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

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ClinicalTrials.gov Identifier: NCT00293475
Recruitment Status : Recruiting
First Posted : February 17, 2006
Last Update Posted : May 3, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Edward Neuwelt, OHSU Knight Cancer Institute

Tracking Information
First Submitted Date  ICMJE February 16, 2006
First Posted Date  ICMJE February 17, 2006
Last Update Posted Date May 3, 2018
Study Start Date  ICMJE October 2005
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 20, 2015)
  • CR rate (Phase II) [ Time Frame: Within the first 3 months of treatment ]
  • 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 ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00293475 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 20, 2015)
  • Event-free survival [ Time Frame: From entry onto study until death or progression of disease, assessed at 2 years ]
    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.
  • Overall survival [ Time Frame: From entry onto study until death from any cause, assessed at 2 years ]
    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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Methotrexate, Mannitol, Rituximab, and Carboplatin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma
Official Title  ICMJE 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
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 OBJECTIVES:

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Central Nervous System Lymphoma
Intervention  ICMJE
  • Drug: Carboplatin
    Given IA
    Other Names:
    • Blastocarb
    • Carboplat
    • Carboplatin Hexal
    • Carboplatino
    • Carbosin
    • Carbosol
    • Carbotec
    • CBDCA
    • Displata
    • Ercar
    • JM-8
    • Nealorin
    • Novoplatinum
    • Paraplat
    • Paraplatin
    • Paraplatin AQ
    • Paraplatine
    • Platinwas
    • Ribocarbo
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mannitol
    Given IA
    Other Names:
    • D-Mannitol
    • Mannitol, D-
    • Osmitrol
    • Resectisol
  • Drug: Methotrexate
    Given IA
    Other Names:
    • 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
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Biological: Rituximab
    Given IV
    Other Names:
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Rituxan
    • Rituximab Biosimilar BI 695500
    • Rituximab Biosimilar PF-05280586
    • Rituximab Biosimilar RTXM83
    • RTXM83
  • Drug: Sodium Thiosulfate
    Given IV
    Other Names:
    • Cyanide Antidote Package
    • Disodium Thiosulfate
    • S-Hydril
    • Sodium Hyposulfate
    • Sodium Thiosulfate Pentahydrate
    • Sodium Thiosulphate
    • Sodothiol
    • Thiosulfate, Sodium, Pentahydrate
    • Thiosulfuric Acid Disodium Salt
Study Arms  ICMJE Experimental: Treatment (rituximab, mannitol, methotrexate, carboplatin)
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.
Interventions:
  • Drug: Carboplatin
  • Other: Laboratory Biomarker Analysis
  • Drug: Mannitol
  • Drug: Methotrexate
  • Other: Quality-of-Life Assessment
  • Biological: Rituximab
  • Drug: Sodium Thiosulfate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 8, 2006)
81
Original Enrollment  ICMJE Not Provided
Estimated Study Completion Date  ICMJE January 2020
Estimated Primary Completion Date January 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
  • White blood cell count >= 2.5 x 10^3/mm^3
  • Absolute granulocyte count >= 1.2 x 10^3/mm^3
  • Platelets >= 100 x 10^3/mm^3 (or >= lower limit of institutional normal value)
  • Calculated creatinine clearance (Cr Cl) >= 50 ml/min; eligible for full dose methotrexate
  • Calculated Cr Cl >= 30 ml/min; eligible for reduced dose methotrexate
  • Bilirubin =< 2.0 x upper limit of institutional normal value
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00293475
Other Study ID Numbers  ICMJE IRB00001012
NCI-2013-00787 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CR00022596
HEM-08059-LX
MR00041596
SOL-05025-L
SOL-05025-LM
MR00045915
IRB00001012 ( Other Identifier: OHSU Knight Cancer Institute )
P30CA069533 ( U.S. NIH Grant/Contract )
R01CA137488 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Edward Neuwelt, OHSU Knight Cancer Institute
Study Sponsor  ICMJE OHSU Knight Cancer Institute
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Edward Neuwelt OHSU Knight Cancer Institute
PRS Account OHSU Knight Cancer Institute
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP