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

• ClinicalTrials.gov Identifier: NCT04841434
• Recruitment Status: Recruiting
• First Posted: April 12, 2021
• Last Update Posted: July 19, 2022
• Sponsor: Charite University, Berlin, Germany
• Information provided by (Responsible Party): Stefan Schwartz, Charite University, Berlin, Germany

Tracking Information

• First Submitted Date: April 8, 2021
• First Posted Date: April 12, 2021
• Last Update Posted Date: July 19, 2022
• Actual Study Start Date: June 1, 2021
• Estimated Primary Completion Date: August 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 8, 2021)

• Tolerability of Voraxaze [ Time Frame: 1 year ]
  absence of severe non-hematological toxicity
• Efficacy of Voraxaze [ Time Frame: 1 year ]
  immediate and sustained reduction in plasma MTX concentration

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 8, 2021)

• Dose Limiting Toxicities (DLTs) [ Time Frame: 1 year ]
  appearance of DLTs for each dose level of MTX
• Anti-glucarpidase antibodies [ Time Frame: 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 [ Time Frame: 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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 Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Dose escalation will be performed using three dose levels of MTX.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: CNS Lymphoma

Intervention

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.

Other Name: High-dose Methotrexat Infusion

Study 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

Intervention: Drug: Voraxaze Injectable Product

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 8, 2021): 18
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 1, 2024
• Estimated Primary Completion Date: August 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Susen Burock, MD; +49 (030) 450 564 648; susen.burock@charite.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04841434
• Other Study ID Numbers: CNS-Lymphoma-Vorax-1
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Stefan Schwartz, Charite University, Berlin, Germany
• Original Responsible Party: Same as current
• Current Study Sponsor: Charite University, Berlin, Germany
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Charite University, Berlin, Germany
• Verification Date: July 2022