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Glucarpidase in Treating Patients with Central Nervous System B-Cell Non-Hodgkin Lymphoma

Trial Status: Active

This early phase I trial studies how well glucarpidase works in treating patients with central nervous system B-cell non-Hodgkin lymphoma. Glucarpidase is a type of bacterial enzyme that breaks down proteins and other substances. It may also help activate certain drugs to kill cancer. Giving glucarpidase may work better in treating patients with central nervous system B-cell non-Hodgkin lymphoma.

Inclusion Criteria

  • ARM A: Histologically documented B-cell non-Hodgkin's lymphoma involving the brain, spinal cord, and/or leptomeningeal space * Patients in whom the type of lymphoma could not be determined or is unknown (e.g., not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible
  • ARM A: Patients with parenchymal lesions must have received no more than two cycles of treatment for treatment of CNS lymphoma or have unequivocal evidence of disease progression on imaging (magnetic resonance imaging [MRI] of the brain/spine or computed tomography [CT] head) 28 days prior to study registration. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings must be consistent with CSF disease 28 days prior to study registration (at the discretion of the investigator)
  • ARM A: Patients who have already received one or two cycles of treatment of central nervous system (CNS) lymphoma are eligible for enrollment as long as they are planned for at least 6 additional doses of methotrexate. Patients must not have evidence of systemic non-Hodgkin lymphoma requiring active treatment
  • ARM A: Patients must have a Karnofsky Performance Status (KPS) >= 50
  • ARM A: Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests
  • ARM A: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
  • ARM A: Platelets >= 100 x 10^9 /L and no platelet transfusion within the past 28 days prior to study registration
  • ARM A: Hemoglobin (Hgb) >= 8 g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration
  • ARM A: International normalized ratio (INR) =< 1.5 and partial thromboplastin time (PTT) (activated [a] PTT) =< 1.5 times the upper limit of normal
  • ARM A: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 times the upper limit of normal
  • ARM A: 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
  • ARM A: Creatinine clearance (CrCl) >= 60 mL/min using the Cockcroft-Gault equation
  • ARM A: 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
  • ARM A: Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry
  • ARM A: Patients must be able to tolerate MRI/CT scans
  • ARM A: Patients must be able to tolerate lumbar puncture and/or Ommaya taps
  • ARM A: Participants must have recovered to grade 1 toxicity from prior therapy
  • NOTE: Patients who have initiated and received up to two cycles of treatment will not be excluded from study Arm A as long as all pretreatment assessments have been completed within 28 days of trial initiation
  • ARM B: Histologically documented B-cell non-Hodgkin’s lymphoma involving the brain, spinal cord, and/or leptomeningeal space * Patients in whom the type of lymphoma could not be determined or is unknown (e.g., not enough tissue for further analysis) are assumed to have a B cell lymphoma and are eligible
  • ARM B: Patients must be treatment naive or have unequivocal evidence of disease progression on imaging (MRI of the brain/spine or CT head) 28 days prior to study registration. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings must be consistent with CSF disease 28 days prior to study registration (at the discretion of the investigator)
  • ARM B: Patients must not have evidence of systemic non-Hodgkin lymphoma requiring active treatment
  • ARM B: Patients must have a KPS >= 70 or >= 50 if KPS is due to a neurologic deficit attributed to active disease
  • ARM B: Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests
  • ARM B: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L;
  • ARM B: Platelets >= 100 x 10^9/L and no platelet transfusion within the past 28 days prior to study registration
  • ARM B: Hemoglobin (Hgb) >= 8 g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration
  • ARM B: International normalized ratio (INR) =< 1.5 and PTT (aPTT) =< 1.5 times the upper limit of normal
  • ARM B: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 times the upper limit of normal
  • ARM B: 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
  • ARM B: CrCl >= 60 mL/min using the Cockcroft-Gault equation
  • ARM B: 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
  • ARM B: Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry
  • ARM B: Patients must be able to tolerate MRI/CT scans
  • ARM B: Patients must be able to tolerate lumbar puncture and/or Ommaya taps
  • ARM B: Participants must have recovered to grade 1 toxicity from prior therapy
  • ARM B: Patients with ocular manifestation of systemic lymphoma are allowed if repeat ophthalmologic exam is planned for the end of therapy. If ocular disease remains present, ocular-directed therapy may be administered after treatment with methotrexate
  • NOTE: Prior autologous stem cell transplant as w ell as prior radiation to the CNS does NOT prevent patients from enrollment into the trial.
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients eligible for inclusion in this arm must be eligible for inpatient MTX administration for treatment of CNS lymphoma. Patients should have received prior MTX therapy without major adverse events
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry

