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Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be administered every 2 weeks for 6 cycles. Two additional consolidation cycles of high-dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks following completion of the combined therapy.

6000 mg/m\^2 will be administered by intravenous infusion over 4 hours after confirming that the recipient patients urine pH is within the range greater than or equal to 7 to less than or equal to 8, and urine output is greater than or equal to 100 mL/hour.

375 mg/m\^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate

Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes

Robert Yarchoan, M.D.

This study will investigate the use of chemotherapy plus highly active antiretroviral therapy (HAART) in patients with Acquired Immunodeficiency Syndrome (AIDS)-related primary brain lymphoma. None of the drugs used in this study are experimental, but chemotherapy plus HAART has not been established as a standard treatment in patients with AIDS. The chemotherapy regimen used in this study (see below) was chosen because it may be less toxic to immune cells called T-lymphocytes than most drug treatments for lymphoma.

People with AIDS 18 and older and have primary brain lymphoma may be eligible for this study. Candidates are screened with a medical history and physical examination, magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans, cerebrospinal fluid studies, brain biopsy at tumor sites, if possible, electrocardiogram and blood tests.

Participants undergo six 2-week "induction treatment" cycles of HAART plus chemotherapy with methotrexate, rituximab and leucovorin, followed by two 4-week "consolidation" treatment cycles using HAART, methotrexate and leucovorin, and then HAART alone. Rituximab is given by intravenous (intravenous (IV), through a vein) day 1 of each cycle. Also on day 1 IV fluids are given to lower acidity in the urine to protect the kidneys from the methotrexate. On day 2, methotrexate is infused through a vein over 4 hours. Starting 24 hours after initiation of the methotrexate infusion, leucovorin is given every 3 to 6 hours (first IV and then possibly by mouth) until the drug decreases to a target level in the blood. HAART is begun as soon as possible. The specific HAART regimen for each patient is determined individually. All patients are hospitalized the first week of every 2-week treatment cycle for safety monitoring. In addition to HAART and chemotherapy, patients undergo the following tests and procedures:

* Intellectual functioning: Before starting treatment, patients are tested for their ability to understand basic concepts and coordination in order to be able to evaluate how the brain lymphoma affects thinking and concentration. After the lymphoma appears to have resolved, more formal and intensive tests are done. The intensive tests are repeated each year, and shorter, interim tests are done about every 6 months. Also, a specialist periodically monitors patients' understanding of HAART and the importance of this therapy.
* Blood tests: Blood is drawn every day during hospitalizations to measure methotrexate levels and to evaluate kidney and liver function and blood counts. Blood is also drawn before starting therapy, when the lymphoma disappears, 6 months after completing treatment, and any time it appears that the lymphoma may have recurred to test for Epstein-Barr virus (EBV), a virus that is almost always present in AIDS-related primary brain lymphoma.
* Imaging tests: Patients undergo magnetic resonance imaging (MRI) and positron emission tomography (PET) scans periodically to monitor the effects of treatment on the lymphoma. MRI scans are done after the 2nd, 4th, 6th, and 8th treatments, then every 2 months for three times, every 3 months for six times, every 6 months for four times, and then every year for 5 years, or sooner if there is a concern about the brain. PET scans are done after the first cycle, after the MRI suggests the lymphoma is gone, and then yearly.
* Lumbar puncture (spinal tap): This test is done to look for EBV in the cerebrospinal fluid (CSF). Under local anesthetic, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord and a small amount of fluid is collected through the needle. This test is done at the same times as the blood tests for EBV.
* Eye examinations: Patients' eyes are examined periodically because brain lymphoma can sometimes spread to the eye and because some people with AIDS-related primary brain lymphoma are at risk of certain eye infections.

Background: Acquired Immunodeficiency Syndrome (AIDS)-related primary central nervous system lymphoma (AR-PCNSL) is an Epstein-Barr virus (EBV)-driven lymphoproliferative process that typically results in death within a few months. Essentially all of the cases are immunoblastic cluster of differentiation 20 (CD20+) tumors, and occur once the cluster of differentiation 4 (CD4+) cells have fallen to below 50 cells/mm\^3. Highly active antiretroviral therapy (HAART) can result in immune reconstitution that decreases the risk of AR-PCNSL. However, a subset of human immunodeficiency virus (HIV)-infected patients still develops ARPCNSL, often because they are unaware that they are HIV infected, or they do not take HAART. Treatment options for such patients are limited. In the non-AIDS setting, chemotherapy has become the standard of care for primary central nervous system lymphoma (PCNSL) and late neurocognitive decline consequent to radiotherapy can be avoided by such approaches. In the pre-HAART era, AR-PCNSL was generally treated with whole brain radiotherapy, however death due to recurrent lymphoma or to other AIDS complications occurred prior to the potential manifestations of late occurring radiation-related neurotoxicity. Radiation-sparing approaches have not been studied in AR-PCNSL in the HAART era, where advances in antiretroviral therapy have made curative intent chemotherapy feasible for most patients with HIV infection.

Objectives: The primary objective of this study is to estimate the fraction of patients with AR-PCNSL receiving experimental treatment consisting of HAART, combined with rituximab, high-dose methotrexate and leucovorin (R-HD-MTX) who are alive and without recurrent lymphoma or severe cognitive problems at two years. .

Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously been treated, and be able to give informed consent or have a durable power of attorney who can provide informed consent, HIV profile that makes them likely to respond to HAART. There are a number of other specific inclusion and exclusion criteria, in part to exclude patients who would be unlikely to tolerate the therapy.

Design: Phase II pilot study investigating R-HD-MTX given with leucovorin rescue and HAART as a treatment for AR-PCNSL. Evaluation will include quantitative measurement of lymphocyte subsets, quantitative polymerase chain reaction (PCR) of HIV and EBV viral loads (including both blood and cerebrospinal fluid in the case of EBV) to assess immune response and anti-viral effects. Tumor evaluation with brain magnetic resonance imaging (MRI) and brain fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET scans) will be used for staging and response assessment. Longitudinal neuropsychologic testing after complete responses are documented will serve to evaluate neurocognitive parameters post therapy.

a separate cohort for additional secondary endpoints.

Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma

AIDS-Related Primary Central Nervous System Lymphoma: A Phase II Pilot Study of High-Dose Intravenous Methotrexate With Rituximab Leucovorin Rescue and Highly Active Antiretroviral Therapy

Recurrent lymphoma as defined by the International Primary Central Nervous System (CNS) Lymphoma Collaborative Group for response assessment of aggressive Non-Hodgkin's Lymphoma (NHL) using fluorodeoxyglucose F 18 (18FDG-PET). Severe cognitive problems are defined as the inability to carry out normal activities with minimal difficulty and not requiring nursing care or hospitalization because of neurological impairment.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Response was assessed by the International Workshop Criteria for Non-Hodgkin's Lymphoma. Complete Response is disappearance of all enhancing lesions on magnetic resonance imaging of the brain. Partial Response is a reduction of enhancing tumor volume by more than 50% for at least 4 weeks. Progressive Disease is an increase of tumor volume of more than 25% or occurrence of new lesions.

Participants that are estimated to be alive or last known to be alive after Rituximab, High-Dose Methotrexate and Leucovorin treatment.

The MMSE is scored out of a maximum of 30 points. A score of \>25 is considered normal, with scores \<25 indicating different levels of cognitive impairment: mild (21-24) moderate (10-20), and severe (0-10).

An increase in CD4 cells is determined by the number of CD4+ T lymphocytes /µL of peripheral blood.

National Cancer Institute (NCI)

Principal Investigator

Induction treatment cycles with rituximab, high-dose methotrexate and leucovorin will be administered every 2 weeks for 6 cycles. Two additional consolidation cycles of high-dose methotrexate without rituximab will be administered at 4 weeks and 8 weeks following completion of the combined therapy.

