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Methotrexate, Glucarpidase, and Leucovorin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00727831
Recruitment Status : Completed
First Posted : August 4, 2008
Last Update Posted : January 27, 2014
Cancer Research UK
Information provided by (Responsible Party):
University College, London

Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as methotrexate and leucovorin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Glucarpidase may help return the level of methotrexate in the blood to a safe range. Giving high-dose methotrexate together with glucarpidase and leucovorin may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of methotrexate when given together with glucarpidase and leucovorin in treating patients with newly diagnosed primary central nervous system lymphoma.

Condition or disease Intervention/treatment Phase
Chemotherapeutic Agent Toxicity Lymphoma Mucositis Neurotoxicity Drug: glucarpidase Drug: leucovorin calcium Drug: methotrexate Other: laboratory biomarker analysis Procedure: quality-of-life assessment Radiation: radiation therapy Phase 1 Phase 2

Detailed Description:



  • To determine the dose-limiting toxicity of methotrexate (MTX) when given in combination with glucarpidase in patients with newly diagnosed primary CNS lymphoma (PCNSL).
  • To determine the incidence of immediate reactions related to the use of glucarpidase in these patients.
  • To define a safer, more practical, and simpler regimen for delivering multiple courses of high-dose MTX using glucarpidase and 'short' leucovorin calcium rescue in these patients.
  • To monitor quality of life and mental function during and after therapy in these patients.


  • To use this regimen as a platform for phase III studies in PCNSL.
  • To record disease response, duration of response, and overall survival of patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of high-dose methotrexate (HD-MTX).

Patients receive HD-MTX IV over 4 hours on day 1. Beginning 22 hours after the start of HD-MTX, patients receive glucarpidase IV over 15 minutes on day 2 followed by leucovorin calcium orally or IV on days 2-7. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Within 2-4 weeks after completion of study treatment, patients achieving maximum response are stratified according to age (< 60 years vs ≥ 60 years) and may undergo whole brain radiotherapy (WBRT) once daily, 5 days a week, for 3 to 5 weeks.

Patients undergo blood sample collection periodically to assess glucarpidase antibodies and MTX levels.

Patients are assessed for mucositis incidence and severity periodically, and complete quality of life assessments using the EORTC QLQ-30 questionnaire and the Mini-Mental State questionnaire at baseline, during, and after completion of study.

After completion of study treatment, patients are followed at 6 weeks after WBRT, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 3 years, and then annually thereafter.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Escalating High Dose Methotrexate Supported by Glucarpidase to Treat Patients With Primary Central Nervous Lymphoma (PCNSL)
Study Start Date : July 2008
Actual Primary Completion Date : July 2011
Actual Study Completion Date : July 2011

Primary Outcome Measures :
  1. Immediate toxicity (incidence of reactions to glucarpidase) as determined by the NCI CTC
  2. Incidence and severity of renal dysfunction as determined by the NCI CTC
  3. Incidence and severity of mucositis as determined by the NCI CTC and WHO mucositis grading scale
  4. Incidence and severity of CNS toxicity and neurocognitive changes taken from patients' medical records and measured using the Mini-Mental State questionnaire and MRI data

Secondary Outcome Measures :
  1. Hematological toxicity (i.e., number of courses of therapy associated with neutrophils < 0.5 x 10e9/L or platelets < 50 x 10e9/L as measured by routine blood counts)
  2. Incidence of infection (i.e., number of days with fever ≥ 38 C° measured by clinical examination and days of intravenous antibiotics taken from patients' medical records)
  3. Number of inpatient days taken from patients' medical records
  4. Disease response and remission rates measured by serial MRI scanning (and eye examination and lumbar puncture if necessary)
  5. Disease outcome, time to progression, and overall survival at 2 years from start of therapy measured by clinical examination and serial MRI scanning
  6. Relative dose intensity
  7. Methotrexate levels post-glucarpidase (expressed as a clinically important reduction, which is defined as a methotrexate level of < 1 μmol/L in all post-glucarpidase samples)
  8. Incidence of antibodies to glucarpidase measured serologically at the start of each methotrexate course and at follow-up visits if present during therapy

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Histologically confirmed newly diagnosed primary CNS lymphoma (PCNSL)

    • Previously untreated disease
    • Diffuse large B-cell lymphoma histology
  • Must be clinically eligible to receive standard 3 g/m² methotrexate if outside trial
  • No clinically significant effusions or edema


Inclusion criteria:

  • ECOG performance status 0-3
  • Neutrophils ≥ 1 x 10^9/L
  • Platelet count ≥ 100 x 10^9/L
  • Bilirubin < 1.5 times upper limit of normal
  • Glomerular filtration rate (initially measured by EDTA/isotope method) ≥ 50 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 6 months after completion of study therapy

Exclusion criteria:

  • HIV positivity
  • Dementia or neurological dysfunction not considered to be due to the PCNSL
  • Other serious or uncontrolled medical conditions
  • Prior malignancy, except adequately treated nonmelanoma skin cancer or carcinoma in situ


  • No prior cytotoxic chemotherapy
  • No concurrent prophylactic antibiotics
  • No concurrent co-trimoxazole

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00727831

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United Kingdom
Leeds General Infirmary
Leeds, England, United Kingdom, LS1 3EX
Torbay Hospital
Torquay, England, United Kingdom, TQ2 7AA
Sponsors and Collaborators
University College, London
Cancer Research UK
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Principal Investigator: Roderick Johnson, MD Leeds General Infirmary
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Responsible Party: University College, London Identifier: NCT00727831    
Other Study ID Numbers: CDR0000599206
First Posted: August 4, 2008    Key Record Dates
Last Update Posted: January 27, 2014
Last Verified: January 2014
Keywords provided by University College, London:
chemotherapeutic agent toxicity
primary central nervous system non-Hodgkin lymphoma
contiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
stage I adult diffuse large cell lymphoma
stage III adult diffuse large cell lymphoma
stage IV adult diffuse large cell lymphoma
Additional relevant MeSH terms:
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Neurotoxicity Syndromes
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Nervous System Diseases
Chemically-Induced Disorders
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents