Temozolomide, Thalidomide, and Lomustine (TTL) in Melanoma Patients

Temozolomide works by blocking a tumor cell's ability to grow. Lomustine is also a
chemotherapy drug that works by killing tumor cells. Studies have shown that when lomustine
and temozolomide are given together, they decrease the amount of a certain protein, allowing
the tumor cells to be more easily killed. Thalidomide is a drug that alters the immune
system. it may also interfere with the development of tiny blood vessels that help support
tumor growth. Therefore, in theory, it may decrease or prevent the growth of cancer cells.

If you are found to be eligible to take part in this study, you will begin treatment. All 3
drugs will be taken by mouth at home. Each treatment cycle will last for 8 weeks. You will
take temozolomide once a day for 6 weeks followed by two weeks off. The best time to take
temozolomide is around bedtime, since you must not eat for at least 1 hour before and 1 hour
after taking it. The number of capsules you will take is based on your height and weight. You
must swallow all the temozolomide capsules at the same time with 8 ounces of water (do not
chew them).

You will take thalidomide every day for the entire 8-week cycle. Thalidomide should also be
taken near bedtime, usually 30 to 45 minutes before the temozolomide dose. If you are under
70 years of age, you will start at a set dose and take the same dose throughout the study. If
you are age 70 or over, the dose will start lower and will increase every 2 weeks until you
are taking the prearranged set dose that those under the age of 70 are taking. Your doctor
will be watching for side effects as the dose increases and may keep you at a lower dose if
necessary.

In the first groups of patients (3-6 patients per group, total up to 18 patients) to be
enrolled, each new group of participants will be given a higher dose of lomustine than the
previous group until the highest safe dose of lomustine is found or until 18 patients have
been enrolled. Responses to these doses will be evaluated. Once the best dose is found, all
future participants will receive that dose of lomustine.

You will take 2 doses of lomustine every 8 weeks. You will take the first dose of lomustine
on Day 1 of the 8-week cycle. You will take the second dose, which will be half as big as the
first dose, on Day 29 (the day after the first 4 weeks) of the 8-week cycle. The dose of
lomustine is also based on your height and weight. Lomustine should be swallowed and not
chewed.

During treatment, every 2-4 weeks, you will have a complete physical exam and blood drawn for
testing (1-2 tablespoons). These tests will let the doctor know if the treatment should be
changed, briefly interrupted, or stopped. Women who are able to have children must have a
negative pregnancy test every week for the first 4 weeks if they have regular menstruation
and every 2 weeks if their periods are irregular.

At the end of 8 weeks, you will have x-rays or scans done again to see how the tumors have
responded. If they are the same size or have gotten smaller, you may continue the treatment.
You may stay on treatment as long as you are not having severe side effects and your tumor is
either staying the same size or getting smaller. Treatment will be stopped if the tumors are
getting bigger.

If you are withdrawn from the study for any reason you will be contacted by phone every three
months to learn how are you doing health wise.

This is an investigational study. None of the 3 drugs used in this study have been approved
by the FDA for the treatment of melanoma. Temozolomide has been approved for the treatment of
brain cancer. Thalidomide has not yet been approved for the treatment of cancer. Lomustine is
approved for the treatment of brain tumors and Hodgkin's disease. All of the drugs are
commercially available. Their use together in this study is experimental.

Up to 18 patients will take part in this Phase I portion of the study, and another 30
patients in Phase II if progresses, with up to 48 patients total. All will be enrolled at M.
D. Anderson.

Inclusion Criteria:

1. Histologic Documentation: Histologic or cytologic diagnosis of distant metastatic
melanoma and clinical evidence of brain metastasis.

2. Pts must have brain lesions of =/> 1.0cm longest dimension by MRI or spiral CT, if MRI
not feasible or > 0.5cm by MRI with 3D images. Pts with/without extracranial disease
are eligible. Measurable extracranial disease is not required. Lesions that are
considered non-measurable include: <1.0 cm by MRI or Spiral CT, Bone lesions,
Leptomeningeal disease, Ascites, Pleural/pericardial effusion, Lymphangitis
cutis/pulmonis, Abdominal masses that are not confirmed and followed by imaging
techniques, Cystic lesions, lesions that are in a previously irradiated area, unless
new growth can be documented.

3. Age >/= 18 years of age.

4. Eastern Cooperative Oncology Group (ECOG) Performance Status: 0 or 1

5. No more than 1 prior chemotherapy regimen and no prior chemotherapy for brain
metastases. No prior treatment with continuous daily dose of temozolomide; prior
immunotherapy and surgical resection are permitted. Patients with prior history of
whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) are permitted
providing that there is measurable lesion with documented growth post radiation or new
disease.

6. (#5 continued) Progression of lesions treated with WBRT must be shown by 2 post
treatment brain imaging at least 3 weeks apart. Progression of disease is also
considered when the patient had increase of lesions as per MRI of brain obtained 4
weeks or more after WBRT completed when compared to baseline MRI obtained less than 1
week prior to start of radiation. Lesions treated with SRS must have responded and
then progressed.