Exclusion Criteria

  • ARMS A AND B: Patient with secondary central nervous system lymphoma (SCNSL) requiring treatment for extra-CNS disease are excluded
  • ARMS A AND B: Patient concurrently using other approved or investigational antineoplastic agents
  • ARMS A AND B: Patient has received chemotherapy, monoclonal antibodies or targeted anticancer therapy =< 4 weeks or 5 half-lives, whichever is shorter, or 6 weeks for nitrosoureas or mitomycin-C prior to starting the study drug, or the patient has not recovered from the side effects of such therapy. Exceptions are allowed for rituximab and methotrexate for patients enrolling Arm A as long as patients have recovered from side effects
  • ARMS A AND B: Patient has received external beam radiation therapy to the CNS within 28 days of the first dose of the study drug
  • ARMS A AND B: Patient has an active concurrent malignancy requiring active therapy
  • ARMS A AND B: The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first dose of the study drug
  • ARMS A AND B: Patient weighs < 40 kg
  • ARMS A AND B: Patient is allergic to components of the study drug
  • ARMS A AND B: Patient is known to have human immunodeficiency virus (HIV) infection
  • ARMS A AND B: Patient is known to have a history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests
  • ARMS A AND B: Severe, active medical co-morbidity such as unstable angina and/or congestive heart failure, coronary artery disease, significant abnormalities on electrocardiogram (EKG), uncontrolled or symptomatic arrhythmias or valvular disease; active infection, severe chronic obstructive pulmonary disease or other respiratory illness, hepatic insufficiency, known pre-existing immunodeficiency as seen in organ transplant recipients, renal failure with CrCl < 60 mL/min
  • ARMS A AND B: Patient has a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject's safety or put the study outcomes at undue risk
  • ARMS A AND B: Patient has large pleural or ascetic fluid collection
  • ARMS A AND B: Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
  • ARMS A AND B: Prior severe allergic reaction to any of the study drugs that cannot be resolved with medication
  • ARMS A AND B: Patient has undergone prior allogenic stem cell transplant (autologous stem cell transplant is NOT an exclusion)
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients with SCNSL requiring treatment for extra-CNS disease are excluded
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients weighing < 40 kg
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Absolute neutrophil count (ANC) =< 0.5 x 10^9/L
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Platelets =< 75 x 10^9/L
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Hemoglobin (Hgb) =< 8 g/dL
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 times the upper limit of normal
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Serum bilirubin >= 1.5 times the upper limit of normal; or total bilirubin >= 3 times the upper limit of normal with direct bilirubin outside of the normal range in patients with well documented Gilbert syndrome
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Creatinine >= 1.3 mg/dL
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients allergic to components of the study drug
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients with severe, active medical co-morbidity such as unstable angina and/or congestive heart failure, coronary artery disease, significant abnormalities on electrocardiogram (EKG), uncontrolled or symptomatic arrhythmias or valvular disease; active infection, severe chronic obstructive pulmonary disease or other respiratory illness, hepatic insufficiency, known pre-existing immunodeficiency as seen in organ transplant recipients, renal failure with creatinine >= 1.3 mg/dL
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients with a life-threatening illness, medical condition, or organ system dysfunction that, in the opinion of the investigator, could compromise the subject’s safety or put the study outcomes at undue risk
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Patients with large pleural or ascetic fluid collection
  • ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19: Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 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

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: ACTIVE
Contact: Louis Burton Nabors
Phone: 205-934-1432

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Lauren R Schaff
Phone: 212-610-0485

PRIMARY OBJECTIVES:

I. To demonstrate that reduced glucarpidase doses (2000 units and 1000 units) routinely result in significant reduction of serum methotrexate (MTX) levels (> 95% reduction in 6 hours) when administered 24 hours following start of MTX infusion in central nervous system lymphoma (CNSL) patients receiving multiple cycles of MTX. (Arm A)

II. To demonstrate that reduced dose of glucarpidase (2000 units) routinely results in significant reduction of serum MTX levels (> 95% reduction of serum MTX level within 1 hour following glucarpidase administration) in patients receiving multiple cycles of MTX 8 g/m^2. (Arm B)

