RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the effectiveness of gemcitabine in treating neoplastic meningitis in patients who have leukemia, lymphoma, or solid tumors.

Condition	Treatment or Intervention	Phase
leptomeningeal metastases	Drug: gemcitabine  Procedure: chemotherapy	Phase I

Further Study Details: 

OBJECTIVES:

• Determine the maximum tolerated dose of intrathecal gemcitabine in patients with neoplastic meningitis secondary to leukemia, lymphoma, or a solid tumor.
• Determine the qualitative and quantitative toxicity of this drug in these patients.
• Determine the recommended phase II dose of this drug in these patients.
• Determine the plasma and CSF pharmacokinetics of this drug and its major metabolite (2^', 2^'-difluoro-deoxyuridine) in these patients.
• Investigate matrix metalloproteinase expression in pediatric and adult patients with a variety of primary diseases treated with this drug.
• Determine response in patients treated with this drug.

OUTLINE: This is a dose-escalation, nonrandomized, multicenter study.

• The first cohort of at least 3 patients receives gemcitabine intrathecally (IT) weekly for a total of 6 weeks. If that dose level is tolerated, subsequent cohorts receive gemcitabine IT twice weekly for a total of 6 weeks. Cohorts of 3-6 patients receive escalating doses of gemcitabine until the maximum tolerated dose (MTD) has been determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
• Consolidation: Beginning 1 week after the completion of the last dose of induction therapy, patients receive gemcitabine IT weekly for a total of 6 weeks.
• Maintenance: Patients receive gemcitabine IT twice monthly for 4 months and then monthly thereafter. Treatment continues for up to 1 year in the absence of disease progression or unacceptable toxicity.

Patients are followed monthly for 3 months and then every 3-4 months for up to 1 year.

PROJECTED ACCRUAL: A total of 25-30 patients will be accrued for this study within 2-3 years..

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

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 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
• CNS leukemia/lymphoma must be refractory to conventional therapy, including radiotherapy (i.e., 2^nd or greater relapse)
• Neoplastic meningitis in leukemia/lymphoma is defined as a CSF count greater than 5/µL and evidence of blast cells on cytospin preparation or by cytology
• Neoplastic meningitis in solid tumors is defined as presence of tumor cells on cytospin preparation or by cytology or presence of meningeal disease on MRI
• No leukemia/lymphoma with a concurrent bone marrow relapse
• No ventriculoperitoneal or ventriculoatrial shunt (unless shunt-independent and evidence by CSF flow study that shunt is nonfunctional)
• No clinical evidence of obstructive hydrocephalus or compartmentalization of CSF flow documented by radioisotope (indium In III or technetium Tc 99m-diethylenetriaminepentaacetic acid)
• No impending spinal cord compression
• No CNS involvement requiring local radiotherapy (e.g., optic nerve)

PATIENT CHARACTERISTICS: Age

• 3 and over

Performance status

• Karnofsky 50-100% (over 10 years of age)
• Lansky 50-100% (10 years of age and under)

Life expectancy

• At least 6 weeks

Hematopoietic

• Absolute neutrophil count greater than 1,000/mm^3
• Platelet count greater than 40,000/mm^3*
• Hematocrit greater than 30%* NOTE: *Transfusions allowed to achieve these values

Hepatic

• Bilirubin less than 2.0 mg/dL
• SGPT less than 5 times upper limit of normal (ULN)

Renal

• Creatinine less than 2 times ULN based on age as follows:
• 0.8 mg/dL (5 years and under)
• 1.0 mg/dL (6 to 10 years)
• 1.2 mg/dL (11 to 15 years)
• 1.5 mg/dL (Over 15 years)

Other

• No uncontrolled infection except HIV (AIDS-related lymphomatous meningitis allowed)
• No other significant uncontrolled systemic disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy

• Recovered from prior immunotherapy

Chemotherapy

• Recovered from prior chemotherapy
• Concurrent chemotherapy to control systemic disease or bulk CNS disease allowed provided the systemic chemotherapy is not a phase I agent or an agent that significantly penetrates the CSF such as:
• High-dose methotrexate (greater than 1 g/m^2)
• Thiotepa
• High-dose cytarabine (greater than 1 g/m^2)
• Fluorouracil
• IV mercaptopurine
• Nitrosoureas
• Temozolomide
• Topotecan
• No concurrent chemotherapy known to have serious unpredictable CNS side effects

Endocrine therapy

• Not specified

Radiotherapy

• Recovered from prior radiotherapy
• At least 8 weeks since prior cranial or craniospinal radiotherapy
• No concurrent radiotherapy to any port that encompasses any part of the brain or spinal cord
• Concurrent radiotherapy allowed to extra-CNS sites (e.g., painful bone metastases not in the craniospinal axis)

Other

• At least 3 weeks since prior systemic CNS-directed therapy
• At least 1 week since prior intrathecal therapy
• More than 14 days since prior investigational agents
• No other concurrent investigational agents
• No concurrent intrathecal or systemic therapy for leptomeningeal disease

Maryland
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892,  United States; Recruiting
Pennsylvania
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States; Recruiting
      Hillman Cancer Center at University of Pittsburgh Cancer Institute, Pittsburgh,  Pennsylvania,  15213-1863,  United States; Recruiting
Texas
      Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital, Houston,  Texas,  77030-2399,  United States; Recruiting
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States; Recruiting

Study chairs or principal investigators

Lisa Bomgaars, MD,  Study Chair,  Texas Children's Cancer Center   

Study ID Numbers:  CDR0000258743; NCI-03-C-0032; NCT00052806
Record last reviewed:  November 2004
Last Updated:  April 4, 2005
Record first received:  January 24, 2003
ClinicalTrials.gov Identifier:  NCT00052806
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08