Clinical trial NCT00221325: A Safety Study of Rituximab Plus MTX Injected Into the Cerebrospinal Fluid in the Treatment of Brain Lymphoma
Official title: Phase I Study of Intraventricular Administration of Rituximab in Combination With Methotrexate in the Treatment of Recurrent CNS and Intraocular Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Central Nervous System Lymphoma
Intraocular Lymphoma
Keywords: Phase I Clinical Trial
Pharmacokinetics
Pharmacodynamics
CNS Lymphoma
Ocular Lymphoma
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2005-09-22
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Rituximab is the first monoclonal antibody to receive approval in the treatment of cancer and has been proven to lead to extended survival when administered intravenously in the treatment of patients with systemic non-Hodgkin's lymphoma. We have previously demonstrated that a small fraction of Rituximab administered intravenously is able to cross the blood-brain-barrier into the brain.

We will test the idea that the direct injection into the cerebrospinal fluid of Rituximab, a monoclonal antibody which attacks and kills lymphoma cells, is safe and when used in combination with methotrexate in patients with recurrent brain and intraocular lymphoma.

We will also test the idea that the combination of rituximab plus methotrexate has activity and is effective in the treatment of recurrent brain and intraocular lymphoma.

Detailed description: Rituximab is the first monoclonal antibody to receive FDA approval in the treatment of cancer. Intravenous administration of rituximab has been demonstrated to lead to prolongation of survival when used in combination with chemotherapy in the treatment of patients with systemic non-Hodgkin's lymphoma. We have previously demonstrated that a small fraction of Rituximab administered intravenously is able to cross the blood-brain-barrier into the brain and we have also previously demonstrated that direct intraventricular administration of Rituximab is able to achieve high concentrations within the cerebrospinal fluid ventricles and lumbar sac.

We will test the hypothesis that the direct intraventricular injection of Rituximab in combination with Methotrexate is safe and when used in combination in patients with recurrent brain and intraocular lymphoma. We will evaluate the safety of this combination by testing different dose levels of Rituximab. We will also measure the concentration of Rituximab in the intraocular compartments and cerebrospinal fluid at different time points after intraventricular administration to determine the pharmacokinetics of intrathecal Rituximab as well as the potential impact of Methotrexate on Rituximab distribution.

We will also test the hypothesis that the intraventricular administration of the combination of rituximab plus methotrexate has activity and is effective in the treatment of recurrent brain and intraocular lymphoma.

Eligibility criteria: Inclusion Criteria:

1. Relapsed, refractory CNS lymphoma, ocular lymphoma, lymphomatous meningitis
2. Tumors must be CD20 + on pathologic analysis.
3. Patients must have an Ommaya reservoir (ventricular access device.
4. Patients may have had prior intrathecal methotrexate, ara-C or thiotepa but must have recovered from any reversible toxicity caused by prior treatment.
5. Concurrent systemic chemotherapy is allowed for treatment of disease outside the meninges with the exception of high-dose methotrexate (\>500 mg/m2/d, high-dose ara-C (\> 2 gm/m2/d), high-dose thiotepa (\>300 mg/m2/d) or investigational agents.
6. Patients must have sufficient baseline hematologic function: \>1,500 granulocytes and \>50,000 platelets/ul.
7. Patients must have had a nuclear medicine CSF flow study performed within 30 days of treatment which shows no significant obstruction within the ventricles.

Exclusion Criteria:

1. History of whole brain or craniospinal irradiation or intrathecal chemotherapy \< 4 days before initiation of intra-CSF administration of rituximab.
2. Anticipated survival of less than one month.
3. HIV infection. -

Primary outcomes:
measure: whether intra-CSF administration of rituximab in combination with MTX in patients with recurrent CNS and intraocular lymphoma is associated with neurotoxicity
timeFrame: 4 weeks
Secondary outcomes:
measure: To define the rate of tumor response (CR plus PR) in the brain, spine, eye, or CSF.
timeFrame: 4 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: University of California, San Francisco
name: James L. Rubenstein, MD PhD
role: STUDY_CHAIR
References:
citation: Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, Batchelor T, Krouwer H, Hwang J, Auerback G, Kadoch C, Lowell C, Munster P, Cha S, Shuman MA, Damon LE. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013 Jan 31;121(5):745-51. doi: 10.1182/blood-2012-07-440974. Epub 2012 Nov 29.