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Methotrexate, Mannitol, Rituximab, and Carboplatin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma

Primary Purpose

Central Nervous System Lymphoma

Status
Unknown status
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carboplatin
Mannitol
Methotrexate
Quality-of-Life Assessment
Rituximab
Sodium Thiosulfate
Sponsored by
OHSU Knight Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Central Nervous System Lymphoma

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Subjects with histopathologic confirmation of intermediate or high-grade primary central nervous system lymphoma (PCNSL) as documented by brain biopsy, or cytology (analysis from cerebral spinal fluid [CSF] or vitrectomy), and cluster of differentiation 20 (CD20) positive; whenever possible, the tumor should be characterized by immunophenotype Subjects must be =< 90 days from diagnosis of PCNSL in the brain or spine; time from pathologic diagnosis to initiation of treatment should be specified; subjects with history of only ocular lymphoma are eligible if < 90 days since documented brain parenchymal disease (by imaging or by biopsy) Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance score =< 3 (Karnofsky >= 30) Hematocrit >= 25% (may be reached by transfusion) (performed within 14 days of registration) White blood cell count >= 2.5 x 10^3/mm^3 (performed within 14 days of registration) Absolute granulocyte count >= 1.2 x 10^3/mm^3 (performed within 14 days of registration) Platelets >= 100 x 10^3/mm^3 (or >= lower limit of institutional normal value) (performed within 14 days of registration) Calculated creatinine clearance (Cr Cl) >= 50 ml/min (performed within 14 days of registration); eligible for full dose methotrexate Calculated Cr Cl >= 30 ml/min (performed within 14 days of registration); eligible for reduced dose methotrexate Bilirubin =< 2.0 x upper limit of institutional normal value (performed within 14 days of registration) The subject may have had other systemic chemotherapy for PCNSL during the 90 days since PCNSL diagnosis; prior systemic chemotherapy must have been given at least 4 weeks prior to study entry (6 weeks for nitrosourea agents), with the exceptions of methotrexate and rituximab which may have been given at least 10 days prior; ocular lymphoma treatment may have been given any time prior to study entry; if the subject has undergone treatment for parenchymal disease and the parenchymal disease has progressed on a stable or increasing dose of steroids, the subject is not eligible for enrollment Sexually active women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study treatment and for the duration of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Subjects with a bone marrow biopsy which shows microscopic, low-level involvement of lymphoma are eligible Subject with seropositivity for hepatitis B or hepatitis C must be cleared by hepatology service prior to participating in treatment protocol Exclusion Criteria: Prior cranial or spinal radiotherapy Subjects with radiographic signs of excessive intra-cranial mass effect with associated rapid neurologic deterioration, and/or spinal block, are unsafe to undergo BBBD chemotherapy and are not eligible Uncontrolled (over the last 30 days), clinically significant confounding medical conditions Seropositivity for the human immunodeficiency virus Systemic lymphoma Subjects who have a positive serum human chorionic gonadotropin (hCG), are pregnant or lactating are ineligible Known allergy to any of the study agents Subjects who are at significant risk for general anesthesia

Sites / Locations

  • Good Samaritan Hospital - Cincinnati
  • Cleveland Clinic Foundation
  • Ohio State University Comprehensive Cancer Center
  • OHSU Knight Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (rituximab, mannitol, methotrexate, carboplatin)

Arm Description

Patients receive rituximab IV over 5 hours on day 1, mannitol IA, methotrexate IA over 10 minutes, and carboplatin IA over 10 minutes on days 2 and 3. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats monthly for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of toxicities, assessed using National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (Phase I)
CR rate (Phase II)

Secondary Outcome Measures

Overall survival
Kaplan-Meier estimates of these survival distributions will be plotted. Descriptive stratifications of these survival distributions by baseline characteristics will be evaluated using the log-rank statistic. If there are multiple predictors of these outcomes, Cox proportional hazard models will be fit to these data to determine which predictors are independent of others in a multi-variable model.
Event-free survival
Kaplan-Meier estimates of these survival distributions will be plotted. Descriptive stratifications of these survival distributions by baseline characteristics will be evaluated using the log-rank statistic. If there are multiple predictors of these outcomes, Cox proportional hazard models will be fit to these data to determine which predictors are independent of others in a multi-variable model.

