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Glucarpidase for the Improvement of Methotrexate Toxicity and Detection in Central Nervous System Involvement of Aggressive Lymphoma

Trial Status: Active

This phase II trial studies the effect of glucarpidase in improving methotrexate toxicity and detection in patients with central nervous system involvement of aggressive lymphoma. Patients with aggressive lymphomas who are at high risk of their cancer spreading to the brain and / or spinal cord or are found to have spread to the brain and / or spinal cord are often recommended to receive an additional chemotherapy drug, called methotrexate, as part of their treatment course. High-dose methotrexate is given because it is able to penetrate the brain and spinal cord more effectively than the other standard chemotherapy drugs used for lymphoma. Normally, methotrexate is administered intravenously over 4 hours followed by administration of intravenous fluids and a medication called leucovorin which both help clear the methotrexate from the body. Patients are discharged from the hospital once the methotrexate has cleared and side effects from methotrexate, if any, are resolved or improved. However, patients who are older or have a history of kidney disease are at higher risk for side effects associated with methotrexate and often require a longer time to clear the methotrexate out of the body. Patients who have a prolonged time to clear methotrexate or who have kidney damage caused by methotrexate are candidates to receive an antidote, called glucarpidase (carboxypeptidase G2), which may help to clear methotrexate more quickly form the body.

Inclusion Criteria

  • Patients must have histologically or cytologically confirmed diagnosis of non-Hodgkin lymphoma and either: * High risk of CNS relapse warranting MTX prophylaxis * Evidence of CNS involvement (either primary central nervous system lymphoma [PCNSL] or secondary CNS lymphoma) warranting therapeutic MTX treatment * Diffuse large B-cell lymphoma (DLBCL) ** Transformation to DLBCL from an antecedent low-grade lymphoma is permitted * Burkitt lymphoma (BL) * Plasmablastic lymphoma * Blastoid variant of mantle cell lymphoma * Richter transformation * Primary CNS lymphoma * Secondary CNS lymphoma of any B cell lineage * B cell non-Hodgkin lymphoma with neurologic symptoms suspicious for CNS involvement
  • Patients must have at least one of the following 2 criteria; * Aged >= 65 year with baseline CrCl > 30 ml/min/1.73 m^2 * Any age with a baseline CrCl of 30-59 ml/min/1.73 m^2
  • Patients must meet criteria for and are appropriate candidates for treatment or prophylaxis with high dose systemic MTX of 3.5 g/m^2 if CrCl > 60 ml/min and 2 g/m^2 if creatinine (Cr) 30-59 mL/min
  • Patients planned to have 2 or more cycles of high dose MTX as part of treatment regimen. If patents are planned to have more than 4 cycles of MTX, they can be included in study, however glucarpidase will be provided only for up to 4 cycles of MTX
  • Patients must be willing and eligible to undergo diagnostic lumbar puncture for initial staging and also post treatment if evidence of CNS involvement
  • Patients with confirmed CNS involvement of disease on lumbar puncture testing or those with clinical symptoms of CNS involvement will require baseline and post treatment brain and spinal magnetic resonance imaging (MRI). If there is contraindication to MRI, computed tomography (CT) scan is permitted
  • Patients must be willing and able to comply with scheduled visits and testing
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • Platelets >= 100 x 10^9/L and no platelet transfusion within the past 28 days prior to study registration
  • Hemoglobin (Hgb) >= 8g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration
  • International normalized ratio (INR) =< 1.5 and partial thromboplastin time (PTT) (activated [a]PTT) =< 1.5 times the upper limit of normal
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 times the upper limit of normal
  • Serum bilirubin =< 1.5 times the upper limit of normal; or total bilirubin =< 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert syndrome
  • CrCl >= 30 mL/min using the Cockcroft-Gault equation
  • Patients with therapeutically intervenable ascites fluid and/or pleural effusions are permitted on trial. However, patients must demonstrate absent or mild/trace effusion on post procedure imaging with ultrasound or CT scan within 7 days of each MTX cycle
  • Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 30 days after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 3 months after the last dose
  • Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry

Exclusion Criteria

  • Patients who received CNS directed therapy (intrathecal chemotherapy or systemic HD-MTX) or glucarpidase prior to enrollment. Patients may receive intrathecal prophylaxis at time of initial CSF fluid collection or as part of treatment protocol
  • Patients with moderate or severe pleural effusion and/or abdominal ascites at time of enrollment that are not amenable to therapeutic thoracentesis or paracentesis, respectively
  • Patients with contraindication or refusal to have cerebrospinal fluid sampling
  • Patients with contraindication or refusal to have inpatient HD-MTX administration as part of therapy Patients may not be receiving any other investigational agent
  • Patients who will require any medications or substances that are inhibitors or inducers of glucarpidase or MTX during hospitalization for therapy administration are ineligible

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: ACTIVE
Contact: Shazia Nakhoda
Phone: 267-844-2772

PRIMARY OBJECTIVE:

I. To assess efficacy of glucarpidase in reducing rate of delayed methotrexate (MTX) clearance compared to historical controls in patients that are high risk of delayed clearance and toxicity (age 65 years and older and/or baseline creatinine clearance [CrCl] of 30-59 ml/min) and receiving MTX as part of treatment for or prophylaxis against central nervous system involvement of B cell lymphoma.

SECONDARY OBJECTIVES:

I. To assess the efficacy of glucarpidase in preventing systemic chemotherapy treatment delay.

II. To assess the efficacy of glucarpidase in decreasing complication rate.

III. To assess the pharmacokinetics of MTX clearance after prophylactic glucarpidase administration with standard 2000 unit dosing with each cycle.

IV. To assess the rate of anti-drug antibody detection in patients receiving glucarpidase.

V. To assess the concordance of cell free deoxyribonucleic acid (cfDNA) compared to cell cytology and flow cytometry in the cerebrospinal fluid (CSF).

VI. To describe the rate of central nervous system (CNS) lymphoma clearance in patients with evidence of CNS involvement at baseline who receive glucarpidase.

VII. To describe the rate of CNS relapse in patients receiving prophylactic MTX who receive glucarpidase.

OUTLINE:

Patients receive high-dose methotrexate (HD-MTX) via infusion over 4 hours, then within 24-27 hours, receive glucarpidase intravenously (IV) over 5 minutes. Treatment repeats for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Fox Chase Cancer Center

Principal Investigator
Shazia Nakhoda

  • Primary ID 20-1071
  • Secondary IDs NCI-2021-04263
  • Clinicaltrials.gov ID NCT04668768