Methotrexate: 6000 mg/m\^2 will be administered by intravenous infusion over 4 hours after confirming that the recipient patients urine pH is within the range greater than or equal to 7 to less than or equal to 8, and urine output is greater than or equal to 100 mL/hour.

Rituximab: 375 mg/m\^2 intravenous (IV) day 1 of each cycle prior to administration of high-dose methotrexate

Leucovorin: Leucovorin calcium doses will be administered orally or by short intravenous (IV) infusion over 15 minutes

Rituximab, High-Dose Methotrexate & Leucovorin Treatment

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Median Baseline Mini Mental State Exam (MMSE) Score

ECOG Scale: 0 is fully active and able to carry on activities of daily living without restriction; 1 is restricted in physically strenuous activity but ambulatory, can perform light housework; 2 is ambulatory and able to perform self care but unable to carry out work activities; 3 is capable of limited self care and confined to bed or chair more than 50% of waking hours; 4 is completely disabled, unable to perform selfcare, and confined to bed or chair; and 5 is dead.

Median Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status

Primary central nervous system lymphoma (PCNSL). PCNSL was biopsy confirmed or made by fludeoxyglucose positron emission tomography/cerebral spinal fluid Epstein Barr-Virus (EBV) viral load criteria.

Baseline Cluster of Differentiation (CD4) T Cell Count at PCNSL Diagnosis

Dr. Robert Yarchoan

Number of Patients Alive at 2 Years Without Recurrent Brain Lymphoma or Severe Neurocognitive Defects

Number of Participants With Serious and Non-serious Adverse Events

Complete Response

Partial Response

Progressive Disease

Two participants were not evaluable. One participant received one cycle of therapy and one was not evaluable due to treatment failure.

Number of Participants With Response to Treatment After Rituximab, High-Dose Methotrexate (R-HD-MTX) Induction

Estimated Percentage of Participants Overall Survival

Median Mini Mental Status Exam (MMSE) Score in Surviving Participants After Rituximab, High-Dose Methotrexate & Leucovorin ( R-HD-MTX) Treatment

Change From Baseline in Cluster of Differentiation 4 (CD4) T Cell Count at up to 2.5 Years

Induction Treatment

Consolidation Treatment

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Hematologic Diseases

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

Childhood Acute Lymphoblastic Leukemia

In the standard intravenous fluid (IVF) protocol, following completion of HDMTX infusion, post HDMTX IVF will be initiated at 125 mL/m2/hr (no maximum mL/hr total rate).

The reduced intravenous fluid (IVF) protocol, post HDMTX IVF will be initiated at 62.5 mL/m2/hr following completion of HDMTX infusion.

Administration of post HDMTX intravenous fluids (IVF)

Intravenous fluids

Cady P Noda, PharmD

To determine whether a reduced volume hydration regimen will lead to a shorter time to methotrexate clearance when compared to a standard intravenous (IV) hydration regimen.

This study uses a prospective randomized controlled crossover study design. Neither patients nor clinicians are blinded to the standard versus reduced intravenous fluids (IVF) regimen. Patients are randomized to begin with standard volume or reduced volume IVF. Over the course of 4 cycles of High Dose Methotrexate (HDMTX), patients alternate between standard and reduced volume post hydration fluids protocols.

The study uses a prospective randomized controlled crossover study design.

Reduced IV Fluids to Improve Clearance of HDMTX in Children w/Lymphoma or Acute Lymphoblastic Leukemia

Pilot Study on the Reduced Intravenous Fluids to Improve Clearance of High-Dose Methotrexate (HDMTX) in Children With Lymphoma or Acute Lymphoblastic Leukemia

To determine whether a reduced volume hydration regimen will lead to a shorter time to methotrexate clearance when compared to a standard IV hydration regimen by measuring serum methotrexate levels twenty-four hours following the end of the high dose methotrexate ( HDMTX) infusion, and continuing every twelve hours until the methotrexate level is less than 0.1 micromol/L.

