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
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by University College, London:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 4
Study Start Date: July 2008
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00727831

Locations
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
Investigators
Principal Investigator: Roderick Johnson, MD Leeds General Infirmary
  More Information

No publications provided

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT00727831     History of Changes
Other Study ID Numbers: CDR0000599206, CRUK-BRD/07/004, 2007-002570-58, EU-20861
Study First Received: August 1, 2008
Last Updated: January 24, 2014
Health Authority: UK: Medicines & Healthcare Products Regulatory Agency

Keywords provided by University College, London:
neurotoxicity
chemotherapeutic agent toxicity
mucositis
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:
Lymphoma
Mucositis
Neurotoxicity Syndromes
Chemically-Induced Disorders
Digestive System Diseases
Gastroenteritis
Gastrointestinal Diseases
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Mouth Diseases
Neoplasms
Neoplasms by Histologic Type
Nervous System Diseases
Poisoning
Stomatognathic Diseases
Levoleucovorin
Methotrexate
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors

ClinicalTrials.gov processed this record on October 20, 2014