Clinical Trial Finder

Inclusion Criteria:

• - Primary or secondary CNSL (PCNSL or SCNSL) confirmed by histology or cytology.

• - Renal insufficiency defined as a glomerular filtration rate (GFR, assessed by CKD-EPI or MDRD equation) of 40-80 mL/min or patients with a GFR >80mL/min who have experienced renal failure, defined as doubling of the serum creatinine compared to the baseline value during a previous HD-MTX treatment.

• - Age ≥ 18 years (male or female).

• - Life expectancy >3 months.

• - Adequate organ function (i.e., bone marrow, liver, lungs) allowing intensive chemotherapy with MTX.

• - Adequate clinical pathology values: - Absolute neutrophil count ≥1.0 x 109/L, hemoglobin ≥9mg/dL (transfusion allowed), platelets ≥100 x 109/L.

• - Total bilirubin ≤1.5x the upper limit of normal except for patients with known Gilbert syndrome.

• - Alanine amino-transferase (ALT) and aspartate amino-transferase (AST) ≤2x the upper limit of normal.

• - Alkaline phosphatase ≤2x the upper limit of normal.

• - Prothrombin time within the normal range for the institution.

• - Signed informed consent by the patient or legal representative prior to start of any study specific procedure.

• - Females of childbearing potential and males must be willing and able to use an adequate method of contraception to avoid pregnancy for the duration of the study in such a manner that the risk of pregnancy is minimized.

Acceptable contraceptives include intra-uterine devices (IUDs), hormonal contraceptives (oral, depot, patch or injectable) and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.

Exclusion Criteria:

• - Ongoing or expected need for therapy with drugs interfering with MTX-clearance (i.e., beta-lactam antibiotics, NSAIDs, probenicid, salicylates, sulphonamides) or other nephrotoxic drugs.

• - Prior brain radiotherapy within 28 days of first dose of the study drug.

• - Concurrent illness interfering with hydration (i.e., relevant congestive heart failure, SIADH syndrome).

• - Relevant third space (i.e., pleural effusion, ascites, extended edema) precluding HD-MTX treatment.

• - Obesity (body mass index >30 kg/m2).

• - Uncontrolled diabetes.

• - Active hepatitis.

• - HIV-infection.

• - Pregnant or lactating woman.

• - Participation in any other clinical trial either 1 month prior to or during this study.

- Previous intolerance to any of the drugs used in this study (i.e., MTX, LV)

MTX is used either alone or as part of a combined chemotherapy protocol either in standard or high doses in the treatment of a range of cancers and other diseases. Dose escalation will be performed using three dose levels of MTX: Level 1: 3.0 g/m2 Level 2: 3.5 g/m2 Level 3: 4.0 g/m2 Up to 6 patients will be treated at each dose level; each will receive a maximum of 6 cycles of treatment. The dose may be increased in Cycle 3 in individual patients to the next level, if renal function is adequate (GFR ≥ 40 mL/min, or in the case of decreased GFR, the decrease is <10% compared with the pre-treatment value), and absence of grade 3 or 4 non-hematological toxicities.

Arms

Experimental: Dose escalation

Patients will receive up to 6 cycles of HD-MTX Treatment Dose escalation will be performed using three dose levels of MTX: 3.0 g/m2, 3.5 g/m2, 4.0 g/m2

Interventions

Drug: - Voraxaze Injectable Product

High-dose Methotrexat Infusion: MTX is given at a dose according to the allocated dose level cohort as a 4-hour IV infusion. HD-MTX cycles (up to 6) should be repeated every 14 days, provided that the patient has recovered (i.e., hematopoietic reconstitution) between cycles. A delay of up to 28 days between cycles is permitted in order to allow patients to recover from the preceding dose of MTX. In patients with a decline of the GFR to <40 mL/min, or in the case of decreased GFR, the decrease is >50% compared with the pretreatment value, treatment will be terminated. At the start of Cycle 3 the dose of MTX can be escalated to the next level if MTX has been well-tolerated according to the criteria described under dose escalation. Voraxaze: 2000 Units in patients weighing ≤100kg and at least 20 Units per kg body weight in patients weighing >100kg is given in each HD-MTX cycle as a slow IV injection at 24 hours (+/- 2 hours) after the start of HD-MTX infusion.