To determine the effect of a reduced volume hydration regimen on markers of kidney toxicity (nephrotoxicity) by evaluating serum creatinine levels from baseline levels as well as the maximum decrease in estimated glomerular filtration rate (GFR) utilizing the modified Schwartz equation, following each HDMTX cycle.

To determine the effect of a reduced volume hydration regimen on markers of fluid overload by evaluating maximum weight gain during each hospitalization, and by evaluating the incidence of NCI Common Terminology Criteria for Adverse Events (CTCAE) version v5.0 ≥ grade 1 clinical sequelae of hydration such as facial edema, pulmonary edema, abdominal distension, extremity edema, and weight gain.

To examine the effects of a reduced volume hydration regimen on treatment schedule by measuring the number of days subsequent therapy is delayed for reasons other than scheduling issues or preferences.

To examine the effects of a reduced volume hydration regimen on development of severe mucositis by measuring the incidence of grade ≥ 3 (CTCAE v5.0) mucositis.

Virginia Commonwealth University

Skin and Connective Tissue Diseases

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

Soft Tissue Sarcoma

compassionate use group to treat or prevent life threatening toxicity in the event of delayed elimination of MTX and/or renal impairment

IV dose based on weight, two doses given for 5 minutes, 24 hours apart

glucarpidase

leucovorin

Pete Anderson, MD, PhD

The purpose of this study is to demonstrate whether use of glucarpidase facilitates administration of the next cycle of chemotherapy as scheduled and improves safety and tolerability of HDMTX given with LV

High Dose Methotrexate With Leucovorin Rescue With or Without Glucarpidase in Osteosarcoma

Randomized, Blinded, Placebo-Controlled Trial of High Dose Methotrexate With Leucovorin Rescue (HDMTX-LV) With or Without Glucarpidase in Osteosarcoma

M.D. Anderson Cancer Center

BTG International Inc.

First cycle: High-dose methotrexate with leucovorin, plus 2 doses of glucarpidase 24 hours apart Second cycle: High-dose methotrexate with leucovorin, plus 2 doses of placebo 24 hours apart

High-dose Methotrexate Plus Glucarpidase Then Placebo

First cycle: High-dose methotrexate with leucovorin, plus 2 doses of placebo 24 hours apart Second cycle: High-dose methotrexate with leucovorin, plus 2 doses of glucarpidase 24 hours apart

High-dose Methotrexate Plus Placebo Then Glucarpidase

Compassionate use group to treat or prevent life threatening toxicity in the event of delayed elimination of MTX and/or renal impairment. Patients received glucarpidase 50 U/kg

Arm C, Compassionate Use of Glucarpidase

Total

No efficacy endpoints were reported due to early termination (insufficient enrollment).

VP Clinical Development, BTG International

Patients Progressing to Next Chemotherapy Cycle

Overall Study

Renal Insufficiency

High-dose methotrexate, leucovorin, and Voraxaze

High-dose methotrexate and leucovorin without Voraxaze (glucarpidase)

glucarpidase, high-dose methotrexate, leucovorin

standard of care, leucovorin every 6 hours

high-dose methotrexate, leucovorin

Andrew Saunders, MD

Suzanne Kincaid, CCRA

The purpose of this study is to investigate whether the administration of Voraxaze reduces exposure to leucovorin and its active metabolite to below the level achieved in patients who have not received Voraxaze.

Open-label Leucovorin Pharmacokinetic Study in Patients Receiving High Dose Methotrexate With or Without Voraxaze

An Open-Label Study to Assess the Pharmacokinetics of Leucovorin in Patients Receiving High Dose Methotrexate, With or Without Voraxaze Treatment

Geometric mean (6S)-leucovorin area under the plasma concentration vs. time curve from time 0 to the 3-hour time point.

