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Immunotoxin Therapy in Treating Children With Recurrent Malignant Gliomas

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ClinicalTrials.gov Identifier: NCT00053040
Recruitment Status : Withdrawn (Withdrawal of pharmaceutical company support for the investigational drug)
First Posted : January 28, 2003
Last Update Posted : September 24, 2010
Sponsor:
Collaborator:
Information provided by:

Study Description
Brief Summary:

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of immunotoxin therapy and to see how well it works in treating children undergoing surgery for recurrent or progressive malignant glioma.


Condition or disease Intervention/treatment Phase
Brain and Central Nervous System Tumors Biological: cintredekin besudotox Procedure: conventional surgery Phase 1 Phase 2

Detailed Description:

OBJECTIVES:

Primary

  • Determine the toxicity of peritumoral IL13-PE38QQR after surgical resection in pediatric patients with recurrent malignant gliomas. (Phase I)
  • Determine the maximum tolerated flow rate and maximum tolerated infusion concentration (MTiC) of this drug in these patients. (Phase I)
  • Estimate the rate of survival after initial progression in patients treated at the maximum safe flow rate and MTiC with this drug. (Phase II)

Secondary

  • Describe the overall safety and tolerability of this regimen in these patients from the start of infusion through disease progression or initiation of alternative treatment.
  • Determine the IL13 receptor α2 chain expression status and distribution in pediatric recurrent or progressive malignant gliomas
  • Estimate the progression-free survival of patients treated with this drug. (Phase II)

OUTLINE: This is a multicenter, dose-escalation study.

  • Phase I: Patients undergo surgical resection of the tumor. Within 2-7 days later, patients undergo placement of 2-4 peritumoral catheters. One to 2 days later, patients receive peritumoral IL13-PE38QQR continuously over 96 hours. Catheters are removed after completion of the infusion.

Cohorts of 3 patients receive IL13-PE38QQR at escalating flow rates and a fixed concentration until the maximum safe flow rate is determined. The maximum safe flow rate is defined as the rate prior to the one at which 2 of 3 or more patients experience dose-limiting toxicity.

Following determination of the maximum safe flow rate, cohorts of 2-3 patients receive IL13-PE38QQR at escalating concentrations at the maximum safe flow rate until the maximum tolerated infusion concentration (MTiC) is determined. The MTiC is defined as the concentration prior to the one at which 2 of 3 or more patients experience dose-limiting toxicity.

  • Phase II: Patients receive IL13-PE38QQR as above at the maximum safe flow rate and MTiC determined in the phase I of the study.

Patients are followed at week 18 after catheter placement and then every 8 weeks thereafter until death, disease progression, or completion of six months (phase I) or 12 months (phase II) of follow-up after the end of IL13-PE38QQR infusion. Phase II patients who complete one year of follow-up without disease progression are followed every 12 weeks thereafter until death.

PROJECTED ACCRUAL: Approximately 2-50 patients (2-24 for phase I and approximately 26 for phase II) will be accrued for this study.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial Of Intracerebral IL13-PE38QQR Infusions In Pediatric Patients With Recurrent Malignant Glioma
Study Start Date : October 2005

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Surgery for tumor resection + IL13-PE38QQR infusion Biological: cintredekin besudotox
IL13-PE38QQR is administered intracerebrally by continuous convection enhanced infusion at a starting concentration of 0.25 μg/mL. Infusion duration will be held constant at 96 hours (4 days). The phase I component of this study is to estimate the maximum safe total flow rate and the maximum safe infusion concentration.
Other Name: IL13-PE38QQR
Procedure: conventional surgery
Conventional surgery is used for tumor resection prior to catheter placement for IL13-PE38QQR infusion.


Outcome Measures

Primary Outcome Measures :
  1. Toxicities from the start of infusion through the dose limiting toxicity observation period(Phase I) [ Time Frame: Start of IL13-PE38QQR infusion to Day 35 or Day 75 ]
    Toxicities reported are those occurring from the start of the IL13 infusion after catheter placement to Day 35 (30 days after the end of the infusion) if there are no or mild MRI changes on Day 35 around the catheter tract or tip. If the MRI change on Day 35 indicates moderate or extensive changes around the catheter tract or tip then the toxicities reported are those occurring from the start of the IL13 infusion to Day 75 (70 days after the end of the infusion).

  2. Maximum safe flow rate (Phase I) [ Time Frame: Start of IL13-PE38QQR infusion to Day 35 or Day 70 ]
    Two total flow rates of IL13-PE38QQR, 500 uL/hr and 750 uL/hr, will be studied based on a traditional phase I design. Dose-limiting toxicities occurring during the dose-finding period will determine the maximum safe flow rate. The dose-finding period is the start of the IL13 infusion after catheter placement to Day 35 if there are none or mild MRI changes around the catheter tract or tip on Day 35. If there are moderate or extensive MRI changes around the catheter tract or tip on Day 35 then the dose-finding period is from the start of the IL13 infusion to Day 75.

  3. Maximum tolerated infusion concentration (Phase I) [ Time Frame: Start of IL13-PE38QQR infusion to Day 35 or Day 70 ]
    Two infusion concentrations of IL13-PE38QQR, .25 ug/mL and .50 ug/mL, will be studied based on a traditional phase I design. Dose-limiting toxicities occurring during the dose-finding period will determine the maximum tolerated infusion concentration. The dose-finding period is the start of the IL13 infusion after catheter placement to Day 35 if there are none or mild MRI changes around the catheter tract or tip on Day 35. If there are moderate or extensive MRI changes around the catheter tract or tip on Day 35 then the dose-finding period is from the start of the IL13 infusion to Day 75.

