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

Primary Purpose

CNS Lymphoma

Status

Recruiting

Phase

Phase 1

Locations

Germany

Study Type

Interventional

Intervention

Voraxaze Injectable Product

About this trial

This is an interventional treatment trial for CNS Lymphoma focused on measuring impaired renal function

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Charité Campus Benjamin Franklin (CBF)Recruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dose escalation

Arm Description

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

Outcomes

Primary Outcome Measures

Tolerability of Voraxaze

absence of severe non-hematological toxicity

Efficacy of Voraxaze

immediate and sustained reduction in plasma MTX concentration

Secondary Outcome Measures

Dose Limiting Toxicities (DLTs)

appearance of DLTs for each dose level of MTX

Anti-glucarpidase antibodies

presence of antibodies to glucarpidase

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

Full Information

NCT ID

NCT04841434

First Posted

April 8, 2021

Last Updated

August 31, 2023

Sponsor

Charite University, Berlin, Germany

1. Study Identification

Unique Protocol Identification Number

NCT04841434

Brief Title

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

Acronym

VALIDATE

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 1, 2021 (Actual)

Primary Completion Date

August 1, 2024 (Anticipated)

Study Completion Date

April 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Charite University, Berlin, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CNS Lymphoma

Keywords

impaired renal function

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

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

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Dose escalation

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

Voraxaze Injectable Product

Other Intervention Name(s)

High-dose Methotrexat Infusion

Intervention Description

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.

Primary Outcome Measure Information:

Title

Tolerability of Voraxaze

Description

absence of severe non-hematological toxicity

Time Frame

1 year

Title

Efficacy of Voraxaze

Description

immediate and sustained reduction in plasma MTX concentration

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Dose Limiting Toxicities (DLTs)

Description

appearance of DLTs for each dose level of MTX

Time Frame

1 year

Title

Anti-glucarpidase antibodies

Description

presence of antibodies to glucarpidase

Time Frame

at screening, prior to the MTX infusion at each treatment cycle and on day 28 of the last cycle

Title

MTX toxicities

Description

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

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Susen Burock, MD

Phone

+49 (030) 450 564 648

susen.burock@charite.de

Facility Information:

Facility Name

Charité Campus Benjamin Franklin (CBF)

City

Berlin

ZIP/Postal Code

12200

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Stefan Schwartz, MD

Phone

030 450 513382

stefan.schwartz@charite.de

12. IPD Sharing Statement

Learn more about this trial

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

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