7. The following time periods must have elapsed since prior therapy: 3 weeks since
surgical resection or stereotactic radiosurgery; 4weeks since prior whole brain
radiation therapy; 6 weeks since prior nitrosureas or mitomycin C. Biologic agents
used as adjuvants and vaccines or cellular therapies will not require 4-week wash out
period if the patient meets all eligibility criteria.

8. No frequent vomiting and/or medical condition that could interfere with oral
medication intake (e.g., partial bowel obstruction).

9. No other concurrent chemotherapy/immunotherapy/radiotherapy.

10. No history of active angina or myocardial infarction within 6 months. No history of
significant ventricular arrythmia or uncontrolled arrythmia or bradycardia. The study
participants must have resting heart rate of 48 or greater (.e.i - to receive
Thalidomide).

11. No prior history of deep vein thrombosis (DVT) or pulmonary embolism (PE).

12. No known HIV disease. Patients with a history of intravenous drug abuse or any other
behavior associated with an increased risk of HIV infection should be tested for
exposure to the HIV virus. Because peripheral neuropathies are a common toxicity of
antiviral therapy and of viral infection in HIV patients, as well as a common
significant toxicity with thalidomide, patients who test positive or who are known to
be infected are not eligible. An HIV test is not required for entry on this protocol,
but is required if the patient is perceived to be at risk.

13. No pre-existing neuropathy that is >/= grade 2, including uncontrolled seizures.

14. No expected need for radiotherapy to brain or any extracranial metastatic site during
the period of participation in the study.

15. Patients may not be taking Coumadin, warfarin or heparin products or their
derivatives.

16. Patients who require anti-platelet therapy such as daily aspirin, Plavix or ibuprofen
are not eligible to participate.

17. Patients requiring the use of bisphosphonates (e.g., zoledronic acid) are not eligible
to participate. Patients who receive thalidomide in combination with zoledronic acid
are potentially at increased risk of renal dysfunction.

18. Required Initial Laboratory Data: Granulocytes >/= 1,500/ml; Platelet count >/=
100,000/ul; Creatinine normal; Alkaline phosphatase hormone (TSH) Within normal limits Serum beta-HCG Negative (in female patients unless
S/P hysterectomy or menopausal or no menses for 24 months). Assay must have a
sensitivity of at least 50 mIU/ml. Serum anticonvulsant levels (for patients on a
measurable anticonvulsant) must be within therapeutic range. EKG must be without acute
abnormalities or uncontrolled arrhythmia.

19. Pregnant and nursing women are not eligible for treatment on this protocol. Women of
childbearing potential must agree to abstain from all intercourse or use two methods
of birth control for 28 days prior to treatment and while under treatment with
thalidomide and for 4 weeks after completing therapy. One of the methods of birth
control must be highly active (IUD, hormonal, tubal ligation or partner's vasectomy)
and used concomitantly with one additional method(e.g., latex condom, diaphragm or
cervical cap. Please see also eligibility criteria 19 and 20.

20. In addition, women of childbearing potential must have morning urine b-HCG performed
within 1 week prior to registration and within 24 hours before beginning study
treatment. All the precautions for childbearing potential women are required even in
patients with infertility unless due to hysterectomy or the patient has been post
menopausal (has had no menses for at least 24 consecutive months). Men must agree to
abstain from unprotected sexual intercourse. Male patients should request that female
partners use a second method of birth control in addition to the male barrier method
(condoms).

21. All patients (men and women) must agree to use medically approved contraceptive
measures simultaneously prior to starting thalidomide therapy, all during drug
therapy, and for at least 1 month after therapy has stopped. Women of childbearing
potential should start using medically approved contraceptive measures 4 weeks prior
to starting thalidomide therapy.

22. Patients must give written consent.

23. Patients must be willing and able to comply with the FDA-mandated S.T.E.P.S version 3
program.

Exclusion Criteria:

1. Presence of any ongoing toxic effect from prior treatment.

2. Serious infection requiring intravenous antibiotics, or nonmalignant medical illnesses
that are uncontrolled or whose control may be jeopardized by the complications of this
therapy.

3. Concurrent active malignancy other than non-melanoma skin cancers or carcinoma-in-situ
of the cervix. Patients with previous malignancies, but which have not required
anti-tumor treatment within the preceding 24 months will be allowed to enter the
trial. Patients with a history of a T1a or b prostate cancer (detected incidentally at
transurethral prostatectomy (TURP) and comprising less than 5% of resected tissue) may
participate if the prostate-specific antigen (PSA) remained within normal limits since
TURP.

4. Any other medical condition or reason that, in the principal investigator's opinion,
makes the patient unsuitable to participate in a clinical trial including but not
limited to active bleeding, prior surgical procedures affecting absorption or
gastrointestinal tract disease resulting in inability to take oral medication.

5. Pregnant and lactating women.