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

This study has been completed.
Sponsor:
Collaborator:
Cancer Research UK
Information provided by (Responsible Party):
University College, London
ClinicalTrials.gov Identifier:
NCT00727831
First received: August 1, 2008
Last updated: January 24, 2014
Last verified: January 2014

August 1, 2008
January 24, 2014
July 2008
July 2011   (final data collection date for primary outcome measure)
  • Immediate toxicity (incidence of reactions to glucarpidase) as determined by the NCI CTC [ Designated as safety issue: Yes ]
  • Incidence and severity of renal dysfunction as determined by the NCI CTC [ Designated as safety issue: Yes ]
  • Incidence and severity of mucositis as determined by the NCI CTC and WHO mucositis grading scale [ Designated as safety issue: Yes ]
  • 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 [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT00727831 on ClinicalTrials.gov Archive Site
  • 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) [ Designated as safety issue: Yes ]
  • 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) [ Designated as safety issue: Yes ]
  • Number of inpatient days taken from patients' medical records [ Designated as safety issue: No ]
  • Disease response and remission rates measured by serial MRI scanning (and eye examination and lumbar puncture if necessary) [ Designated as safety issue: No ]
  • Disease outcome, time to progression, and overall survival at 2 years from start of therapy measured by clinical examination and serial MRI scanning [ Designated as safety issue: No ]
  • Relative dose intensity [ Designated as safety issue: No ]
  • 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) [ Designated as safety issue: No ]
  • Incidence of antibodies to glucarpidase measured serologically at the start of each methotrexate course and at follow-up visits if present during therapy [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Methotrexate, Glucarpidase, and Leucovorin in Treating Patients With Newly Diagnosed Primary Central Nervous System Lymphoma
Phase I Trial of Escalating High Dose Methotrexate Supported by Glucarpidase to Treat Patients With Primary Central Nervous Lymphoma (PCNSL)

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.

OBJECTIVES:

Primary

  • 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.

Secondary

  • 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.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
4
July 2011
July 2011   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

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

PRIOR CONCURRENT THERAPY:

  • No prior cytotoxic chemotherapy
  • No concurrent prophylactic antibiotics
  • No concurrent co-trimoxazole
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United Kingdom
 
NCT00727831
CDR0000599206, CRUK-BRD/07/004, 2007-002570-58, EU-20861
Yes
University College, London
University College, London
Cancer Research UK
Principal Investigator: Roderick Johnson, MD Leeds General Infirmary
University College, London
January 2014

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