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

January 24, 2014 updated by: University College, London

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 2
Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United Kingdom
- England
  - Leeds, England, United Kingdom, LS1 3EX
    - Leeds General Infirmary
  - Torquay, England, United Kingdom, TQ2 7AA
    - Torbay Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: N/A
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Immediate toxicity (incidence of reactions to glucarpidase) as determined by the NCI CTC
Incidence and severity of renal dysfunction as determined by the NCI CTC
Incidence and severity of mucositis as determined by the NCI CTC and WHO mucositis grading scale
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

Outcome Measure
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)
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)
Number of inpatient days taken from patients' medical records
Disease response and remission rates measured by serial MRI scanning (and eye examination and lumbar puncture if necessary)
Disease outcome, time to progression, and overall survival at 2 years from start of therapy measured by clinical examination and serial MRI scanning
Relative dose intensity
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)
Incidence of antibodies to glucarpidase measured serologically at the start of each methotrexate course and at follow-up visits if present during therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College, London

Collaborators

Cancer Research UK

Investigators

Principal Investigator: Roderick Johnson, MD, Leeds General Infirmary

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2008

Primary Completion (Actual)

July 1, 2011

Study Completion (Actual)

July 1, 2011

Study Registration Dates

First Submitted

August 1, 2008

First Submitted That Met QC Criteria

August 1, 2008

First Posted (Estimate)

August 4, 2008

Study Record Updates

Last Update Posted (Estimate)

January 27, 2014

Last Update Submitted That Met QC Criteria

January 24, 2014

Last Verified

January 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

CDR0000599206
CRUK-BRD/07/004
2007-002570-58
EU-20861

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