Full Information

First Posted
February 16, 2006
Last Updated
September 15, 2021
Sponsor
OHSU Knight Cancer Institute
Collaborators
National Cancer Institute (NCI), Oregon Health and Science University
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1. Study Identification

Unique Protocol Identification Number
NCT00293475
Brief Title
Methotrexate, Mannitol, Rituximab, and Carboplatin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma
Official Title
A Phase I/II Study of Patients With Newly Diagnosed Primary Central Nervous System Lymphoma Treated With Methotrexate/BBBD, and Adding Rituximab (an Anti CD-20 Antibody) and Carboplatin, to the Treatment Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Unknown status
Study Start Date
October 14, 2005 (Actual)
Primary Completion Date
January 31, 2022 (Anticipated)
Study Completion Date
January 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
OHSU Knight Cancer Institute
Collaborators
National Cancer Institute (NCI), Oregon Health and Science University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I/II trial studies the side effects of methotrexate, mannitol, rituximab, and carboplatin and to see how well they work in treating patients with primary central nervous system lymphoma. Drugs used in chemotherapy, such as methotrexate and carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Osmotic blood-brain barrier disruption uses mannitol to open the blood vessels around the brain and allow cancer-killing substances to be carried directly to the brain. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving methotrexate, mannitol, rituximab, and carboplatin together may be an effective treatment for primary central nervous system lymphoma.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety and toxicities of a treatment regimen consisting of rituximab (intravenously [IV]) the day prior to methotrexate (intra-arterially [IA]), and carboplatin (IA) in conjunction with blood-brain barrier disruption (BBBD) and delayed sodium thiosulfate (IV). II. To demonstrate, adding a monoclonal antibody and carboplatin to methotrexate BBBD, that a 45% rate of complete response (CR) within the first 3 months of treatment is achieved, while excluding a CR rate as low as 30%. SECONDARY OBJECTIVE: I. To estimate the response rate (counting all CRs), the two-year overall survival and the two-year event-free survival, as baselines for subsequent trials. OUTLINE: Patients receive rituximab IV over 5 hours on day 1, mannitol IA, methotrexate IA over 10 minutes, and carboplatin IA over 10 minutes on days 2 and 3. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats monthly for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 2 months, then every 2 months for 2 years, every 6 months for 1 year, and then annually for at least 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Central Nervous System Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
81 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (rituximab, mannitol, methotrexate, carboplatin)
Arm Type
Experimental
Arm Description
Patients receive rituximab IV over 5 hours on day 1, mannitol IA, methotrexate IA over 10 minutes, and carboplatin IA over 10 minutes on days 2 and 3. Patients then receive sodium thiosulfate IV over 15 minutes at 4 and 8 hours after carboplatin. Treatment repeats monthly for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
Intervention Description
Given IA
Intervention Type
Drug
Intervention Name(s)
Mannitol
Other Intervention Name(s)
D-Mannitol, Mannitol, D-, Osmitrol, Resectisol
Intervention Description
Given IA
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039
Intervention Description
Given IA
Intervention Type
Other
Intervention Name(s)
Quality-of-Life Assessment
Other Intervention Name(s)
Quality of Life Assessment
Intervention Description
Ancillary studies
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Sodium Thiosulfate
Other Intervention Name(s)
Cyanide Antidote Package, Disodium Thiosulfate, S-Hydril, Sodium Hyposulfate, Sodium Thiosulfate Pentahydrate, Sodium Thiosulphate, Sodothiol, Thiosulfate, Sodium, Pentahydrate, Thiosulfuric Acid Disodium Salt
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Incidence of toxicities, assessed using National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (Phase I)
Time Frame
Within 2 months of completion of study treatment
Title
CR rate (Phase II)
Time Frame
Within the first 3 months of treatment
Secondary Outcome Measure Information:
Title
Overall survival
Description
