Phase II Trial of Chemotherapy With Temodar With Topotecan for CNS Metastasis of Solid Tumors

The long-term objective of this research project is to develop chemotherapy-based approach
to the treatment of brain metastases. The specific purpose of this study is to obtain data
on safety and efficacy of combination chemotherapy with temozolomide and topotecan in
patients with central nervous system (CNS) metastases of solid tumors. Patients with brain
metastases of solid tumors have a poor prognosis, despite improvements in survival achieved
with modern neurosurgical and radiation techniques. Chemotherapy does not play any
significant role in this disease, but may have application in salvage of patients who have
failed radiation therapy. In patients who are not surgical candidates, do not require
immediate XRT to relieve symptoms and have controlled systemic disease, effective
chemotherapy as an alternative to XRT might decrease the risk of radiation induced
neurotoxicity.

Recent advances in treatment of systemic disease with the use of modern chemotherapy and
pathobiologic agents have significantly improved overall survival of cancer patients,
putting them at risk for CNS metastases and radiation induced neurotoxicity. Both,
temozolomide and topotecan have good blood-brain barrier penetration and have shown activity
in CNS malignancies. Preclinical studies suggest synergy of this drug combination. This is a
single-arm, open-label phase II drug study. All patients will receive the chemotherapy
combination. Up to 35 patients will be accrued over 2-3 years and followed for up to 5
years. Patients will receive up to 8 cycles of chemotherapy. The primary endpoint is the
rate of radiologic response of brain metastases and secondary endpoints are median overall
survival, progression-free survival, time to progression of brain metastases and toxicity.
The study is expected to provide data to be used in generating further research hypotheses.

Inclusion Criteria:

To be eligible for the study, patients must have evidence of progressive CNS metastases of
a solid tumor (new or progressing lesions), and either:

1. Have failed prior WBRT.

2. Or: not be candidates for surgical intervention and not require immediate radiation
therapy to relieve symptoms, and have controlled systemic disease.

Additional requirements:

1. Patients must be > 18 years old.

2. Patients must have radiographically measurable tumor on the updated scan within 2
weeks prior to starting treatment.

3. Patients must have histopathologic documentation of primary tumor at the time of
initial diagnosis.

4. Patients must be in adequate condition at time of enrollment, as indicated by:

1. Absolute neutrophil count (ANC) greater than or equal 1,500/mm3

2. Hemoglobin greater than or equal 9 gm/dL

3. Platelets greater than or equal 100,000/mm3

4. Karnofsky Performance Status greater than or equal 50

5. Creatinine clearance >40 ml/min

6. Total bilirubin less than or equal 2.0 mg/dl and SGOT, SGPT less than or equal 3
times upper limit of normal

5. Patients must not be receiving concurrent anti-tumor therapy and must have recovered
from toxicity of prior therapy. Minimum intervals required:

1. greater than or equal 6 weeks after receiving nitrosourea cytotoxic drug

2. greater than or equal 4 weeks after receiving any non-nitrosourea cytotoxic drug
or any systemic investigational agent with exception of methotrexate

3. greater than or equal 2 weeks after receiving methotrexate

4. greater than or equal 2 weeks after receiving any non-cytotoxic anti-tumor drug.

5. greater than or equal 4 weeks after radiation therapy or SRS.

6. greater than or equal 3 weeks after craniotomy or other surgery.

6. Female patients of childbearing potential must have a negative pregnancy test at the
time of screening. All patients must be willing to practice an effective method of
birth control during the study. Female patients must not be pregnant or
breast-feeding during the entire study.

7. Patients or legal representatives must understand the investigational nature of this
study and sign a written informed consent form, approved by the Institutional Review
Board (IRB) prior to enrolling into the study.

8. No other prior malignancy except adequately treated basal cell or squamous cell skin
cancer, stage I or II cancer from which the patient is currently in complete
remission, or any other cancer from which the patient has been disease-free for 5
years.

Exclusion Criteria:

1. Patients who are pregnant or breastfeeding, or females of childbearing potential not
using adequate contraception.

2. Known allergy to temozolomide or topotecan.

3. Severe vomiting or other inability to administer medications orally.

4. Major medical illnesses or psychiatric impairment that in the investigator's opinion
will prevent administration or completion of the protocol therapy and/or will
interfere with follow-up.