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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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CNS Lymphoma

Intervention / Treatment
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* Drug: Voraxaze Injectable Product


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Dose escalation will be performed using three dose levels of MTX.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>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 | Drug: Voraxaze Injectable Product<br>* 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.<br>* Other names: High-dose Methotrexat Infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of Voraxaze | absence of severe non-hematological toxicity | 1 year | 
| Efficacy of Voraxaze | immediate and sustained reduction in plasma MTX concentration | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLTs) | appearance of DLTs for each dose level of MTX | 1 year | 
| Anti-glucarpidase antibodies | presence of antibodies to glucarpidase | at screening, prior to the MTX infusion at each treatment cycle and on day 28 of the last cycle | 
| MTX toxicities | incidence and severity of hematological toxicities and stomatitis after each cycle of HD-MTX treatment and renal function before each cycle of HD-MTX treatment | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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impaired renal function