Pemetrexed Disodium in the Cerebrospinal Fluid of Patients With Leptomeningeal Metastases

OBJECTIVES:

- Determine the cerebrospinal fluid (CSF):plasma ratio of pemetrexed disodium at different
IV dose levels in patients with leptomeningeal metastases.

- Determine the safety of this drug in these patients.

- Determine the antitumor activity of this drug in these patients.

- Assess the role of CSF vascular endothelial growth factor and YKL 40 as markers of
response and/or prognosis in these patients.

OUTLINE: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats
every 21 days in the absence of disease progression or unacceptable toxicity.

Patients undergo lumbar puncture and blood collection prior to therapy and 30-60 minutes
after the first dose of pemetrexed disodium for pharmacological studies. Patients with Ommaya
reservoirs undergo cerebrospinal fluid (CSF) collection at baseline and 0.25, 0.50, 1, 2, 4,
6 and 8.0 hours after pemetrexed disodium administration. CSF is then obtained once during
each subsequent course of study treatment. CSF and blood are also evaluated for YKL 40 and
vascular endothelial growth factor.

After completion of study therapy, patients are followed every 2-3 months.

PROJECTED ACCRUAL: A total of 15 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Diagnosis of systemic malignancy (solid tumor or hematologic malignancy) or primary
CNS lymphoma with leptomeningeal metastases (LM) as documented by MRI, cerebrospinal
fluid, or both

- Patients may have brain metastases in addition to LM

- Patients with clinically significant interstitial fluid with effusion controlled by
drainage are eligible

PATIENT CHARACTERISTICS:

- Karnofsky performance status 60-100%

- Life expectancy > 2 months

- Creatinine clearance ≥ 45 mL/min

- Bilirubin < 1.5 times upper limit of normal (ULN)

- Transaminases < 3.0 times ULN (5 times ULN for hepatic metastasis)

- WBC > 3,000/mm³

- Neutrophil count > 1,500/mm³

- Platelet count > 100,000/mm³

- Hemoglobin > 10 g/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- Able to undergo lumbar puncture (i.e., no noncommunicating hydrocephalus or spinal
block) or has an Ommaya reservoir in place

- Able to take steroids, cyanocobalamin (vitamin B12), and folic acid

- No other active cancer except nonmelanoma skin cancer or carcinoma in situ of the
cervix

- Patients with prior malignancies who are in complete remission and are off all therapy
for that malignancy for ≥ 3 years are eligible

- No significant medical or psychiatric illness that would interfere with study
compliance

PRIOR CONCURRENT THERAPY:

- More than 2 weeks since prior radiotherapy and recovered

- No concurrent radiotherapy

- No nonsteroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid within 2 days
before or after study treatment (5 days for long-acting NSAIDs)

- No other concurrent cytotoxic chemotherapy

- Concurrent hormonal or biological therapy allowed