Gemcitabine is an investigational drug for treatment of neoplastic meningitis (cancer that has spread to the lining of the brain and spinal cord). The purposes of this study are:

• to determine the highest dose of gemcitabine, an anti-cancer drug, that can safely be given directly into the spinal fluid of children and adults whose cancer no longer responds to standard treatment;
• to find out what effects (good and bad) gemcitabine has when given directly into the cerebrospinal fluid (called intrathecal administration) in children and adults with neoplastic meningitis (cancer that has spread to the lining of the brain and spinal cord);
• to determine if gemcitabine is beneficial to the patient;
• to understand how gemcitabine is handled by the body after intrathecal administration.

Condition	Treatment or Intervention	Phase
Meningitis Neoplasms	Drug: Gemcitabine  Procedure: Lumbar puncture (LP, Spinal Tap)	Phase I

Further Study Details: 

Expected Total Enrollment:  30

Eligible patients will receive gemcitabine directly into the cerebrospinal fluid (fluid that circulates around the brain and spinal cord) by one of the following methods. It will take about 10 minutes to give the gemcitabine.

• A Lumbar Puncture (Spinal Tap): This involves placing a needle into the lower back into the space where the fluid circulates around the spinal cord. The gemcitabine is directly administered into this needle after the same amount of spinal fluid has been removed. Prior to insertion of the needle your doctor may administer local medicine to numb the area. After gemcitabine has been injected into the spinal fluid, you will have to remain flat on your back for 1 hour.
• Ommaya Reservoir or Lumbar Reservoir: An Ommaya reservoir is a surgically implanted catheter that is used to inject medication or to withdraw cerebrospinal fluid from the fluid chambers in the head. A Lumbar reservoir is a surgically implanted catheter in the lower back used to inject medication or to withdraw cerebrospinal spinal fluid. An ommaya reservoir is not required as part of this study, however you may decide to have one implanted specifically to receive the drug. If you decide to have one implanted, you will be given a separate consent form describing the procedures and risks.

All patients will be hospitalized overnight following their first dose of gemcitabine. If the first dose is well tolerated, further doses of gemcitabine will be administered in the outpatient clinic with close observation for a minimum of 2 hours after administration.

Weeks 1-6 Cohort 1 (first three patients): Gemcitabine will be given once a week for 6 weeks. Patients may continue therapy if the disease has not worsened.

Weeks 1-6 Cohort 2: Gemcitabine will be given twice a week for 6 weeks. Patients may continue therapy if the disease has not worsened.

Weeks 7-12: Gemcitabine will be given twice a week for 6 weeks.

Weeks 13-29 (approximately): Gemcitabine will be given twice monthly for 4 months.

Weeks 30-52 (approximately): Gemcitabine will be given monthly for the duration of the study.

For safety reasons, the first patients treated in the study will receive a low dose of gemcitabine. If that dose does not cause severe side effects, the next group will receive a higher dose of gemcitabine than given to the earlier group, or may receive a lower dose if side effects occur. In addition, the first three patients treated on this study will receive the gemcitabine once weekly. If this is tolerated, subsequent patients will receive the medication twice weekly.

Following the first dose of gemcitabine we would like to draw special blood and spinal fluid samples to help us learn how much of the drug is in the blood and spinal fluid. These studies are called pharmacokinetics. A total of 10 blood samples will be collected. These samples will be drawn with the first dose of gemcitabine. The spinal fluid samples may be collected either via Ommaya reservoir or lumbar reservoir. Participation in the pharmacokinetics portion of this study is optional.

In addition to intrathecal gemcitabine, patients may receive other chemotherapy, not given directly into the fluid surrounding the brain and spine, as recommended by their doctor for the treatment or prevention of cancer outside the lining of the brain and spinal cord.

Ages Eligible for Study:  3 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• >/= 3 years of age.
• Neoplastic meningitis secondary to an underlying leukemia/lymphoma or a solid tumor (including primary CNS tumors or carcinomas of unknown primary site) for which there is no conventional therapy. Patients with CNS leukemia/lymphoma must be refractory to conventional therapy, including XRT (i.e. 2nd or greater relapse).
• Life expectancy of at least 6 weeks.
• Patients > 10 years old: Karnofsky performance status of >/= 50%. Patients </=10 years old: Lansky performance status of >/= 50%.
• Must have recovered from the acute neurotoxic effects of all prior chemo, immuno, or radiotherapy and must be without uncontrolled significant systemic illness (e.g. infection). Must not have received any systemic CNS-directed therapy within 3 weeks or craniospinal irradiation within 8 weeks prior to starting treatment on study. Must not have received any intrathecal therapy within 1 week prior to starting treatment on study.
• Must have a platelet count >40,000/uL and an ANC of > 1000/uL.
• Must have adequate liver function, total bilirubin < 2.0 mg%, SGPT < 2.55 times upper limits of normal; adequate renal function (serum creatinine < 2 times upper limits of normal for age).

Exclusion Criteria:

• Patients receiving other therapy (either intrathecal or systemic) designed to treat their leptomeningeal disease. However, patients receiving concomitant chemotherapy to control systemic disease or bulk CNS disease will be eligible, provided that the systemic chemotherapy is not a phase I agent, an agent that significantly penetrates the CSF, or an agent known to have serious unpredictable CNS side effects.
• Clinical evidence of obstructive hydrocephalus or compartmentalization of CSF flow as documented by radioisotope Indium111 or Technetium99-DTPA flow study. If a CSF flow block or compartmentalization is demonstrated, focal radiotherapy to the site of the block to restore flow followed by a repeat CSF flow study demonstrating clearing of the blockage is required for the patient to be eligible for the study.
• Must not have clinically significant abnormalities of serum electrolytes, including calcium, magnesium, and phosphorus.
• Patients with a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt are not eligible unless they are shunt-independent and there is evidence that their shunt is nonfunctional
• Patients who have leukemia/lymphoma with a concomitant bone marrow relapse.
• Women of childbearing age must not be pregnant or lactating. (Male and female patients who are fertile must be willing to use an effective means of birth control to avoid pregnancy.)
• Must be free of uncontrolled infection except HIV (i.e., AIDS-related lymphomatous meningitis).
• Must NOT be receiving any other investigational agents.
• Patients with impending spinal cord compression, CNS involvement requiring local XRT (e.g. optic nerve), or isolated bulky ventricular or leptomeningeal based lesions are not eligible. Concomitant CNS radiation therapy is not permitted. (Patients are not permitted to receive radiation to any port that encompasses any part of the brain or spine while on study.) Patients may receive radiation therapy to extra-CNS sites, e.g. painful bone metastases not in the craniospinal axis.

Maryland
      National Cancer Institute - Pediatric Oncology Branch, Bethesda,  Maryland,  20892,  United States; Recruiting
Pennsylvania
      University of Pittsburgh Cancer Institute, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
Texas
      Texas Children's Hospital, Houston,  Texas,  77030,  United States; Recruiting
Washington
      Seattle Children's Hospital, Seattle,  Washington,  98105,  United States; Recruiting

Study ID Numbers:  H10564; I.T. Gemcitabine
Record last reviewed:  August 2004
Last Updated:  October 13, 2004
Record first received:  December 16, 2003
ClinicalTrials.gov Identifier:  NCT00074607
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-04-08