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

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

Tracking Information
First Submitted Date  ICMJE April 8, 2021
First Posted Date  ICMJE April 12, 2021
Last Update Posted Date July 19, 2022
Actual Study Start Date  ICMJE June 1, 2021
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase I/II Study to Investigate the Use of VORAXAZE™ as Intended Intervention in Patients With CNSL
Official Title  ICMJE 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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  ICMJE CNS Lymphoma
Intervention  ICMJE 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  ICMJE 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2021)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 1, 2024
Estimated Primary Completion Date August 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Susen Burock, MD +49 (030) 450 564 648 susen.burock@charite.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04841434
Other Study ID Numbers  ICMJE 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  ICMJE Not Provided
Current Responsible Party Stefan Schwartz, Charite University, Berlin, Germany
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Charite University, Berlin, Germany
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Charite University, Berlin, Germany
Verification Date July 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP