have an End-of-Treatment
Visit.

End-of-Treatment Visit:

Within 14 days after you stop study treatment, you will come into the clinic for the
End-of-Treatment Visit. At this visit, the following tests will be performed:

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

- You will be asked about any other medications you are taking or any side effects you
are experiencing.

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

- Your may have a CT or MRI scan performed to check for side effects.

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

This is an investigational study. At this time, temozolomide is FDA approved and
commercially available for the treatment of primary brain cancer. However, the use of
temozolomide in treating metastatic melanoma is considered investigational. At this time,
ipilimumab is being used in research only. The use of these drugs together is also
considered investigational.

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/inoperable metastatic
melanoma of skin or mucosal origin are eligible, provided they fulfill the following
conditions:

2. They are 18 years old to 75 years old with measurable (at least 1 cm) metastatic
disease.

3. They have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. Must be at least 21 days since surgery, radiation therapy and 6 weeks after
immunotherapy with regimens including vaccine, interferon, IL-2 etc. and fully
recovered from adverse effects of these therapies.

5. Must agree not use vaccines for the treatment of cancer or prevention of disease
unless indicated as a component of the protocol regimen (including those for common
medical conditions) for up to one month pre and post dosing with ipilimumab.

6. Required values for initial laboratory tests: white blood cell count (WBC): 2000/uL
or greater, absolute neutrophil count (ANC): 1000/uL or greater, Platelets: 100 x
103/uL or greater, Hemoglobin: 9 g/dL or greater, Creatinine: ALT: LDH
7. They have no significant intercurrent illness such as a serious infection which
requires intravenous antibiotics. No active or chronic infection with HIV, Hepatitis
B, or Hepatitis C. No significant psychiatric illness, which includes any life
threatening psychiatric illness that has not been adequately controlled despite
intervention (with or without medication) despite 6 months of therapy. They should
have no GI tract metastasis or bleeding, no autoimmune disease.

8. They have not been previously exposed to any cytotoxic drugs, targeted therapies or
anti CTLA 4 drugs for metastatic melanoma. Patients that received interferon for
melanoma in the adjuvant setting are eligible. Prior radiation therapy for metastatic
melanoma is permitted provided the patient has unirradiated metastatic sites for
response evaluation and any toxicity has returned to baseline.

9. Patients with brain metastases who have been treated with craniotomy and resection or
stereotactic radiosurgery of all symptomatic brain metastases are eligible provided
they are 4 weeks from the procedures, MRI/CT of the brain performed within 3 weeks
from registration fails to show new metastases and they are off of steroids for at
least 2 weeks. Patients previously treated with whole brain radiotherapy are eligible
if they are without tumor progression in the brain at least 8 weeks from completion
of radiotherapy and are asymptomatic. They should be off steroid therapy for at least
2 weeks.

10. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
last dose of investigational product, in such a manner that the risk of pregnancy is
minimized. In general, the decision for appropriate methods to prevent pregnancy
should be determined by discussions between the investigator and the study subject.

11. (Continued 10) WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:
1) Amenorrhea 12 consecutive months without another cause, or 2) For women with
irregular menstrual periods and taking hormone replacement therapy (HRT), a
documented serum follicle stimulating hormone (FSH) level 35 milli-International unit
(mIU)/mL.

12. (Continued 11) 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 before the start of
ipilimumab.

13. Men should use condoms while participating in this study.

14. must agree not to use vaccines for the treatment of cancer or prevention of disease
unless indicated as a component of the protocol regimen (including those for common
medical conditions) for up to one month pre and post dosing of ipilimumab.

Exclusion Criteria:

1. Patients with Uveal melanoma. Patients with skin or mucosal melanoma who are younger
than 18 years or more than 75 years of age and those with an ECOG performance status
of 2, 3 or 4, or patients without measurable metastases.

2. Patients with prior cytotoxic, targeted therapy or anti-CTLA 4 drugs for metastatic
disease.

3. Patients with significant cardiac illness such as symptomatic coronary artery disease
or previous history of myocardial infarction, impaired left ventricle function or
serious cardiac arrhythmias requiring therapy. Borderline cases must be discussed
with the PI.

4. Patients with significant impairment of pulmonary function on account of chronic
bronchitis or chronic obstructive pulmonary disease (COPD). Pulmonary function test
with the results forced expiratory volume at one second (FEV1) <65% or forced vital
capacity (FVC) <65% of predicted. Borderline cases must be discussed with the PI.

5. Patients on corticosteroids or any other type of immunosuppressive agent (e.g.,
methotrexate, chloroquine, azathioprine, cyclophosphamide) at time of enrollment
only.

6. Patients with history of second malignancies such as basal cell carcinoma, squamous
cell carcinoma and carcinoma in situ of cervix are eligible for therapy. Patients
with history of other types of cancers, are eligible provided that they have been
free of recurrence from second malignancy for at least 3 years. Each case must be
discussed with the PI prior to registration.

7. Patients with symptomatic uncontrolled brain metastasis that is associated with
significant brain edema requiring steroid therapy. Patients will be evaluated by the
principal investigator or his designee. Patients with spinal cord metastasis or
meningeal carcinomatosis.

8. WOCBP who are unwilling or unable to use an acceptable contraceptive method to avoid
pregnancy. Acceptable contraceptive methods are using oral contraceptives, other
hormonal contraceptives (vaginal products, skin patches, 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).