A Phase I/II Study to Investigate the Use of VORAXAZE™ As Intended Intervention in Patients with CNSL

An Open Label, Phase I/II Study to Investigate the Use of VORAXAZE™ As Intended Intervention in Patients with Central Nervous System Lymphoma and with Impaired Renal Function Being Treated with High-dose Methotrexate

This phase I-II trial is intented to demonstrate tolerability (i.e. absence of severe non-hematological toxicity) and efficacy of intended intervention with repeated doses of Voraxaze, in addition to leucovorin (LV), in patients with renal impairment or renal failure during previous HD-MTX therapy.

Patients will receive up to 6 cycles of HD-MTX treatment with 14 days between cycles (a maximum delay of 28 days is permitted in order to allow time for a patient to recover from the previous cycle).

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.

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)