Kaplan-Meier estimates of these survival distributions will be plotted. Descriptive stratifications of these survival distributions by baseline characteristics will be evaluated using the log-rank statistic. If there are multiple predictors of these outcomes, Cox proportional hazard models will be fit to these data to determine which predictors are independent of others in a multi-variable model.
Time Frame
From entry onto study until death from any cause, assessed at 2 years
Title
Event-free survival
Description
Kaplan-Meier estimates of these survival distributions will be plotted. Descriptive stratifications of these survival distributions by baseline characteristics will be evaluated using the log-rank statistic. If there are multiple predictors of these outcomes, Cox proportional hazard models will be fit to these data to determine which predictors are independent of others in a multi-variable model.
Time Frame
From entry onto study until death or progression of disease, assessed at 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subjects with histopathologic confirmation of intermediate or high-grade primary central nervous system lymphoma (PCNSL) as documented by brain biopsy, or cytology (analysis from cerebral spinal fluid [CSF] or vitrectomy), and cluster of differentiation 20 (CD20) positive; whenever possible, the tumor should be characterized by immunophenotype Subjects must be =< 90 days from diagnosis of PCNSL in the brain or spine; time from pathologic diagnosis to initiation of treatment should be specified; subjects with history of only ocular lymphoma are eligible if < 90 days since documented brain parenchymal disease (by imaging or by biopsy) Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance score =< 3 (Karnofsky >= 30) Hematocrit >= 25% (may be reached by transfusion) (performed within 14 days of registration) White blood cell count >= 2.5 x 10^3/mm^3 (performed within 14 days of registration) Absolute granulocyte count >= 1.2 x 10^3/mm^3 (performed within 14 days of registration) Platelets >= 100 x 10^3/mm^3 (or >= lower limit of institutional normal value) (performed within 14 days of registration) Calculated creatinine clearance (Cr Cl) >= 50 ml/min (performed within 14 days of registration); eligible for full dose methotrexate Calculated Cr Cl >= 30 ml/min (performed within 14 days of registration); eligible for reduced dose methotrexate Bilirubin =< 2.0 x upper limit of institutional normal value (performed within 14 days of registration) The subject may have had other systemic chemotherapy for PCNSL during the 90 days since PCNSL diagnosis; prior systemic chemotherapy must have been given at least 4 weeks prior to study entry (6 weeks for nitrosourea agents), with the exceptions of methotrexate and rituximab which may have been given at least 10 days prior; ocular lymphoma treatment may have been given any time prior to study entry; if the subject has undergone treatment for parenchymal disease and the parenchymal disease has progressed on a stable or increasing dose of steroids, the subject is not eligible for enrollment Sexually active women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study treatment and for the duration of study treatment; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Subjects with a bone marrow biopsy which shows microscopic, low-level involvement of lymphoma are eligible Subject with seropositivity for hepatitis B or hepatitis C must be cleared by hepatology service prior to participating in treatment protocol Exclusion Criteria: Prior cranial or spinal radiotherapy Subjects with radiographic signs of excessive intra-cranial mass effect with associated rapid neurologic deterioration, and/or spinal block, are unsafe to undergo BBBD chemotherapy and are not eligible Uncontrolled (over the last 30 days), clinically significant confounding medical conditions Seropositivity for the human immunodeficiency virus Systemic lymphoma Subjects who have a positive serum human chorionic gonadotropin (hCG), are pregnant or lactating are ineligible Known allergy to any of the study agents Subjects who are at significant risk for general anesthesia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edward A Neuwelt
Organizational Affiliation
OHSU Knight Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Good Samaritan Hospital - Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45220
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
OHSU Knight Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Methotrexate, Mannitol, Rituximab, and Carboplatin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma

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