Phase II Study of Gamma Knife Radiosurgery and Temozolomide for Brain Metastases

This is a phase II study. The primary endpoint is the proportion of patients with newly
developed metastases who develop new brain metastases within the first year of undergoing
stereotactic radiation combined with the administration of temozolamide within the first
year post treatment. Retrospective and prospective studies suggest that 50- 60% of long-term
survivors develop new brain metastases. Since it is important to observe all patients
recruited for a minimum of a year to measure the primary outcome, traditional phase 2
designs such as Simon's two stage optimal design or the mini-max design are not practical in
this case. Survival and QOL are secondary end points. QOL will be measured using the
Functional Assessment of Cancer Therapy (FACT -BR). It will be administered at baseline, at
week four and every three months for 24 months.

This protocol includes radiosurgery with standard radiation doses (15-24 Gy based upon RTOG
9005). Patient may be registered after radiosurgery as long as Temodar is started within two
weeks of radiosurgery.

Beginning within two weeks after radiosurgery: TMZ 200mg/m2 days 1-5 repeat q28 days.
Patients who have received prior chemotherapy will receive 150 mg/m2 days 1-5.

Temozolomide is continued until there is disease progression defined by systemic progression
or new metastases. If lesion treated with radiosurgery progresses in the absence of new CNS
tumors or systemic progression, then TMZ will continue. Temozolomide is discontinued for
systemic progression requiring other systemic chemotherapy.

Palliative radiation may be administered to non-CNS sites during protocol treatment, but
additional systemic chemotherapy will not be administered until patients progress
systemically or until new metastases develop.

Inclusion Criteria:

- All subjects must have history of histologically confirmed malignancy. Brain biopsy
is not required unless diagnosis is judged to be in doubt by the treating physician.

- Newly diagnosed brain metastases (four or fewer by thin slice post-contrast MRI).

- ECOG performance status of less than or equal to 2 for patients with no prior
chemotherapy, and less than or equal to 1 for patients with prior chemotherapy.

- Age greater than 18

- Life expectancy greater than 12 weeks

- Subjects given written informed consent

- Adequate hematologic, renal and liver function as demonstrated by laboratory values
performed within 14 days, inclusive, prior to administration of study drug:

- Absolute neutrophil count (ANC) >= 1500/mm3

- Platelet count >= 100,000/mm3

- Hemoglobin >= 9 g/dL

- BUN and serum creatinine <= 1.5 times upper limit of laboratory normal

- Total and direct bilirubin <= 2 times upper limit of laboratory normal or in the
presence of documented liver metastases, total and direct bilirubin <=5 times
upper limit of normal

- SGOT and SGPT <= 2 times upper limit of laboratory normal or in the presence of
documented liver metastases, SGOT and SGPT <=5 times upper limit of normal

- Alkaline phosphatase <= 2 times upper limit of laboratory normal or in the
presence of documented liver metastases, alkaline phosphatase of <= 5 times
upper limit of normal

Exclusion Criteria:

- Patients with small cell lung cancer and lymphoma are ineligible.

- More than four metastases by thin slice MRI. Note that if a diagnostic study prior to
radiosurgery demonstrates only four tumors but the gamma knife treatment-planning
scan reveals greater than four tumors, the patients will still be eligible for the
protocol if all tumors can be treated with radiosurgery.

- Chemotherapy within four weeks prior to study drug administration

- Patients, who in the opinion of the treating medical oncologist, require immediate
cytotoxic chemotherapy other than the study drug. Allowed medications include
antihormonal agents (i.e., Tamoxifen), herceptin and bisphosphonates.

- Radiation therapy to greater than or equal to 50% of the bone marrow. Completion of
radiation therapy less than 4 weeks prior to study drug administration for
radiotherapy to >= 15% of bone marrow and less than 2 weeks prior for radiotherapy to
< 15% of bone marrow.

- Insufficient recovery from all active toxicities of prior therapies

- Subjects who are poor medical risks because of non-malignant systemic disease

- Frequent vomiting or medical condition that could interfere with oral medication
intake (e.g., partial bowel obstruction).

- Previous or concurrent malignancies at other sites, or treatment for malignancy at
the site within 5 years of study start with the exception of surgically cured
carcinoma in-situ of the cervix and basal or squamous cell carcinoma of the skin.

- Known HIV positively or AIDS-related illness.

- Pregnant or nursing women.

- Women of childbearing potential who are not using an effective method of
contraception. Women of childbearing potential must have a negative serum pregnancy
test 24 hours prior to administration of study drug and be practicing medically
approved contraceptive precautions.

- Men who are not advised to use an effective method of contraception.