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

Phase 1

Completed

• Conditions: CNS Lymphoma
• Interventions: Drug: Voraxaze Injectable Product

• Registration Number: NCT04841434
• Lead Sponsor: Charite University, Berlin, Germany

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.

Study Timeline

• Study First Submitted: 2021-04-08
• Study First Submitted QC: 2021-04-08
• Study First Posted: 2021-04-12
• Study Start: 2021-06-01
• Primary Completion: 2024-12-01
• Study Completion: 2024-12-01
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-03
• Last Update Posted: 2025-01-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 18

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.

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dose escalation	Voraxaze Injectable Product	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

Primary Outcome Measures

Name	Time	Method
Efficacy of Voraxaze	1 year	immediate and sustained reduction in plasma MTX concentration
Tolerability of Voraxaze	1 year	absence of severe non-hematological toxicity

Secondary Outcome Measures

Name	Time	Method
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
Dose Limiting Toxicities (DLTs)	1 year	appearance of DLTs for each dose level of MTX
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

Trial Locations

Locations (1)

Charité Campus Benjamin Franklin (CBF); 🇩🇪 Berlin, Germany