LTA Pilot Study of Glucarpidase in Patients With Central Nervous System Lymphoma

NCT03684980 | Active Not Recruiting Early Phase 1 FDA Drug

• 1 other identifier: 18-410
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 11

Brief Summary

The purpose of this study is to test the effects of a drug called Voraxaze when it's routinely given in combination with methotrexate and rituximab, the standard treatment for CNSL.

Conditions

Central Nervous System Lymphoma

Keywords

Voraxaze (glucarpidase); B-cell non-Hodgkin"s lymphoma involving the brain; B-cell non-Hodgkin"s lymphoma involving spinal cord, and/or leptomeningeal space

Outcome Measures

Primary Outcomes (1)

• number of patients that have significant reduction of serum methotrexate levels

  All serum samples will be tested via MTX immunoassay (measures MTX levels in addition to byproducts) as well as HPLC or mass spectroscopy which will reveal plasma concentrations of MTX and DAMPA separately.

  1 year

Study Arms (5)

Arm A - Rituximab + MTX + Glucarpidase

EXPERIMENTAL

Patients will receive rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m\^2. (Cohort A) will receive MTX 3 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Drug: Methotrexate; Drug: Rituximab; Drug: leucovorin; Drug: Glucarpidase

Arm B - Rituximab + MTX + Glucarpidase

EXPERIMENTAL

Patients will receive up to 8 cycles of treatment consisting of rituximab Day 1 (+/- 7 days) and MTX Day 2 (+/- 7 days) as per standard of care. Voraxaze will be administered each cycle 24 hours (+/- 2 h) after start of MTX infusion. Dose of Voraxaze will be 2000 units during cycles 1-4, and 1000 units during cycles 5-8. Patients will be treated with rituximab 500 mg/m\^2. (Cohort B) will receive MTX 8 g/m2. Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Drug: Rituximab; Drug: Glucarpidase

Arm C - HD-MTX (Arm Outpatient MTX Therapy in times of COVID-19)

EXPERIMENTAL

MTX ≤ 3.5 g/m2 will be administered on Day 1, along with pre- and post- hydration. Patients will return on Day 2 for continued hydration and glucarpidase 2000 units. Glucarpidase rapidly and sustainably reduces serum MTX levels \>95% without crossing the blood brain barrier, effectively resulting in systemic MTX clearance. Patients will return for bloodwork on Day 3 to document MTX clearance. Arm Outpatient MTX Therapy in times of COVID-19 will only be a single-institution arm, only open at Memorial Sloan Kettering Cancer Center.

Drug: Methotrexate; Drug: Glucarpidase

Arm D -Rituximab + MTX + Glucarpidase

EXPERIMENTAL

Up to 12 patients will be included in Arm D of this study. Cycles will be 14 days long. All patients will receive MTX 3.5 g/m2 administered Day 1 of each cycle (+/- 7 days, a minimum of 14 days required between doses). Glucarpidase will be administered 24 hours (+/- 2 hr) after start of MTX infusion except in cycles 1-2 of Cohort B. Dose of glucarpidase will be 2000 units in Cohort A (first 4 patients) and 1000 units in Cohort B (remaining 8 patients). Patients in Arm D will receive 8 cycles of treatment. Cycles 1 and 2 will be administered in patient while Cycles 3-8 may be in the outpatient setting. Concurrent chemotherapy such as vincristine, procarbazine, and/or ibrutinib may be administered at the investigator's discretion and in accordance with standard of care. In Cohort B, all cycles will be administered with rituximab 500 mg/m2. Rituximab should be administered prior to glucarpidase (window -4 days).

Drug: Methotrexate; Drug: Rituximab; Drug: Glucarpidase

Arm E-glucarpidase 1000u + MTX

EXPERIMENTAL

Study treatment consists of glucarpidase 1000u, to be administered at least 24 hours after start of standard of care MTX. Patients will have a standard of care methotrexate level drawn within 6 hours of planned glucarpidase administration to confirm eligibility (must reflect MTX \> 100 nmol/L)

Drug: Methotrexate; Drug: Glucarpidase

Interventions

Methotrexate DRUG

(Cohort A) will receive MTX 3 g/m2 or (Cohort B) will receive MTX 8 g/m\^2 (Cohort E) will receive MTX ≤ 3.5 g/ m2

Arm A - Rituximab + MTX + Glucarpidase; Arm C - HD-MTX (Arm Outpatient MTX Therapy in times of COVID-19); Arm D -Rituximab + MTX + Glucarpidase; Arm E-glucarpidase 1000u + MTX

Rituximab DRUG

Patients will be treated with rituximab 500 mg/m\^2.

Arm A - Rituximab + MTX + Glucarpidase; Arm B - Rituximab + MTX + Glucarpidase; Arm D -Rituximab + MTX + Glucarpidase

leucovorin DRUG

Patients will also receive standard of care leucovorin rescue starting at least 24 hours after MTX and 2 hours after Voraxaze. Cycles will be 14 days long.

Arm A - Rituximab + MTX + Glucarpidase

Glucarpidase DRUG

Glucarpidase 2000 units. Arm E 1000 units.

Also known as: Voraxaze

Arm A - Rituximab + MTX + Glucarpidase; Arm B - Rituximab + MTX + Glucarpidase; Arm C - HD-MTX (Arm Outpatient MTX Therapy in times of COVID-19); Arm D -Rituximab + MTX + Glucarpidase; Arm E-glucarpidase 1000u + MTX

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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 (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).
• Patients who have already received two doses of treatment of CNS lymphoma are eligible for enrollment.
• (Arm A only) 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.
• Men and woman must be at least 18 years of age on the day of consenting to the study.
• Patients must have a Karnofsky Performance Status (KPS) ≥ 50 (See Appendix 2).
• Patients must be willing and able to comply with scheduled visits, treatment plan, and laboratory tests.
• Patients must have adequate bone marrow and organ function shown by:
• 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) ≥ 8 g/dL and no red blood cells (RBC) transfusion within the past 28 days prior to study registration;
• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal;

You may not qualify if:

• Arms A, B and D:
• Patient with SCNSL requiring treatment for extra-CNS disease are excluded.
• Patient concurrently using other approved or investigational antineoplastic agents.
• 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.
• Patient has received external beam radiation therapy to the CNS within 28 days of the first dose of the study drug.
• Patient has an active concurrent malignancy requiring active therapy.
• The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first dose of the study drug.
• Patient weighs \<40kg
• Patient is allergic to components of the study drug.
• Patient is known to have human immunodeficiency virus (HIV) infection.
• 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.
• 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.
• 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.
• Patient has large pleural or ascetic fluid collection.
• Prior severe allergic reaction to any of the study drugs that cannot be resolved with medication.

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead
• University of Alabama at Birmingham: collaborator

Study Sites (11)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Dana Farber Cancer Institute (Data Collection and Specimen Analysis)

Boston, Massachusetts, 02115, United States

Location

Memorial Sloan Kettering Basking Ridge

Basking Ridge, New Jersey, 07920, United States

Location

Memorial Sloan Kettering Monmouth

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Bergen

Montvale, New Jersey, 07645, United States

Location

Memorial Sloan Kettering Commack

Commack, New York, 11725, United States

Location

Memorial Sloan Kettering Westchester

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Memorial Sloan Kettering Nassau

Uniondale, New York, 11553, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Cleveland Clinic (Data Collection and Specimen Collection)

Cleveland, Ohio, 44195, United States

Location

Related Publications (2)

• Schaff LR, Carlow D, Schofield R, Wongchai V, Madzsar J, Hyde A, Reiner AS, Panageas KS, DeAngelis LM, Mellinghoff IK, Lobbous M, Nabors LB, Grommes C. Low-Dose Planned Glucarpidase Allows Safe Outpatient High-Dose Methotrexate Treatment for CNS Lymphoma. JCO Oncol Pract. 2024 Oct;20(10):1384-1390. doi: 10.1200/OP.24.00080. Epub 2024 Jun 25.

  PMID: 38917404 DERIVED

• Schaff LR, Lobbous M, Carlow D, Schofield R, Gavrilovic IT, Miller AM, Stone JB, Piotrowski AF, Sener U, Skakodub A, Acosta EP, Ryan KJ, Mellinghoff IK, DeAngelis LM, Nabors LB, Grommes C. Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study. BMC Cancer. 2022 Jan 13;22(1):60. doi: 10.1186/s12885-021-09164-x.

  PMID: 35027038 DERIVED

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Interventions

Methotrexate; Rituximab; Leucovorin; glucarpidase

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Study Officials

• Lauren Schaff, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open-label, non-randomized, pilot study of Voraxaze administered following standard of care MTX and rituximab in patients with CNS lymphoma.

Study Record Dates

• First Submitted: September 24, 2018
• First Posted: September 26, 2018
• Study Start: November 14, 2018
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2027
• Last Updated: April 15, 2026

Record last verified: 2026-04

Locations

US (11)