CNS Lymphoma
Conditions
Keywords
impaired renal function
Brief summary
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
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.
Interventions
DRUGVoraxaze 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.
Sponsors
Charite University, Berlin, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose escalation will be performed using three dose levels of MTX.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability of Voraxaze | 1 year | absence of severe non-hematological toxicity |
| Efficacy of Voraxaze | 1 year | immediate and sustained reduction in plasma MTX concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLTs) | 1 year | appearance of DLTs for each dose level of MTX |
| Anti-glucarpidase antibodies | at screening, prior to the MTX infusion at each treatment cycle and on day 28 of the last cycle | presence of antibodies to glucarpidase |
| MTX toxicities | 1 year | 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 |
Countries
Germany
Outcome results
None listed