High-dose methotrexate, leucovorin, and glucarpidase

glucarpidase, high-dose methotrexate, leucovorin: single intravenous dose

A (High-dose Methotrexate, Leucovorin, and Glucarpidase)

High-dose methotrexate and leucovorin without glucarpidase

high-dose methotrexate, leucovorin: standard of care, leucovorin every 6 hours

B (High-dose Methotrexate and Leucovorin Without Glucarpidase)

Pre-glucarpidase (Arm A) or Pre-LV (Arm B) methotrexate plasma conc (umol/L)

SVP, Clinical Development

3 participants were excluded from the PK population (all from Arm A), hence why the total participants is 17, not 20.

Pharmacokinetics (PK) of Leucovorin

Drug: High-dose methotrexate (HDMTX) and leucovorin (LV) with a single bolus intravenous injection of 50 units/kg glucarpidase over 5 minutes.

HDMTX followed by intravenous LV administered at doses recommended in the clinical treatment protocols.

LV doses administered as recommended in the package insert for Leucovorin Calcium USP for patients with delayed early MTX elimination and/or evidence of acute renal injury, and should be based upon the pre-glucarpidase MTX concentration. LV doses are maintained for at least 48 hours after dosing with glucarpidase. After this it may be administered at doses recommended in the clinical treatment protocols and existing labeling for LV based on post-Voraxaze MTX concentrations. Patients required IV LV rescue therapy with either ≥15 mg or ≥10 mg/m2 every 6 hours.

Other Names:

Voraxaze, carboxypeptidase G2, high dose methotrexate, leucovorin

High-dose methotrexate (HDMTX) and leucovorin (LV) without glucarpidase

HDMTX followed by intravenous LV should be administered at doses recommended in the clinical treatment protocols and as per standard of care. LV should be given every 6 hours at a dose of ≤25 mg/m2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy and HAART to Treat AIDS-related Primary Brain Lymphoma	NCT00267865	AIDS-Related-Pr...	Methotrexate Rituximab Leucovorin	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Reduced IV Fluids to Improve Clearance of HDMTX in Children w/Lymphoma or Acute Lymphoblastic Leukemia	NCT03964259	Lymphoma Acute Lymphobla... Pediatric Cance... Pediatric ALL Pediatric Lymph...	Intravenous flu...	1 Year - 17 Years	Virginia Commonwealth University
High Dose Methotrexate With Leucovorin Rescue With or Without Glucarpidase in Osteosarcoma	NCT00634322	Osteosarcoma	glucarpidase leucovorin	8 Years - 50 Years	BTG International Inc.
High Dose Methotrexate With Leucovorin Rescue With or Without Glucarpidase in Osteosarcoma	NCT00634322	Osteosarcoma	glucarpidase leucovorin	8 Years - 50 Years	BTG International Inc.
Open-label Leucovorin Pharmacokinetic Study in Patients Receiving High Dose Methotrexate With or Without Voraxaze	NCT00634504	Osteosarcoma Leukemia Lymphoma	glucarpidase, h... high-dose metho...	-	BTG International Inc.
Open-label Leucovorin Pharmacokinetic Study in Patients Receiving High Dose Methotrexate With or Without Voraxaze	NCT00634504	Osteosarcoma Leukemia Lymphoma	glucarpidase, h... high-dose metho...	-	BTG International Inc.
Capizzi Escalating Methotrexate Versus High Dose Methotrexate in Children With Newly Diagnosed T-cell Lymphoblastic Lymphoma (T-LBL)	NCT05681260	T-cell Lymphobl...	Prednisone,Vinc... Prednisone,Vinc... Prednisone,Vinc...	12 Months - 18 Years	Children's Cancer Group, China
High Dose Methotrexate With Leucovorin Rescue With or Without Glucarpidase in Osteosarcoma	NCT00634322	Osteosarcoma	glucarpidase leucovorin	8 Years - 50 Years	BTG International Inc.
Individualized High Dose Methotrexate to Treat Cancer in Children Who Have a Significant Risk for Side Effects to Methotrexate	NCT02076997	Cancer	Methotrexate	1 Year - 22 Years	Baylor College of Medicine

Spots Global Cancer Trial Database for high dose methotrexate