  4. Survival post initial recurrence or progression at the maximum safe total flow rate and maximum tolerated infusion concentration (Phase II) [ Time Frame: Initial progression to date of death from any cause ]

Secondary Outcome Measures :
  1. Progression-free survival (Phase II) [ Time Frame: Initial progression to second progression ]
  2. IL13receptor α2 chain expression status and distribution [ Time Frame: Pre-treatment ]
    Expression of the IL13 receptor α2 chain will be determined by immunohistochemistry analysis of previously banked fixed primary tumor sections in addition to samples obtained during the on-study resection. Expression of the IL13 receptor α2 chain will also be determined by western blot analysis of previously banked fresh frozen primary tumor samples in addition to samples of relapsed fresh frozen tumor obtained during the on-study resection.

  3. Overall safety [ Time Frame: Start of IL13-PE38QQR infusion to disease progression or alternative treatment ]
    Adverse events reported are those occurring from the start of the IL13 infusion after catheter placement to the maximum of disease progression, start of alternative therapy, withdrawal from the study, death, or completion of the follow-up period. Adverse events will be tabulated by first occurrence of the event, by body system, by maximum severity, and by the highest degree of relationship to the study medication.

  4. Tolerability [ Time Frame: Start of IL13-PE38QQR infusion to disease progression or alternative treatment ]
    Adverse events reported are those occurring from the start of the IL13 infusion after catheter placement to the maximum of disease progression, start of alternative therapy, withdrawal from the study, death, or completion of the follow-up period. Adverse events will be tabulated by first occurrence of the event, by body system, by maximum severity, and by the highest degree of relationship to the study medication.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed grade 3 or 4 supratentorial malignant glioma by prior surgery or biopsy

    • Anaplastic astrocytoma
    • Glioblastoma multiforme
    • Malignant mixed oligoastrocytoma
  • Recurrent or progressive disease by radiology

    • In first progression or recurrence (for patients in the phase II portion of the study only)
  • Must have 1 solid primary lesion with a solid component measuring at least 1 cm in diameter
  • Must have received external beam radiotherapy with tumor dose of at least 48 Gy
  • Planning to undergo gross total resection of the tumor to remove all contrast-enhancing components of the tumor

    • No multifocal tumor not amenable to gross tumor resection
  • No contrast-enhancing tumor component crossing the midline
  • No subependymal or leptomeningeal tumor dissemination
  • No clinically significant increased intracranial pressure (e.g., impending herniation)
  • No spinal cord compression
  • No requirement for immediate palliative treatment

PATIENT CHARACTERISTICS:

Age

  • 3 to 21

Performance status

  • Karnofsky 60-100% (over 16 years of age)
  • Lansky 60-100 (16 years of age and under)

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count at least 1,500/mm^3
  • Hemoglobin at least 10 g/dL*
  • Platelet count at least 100,000/mm^3* NOTE: *Transfusion independent

Hepatic

  • PT and PTT normal

Renal

  • Creatinine normal for age

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No uncontrolled seizures

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • At least 8 weeks since prior hematopoietic stem cell transplantation

Chemotherapy

  • No prior intracerebral chemotherapy for malignant glioma (except polifeprosan 20 with carmustine implant)
  • At least 6 months since prior polifeprosan 20 with carmustine implant
  • At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas)
  • At least 2 weeks since prior vincristine or noncytotoxic chemotherapy
  • No concurrent chemotherapy

Endocrine therapy

  • Concurrent steroids allowed

Radiotherapy

  • See Disease Characteristics
  • At least 8 weeks since prior radiotherapy
  • No prior focal radiotherapy for malignant glioma (e.g., single-fraction stereotaxic radiotherapy or brachytherapy)

    • Prior stereotactic radiosurgery boost as part of the initial fractionated external beam radiotherapy regimen allowed

Surgery

  • See Disease Characteristics

Other

  • Recovered from prior therapy
  • No prior investigational intracerebral agents
  • At least 4 weeks since prior systemic investigational agents
  • No prior localized antitumor therapy for malignant glioma
  • No concurrent anticoagulants or antiplatelet therapy, including, but not limited to, any of the following:

    • Heparin
    • Fractionated heparin
    • Warfarin
    • Aspirin
    • Ticlopidine
    • Clopidogrel
    • Dipyridamole
  • No other concurrent investigational agents
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00053040


Sponsors and Collaborators
Pediatric Brain Tumor Consortium
National Cancer Institute (NCI)
Investigators
Study Chair: Anuradha Banerjee, MD University of California, San Francisco
More Information

Responsible Party: James M. Boyett/PBTC Operations and Biostatistics Center Executive Director, Pediatric Brain Tumor Consortium
ClinicalTrials.gov Identifier: NCT00053040     History of Changes
Other Study ID Numbers: CDR0000269073
PBTC-011C ( Other Identifier: Pediatric Brain Tumor Consortium )
NEOPHARM-IL13PEI-151 ( Other Identifier: Neopharm )
NCI-5930 ( Other Identifier: NCI )
First Posted: January 28, 2003    Key Record Dates
Last Update Posted: September 24, 2010
Last Verified: September 2010

Keywords provided by Pediatric Brain Tumor Consortium:
recurrent childhood brain tumor

Additional relevant MeSH terms:
Glioma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases