Clinical Trials /

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

NCT03684980

Description:

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.

Related Conditions:
  • Central Nervous System Lymphoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: LTA Pilot Study of Glucarpidase in Patients With Central Nervous System Lymphoma - ARM A
  • Official Title: LTA Pilot Study of Glucarpidase in Patients With Central Nervous System Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 18-410
  • NCT ID: NCT03684980

Conditions

  • Central Nervous System Lymphoma

Interventions

DrugSynonymsArms
VoraxazeMTX 3 g/m^2
MethotrexateMTX 3 g/m^2
RituximabMTX 3 g/m^2
leucovorinMTX 3 g/m^2

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
MTX 3 g/m^2ExperimentalPatients 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.
  • Voraxaze
  • Methotrexate
  • Rituximab
  • leucovorin
MTX 8 g/m^2ExperimentalPatients 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.
  • Voraxaze
  • Methotrexate
  • Rituximab
  • leucovorin

Eligibility Criteria

        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

          -  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;

               -  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 ≥ 60 mL/min using the Cockcroft-Gault equation. Men: CrCl (min/mL) =
                  (140-age) X (actual weight in kg) / 72 X serum creatinine (mg/dL) Women: CrCl
                  (mL/min) = (140-age) X (actual weight in kg) X 0.85 / 72 X serum creatinine
                  (mg/dL)

          -  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.

          -  Patients must be able to tolerate MRI/CT scans.

          -  Patients must be able to tolerate lumbar puncture and/or Ommaya taps.

          -  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

          -  Patients must be treatment naïve 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 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) >/= 70 or >/= 50 if KPS is due
             to a neurologic deficit attributed to active disease

          -  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) >/= 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 PTT (aPTT) </= 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 >/= 60 mL/min using the Cockcroft-Gault equation Men: CrCl (min/mL) =
                  (140-age) X (actual weight in kg) / 72 X serum creatinine (mg/dL) Women: CrCl
                  (mL/min) = (140-age) X (actual weight in kg) X 0.85 / 72 X serum creatinine
                  (mg/dL)

          -  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

          -  Patients must be able to tolerate MRI/CT scans

          -  Patients must be able to tolerate lumbar puncture and/or Ommaya taps

          -  Participants must have recovered to grade 1 toxicity from prior therapy

        NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT
        prevent patients from enrollment into the trial.

        Exclusion Criteria:

        Arms A and B:

          -  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.

          -  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.

          -  Prior severe allergic reaction to any of the study drugs that cannot be resolved with
             medication.

          -  Patient has undergone prior allogenic stem cell transplant (autologous stem cell
             transplant is NOT an exclusion).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:number of patients that have significant reduction of serum methotrexate levels
Time Frame:1 year
Safety Issue:
Description: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.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial 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

Last Updated

November 14, 2019