III. To demonstrate feasibility of outpatient administration of high dose (HD)-MTX when given in conjunction with glucarpidase 2000 units, defined by ability of glucarpidase to reduce HD-MTX levels to < 100 nmol/L by 48 hours post-MTX administration. (Arm Outpatient MTX Therapy in times of coronavirus disease 2019 [COVID-19])

SECONDARY OBJECTIVES:

I. To determine the time to reach a MTX level =< 100 nmol as measured by MTX immunoassay and mass spectrometry/high pressure liquid chromatography (HPLC). (Arms A and B)

II. To describe levels of MTX and deoxyaminopteroic acid (DAMPA) in plasma and cerebrospinal fluid (CSF) following glucarpidase administration. (Arms A and B)

III. To describe safety, toxicity, and tolerability of glucarpidase when administered following multiple courses of MTX. (Arms A and B)

IV. To describe tumor response to rituximab and MTX in the setting of glucarpidase administration. (Arms A and B)

V. To describe duration of tumor response to rituximab and MTX in the setting of glucarpidase administration. (Arms A and B)

VI. To explore overall and progression free survival in this patient population. (Arms A and B)

VII. To assess development of anti-glucarpidase antibodies after glucarpidase administration. (Arms A and B)

VIII. To describe safety, toxicity, and tolerability of HD-MTX in conjunction with glucarpidase administered in the outpatient setting. (Arm Outpatient MTX Therapy in times of COVID-19)

IX. To describe rate of hospital admission for patients receiving outpatient MTX with glucarpidase. (Arm Outpatient MTX Therapy in times of COVID-19)

X. To describe the number of inpatient hospital days required for patients receiving outpatient MTX with glucarpidase. (Arm Outpatient MTX Therapy in times of COVID-19)

EXPLORATORY OBJECTIVES:

I. To explore the renal elimination of DAMPA by measuring levels in the urine. (Arm A)

II. To explore glucarpidase concentrations in the CSF. (Arms A and B)

III. To explore quality of life metrics in patients with CNSL receiving glucarpidase with MTX and rituximab. (Arms A and B)

IV. To explore glucarpidase levels in serum plasma following administration in a subset of patients. (Arms A and B)

V. To explore feasibility of MTX point of care testing. (Arms A and B)

VI. To describe the sustainability of reduced MTX levels following administration of glucarpidase. (Arms A and B)

OUTLINE: Patients are assigned to 1 of 3 arms.

ARM A: Patients are assigned to 1 of 2 cohorts:

COHORT I: Patients receive rituximab intravenously (IV) on day 1, low dose methotrexate IV over 2 hours on day 2, and glucarpidase IV over 5 minutes on day 3. Patients also receive standard of care leucovorin orally (PO) or IV every 6 hours for 12 doses starting 2 hours after glucarpidase. Treatment repeats every 14 days for 6-8 cycles in the absence of disease progression or unacceptability toxicity.

COHORT II: Patients receive rituximab IV on day 1, high dose methotrexate IV over 2 hours on day 2, and glucarpidase IV over 5 minutes on day 3. Patients also receive standard of care leucovorin PO or IV every 6 hours for 12 doses starting 2 hours after glucarpidase. Treatment repeats every 14 days for 6-8 cycles in the absence of disease progression or unacceptability toxicity.

ARM B:

Patients receive rituximab IV on day 1, methotrexate IV over 4 hours on day 2, and glucarpidase IV over 5 minutes on day 3. Patients also receive standard of care leucovorin PO or IV every 6 hours for 12 doses starting 2 hours after glucarpidase. Treatment repeats every 14 days for up to 8 cycles in the absence of disease progression or unacceptability toxicity.

ARM OUTPATIENT MTX THERAPY IN TIMES OF COVID-19:

If patient's urine pH is < 7, then patients receive sodium bicarbonate PO every 6 hours until urine pH > 7. Patients then receive methotrexate IV over 2 hours on day 1 and glucarpidase IV over 5 minutes on day 2 in the absence of disease progression or unacceptable toxicity. Patients also receive standard of care leucovorin PO every 6 hours for 12 doses starting 2 hours after glucarpidase. Patients may receive rituximab IV per physician preference. Patients have the option of re-enrolling into this arm for subsequent doses of methotrexate.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, then every 6 months for 5 years, then once yearly thereafter.

Trial Phase Phase O

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Lauren R Schaff

  • Primary ID 18-410
  • Secondary IDs NCI-2018-02991
  • Clinicaltrials.gov ID NCT03684980