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All Drugs and Chemicals

Immunotoxins

cintredekin besudotox

adjuvant therapy

conventional surgery

neoadjuvant therapy

Lauren E. Abrey, MD

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells. Immunotoxin therapy may be effective in treating malignant glioma.

PURPOSE: Phase I trial to study the effectiveness of immunotoxin therapy before and after surgery in treating patients who have recurrent malignant glioma.

OBJECTIVES:

* Determine the concentration of interleukin-13 PE38QQR immunotoxin that produces histologic evidence of toxicity to tumor and the corresponding toxic effects of this drug when administered via continuous intratumoral infusion prior to second resection in patients with recurrent resectable supratentorial malignant glioma.
* Determine the toxic effects of this drug when administered via continuous peritumoral infusion, at concentrations determined in objective I, after second resection in these patients.
* Determine any toxic effects of increasing the duration of continuous peritumoral infusion of this drug, at concentrations determined in objective II, after second resection in these patients.
* Determine the time to progression and survival of patients treated with this regimen.

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

* Pre-resection therapy (initial cohorts of patients only): Patients undergo stereotactic biopsy of brain tumor followed by stereotactic placement of 1 intratumoral catheter on day 1. Patients with histologically confirmed malignant glioma receive interleukin-13 PE38QQR immunotoxin via continuous intratumoral infusion over 48 hours on days 2 and 3.

Cohorts of 3-6 patients receive escalating doses of pre-resection interleukin-13 PE38QQR immunotoxin until the histologically effective concentration (HEC) is reached or maximum tolerated dose (MTD) is determined. The HEC is defined by pathologic observations. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. After the HEC is reached or MTD is determined, up to 6 additional patients are enrolled at selected dose levels to study safety and tolerability. Subsequent cohorts of patients are not treated with a pre-resection infusion.

* Resection (all patients): Patients undergo maximal resection (en bloc, if feasible) followed by placement of 2-3 peritumoral catheters (4 days after completion of pre-resection infusion for the initial cohorts of patients and at study entry for subsequent cohorts of patients).
* Post-resection therapy (all patients): Beginning on the second day after resection, patients receive interleukin-13 PE38QQR immunotoxin via continuous peritumoral infusion over 96 hours.

Cohorts of 3-6 patients receive escalating doses of interleukin-13 PE38QQR immunotoxin until the previously-defined HEC is reached or MTD is determined, whichever occurs first. If dose-escalation is stopped after HEC is reached, then three additional cohorts of patients receive escalating durations (5, 6, or 7 days) of post-resection infusion. If dose escalation is stopped after the MTD is determined, then the duration of post-resection infusion is not escalated.

Patients are followed every 8 weeks.

PROJECTED ACCRUAL: A total of 25-50 patients will be accrued for this study.

Immunotoxin Therapy Before and After Surgery in Treating Patients With Recurrent Malignant Glioma

Phase I Study to Assess the Histologic Effect and Safety of Pre-Operative and Post-Operative Infusions of IL13-PE38QQR Cytotoxin in Patients With Recurrent Resectable Supratentorial Malignant Glioma

National Cancer Institute (NCI)

Memorial Sloan Kettering Cancer Center

Brain Tumor, Childhood

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.

Conventional surgery is used for tumor resection prior to catheter placement for IL13-PE38QQR infusion.

Anuradha Banerjee, MD

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.

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.

Immunotoxin Therapy in Treating Children With Recurrent Malignant Gliomas

Phase I/II Trial Of Intracerebral IL13-PE38QQR Infusions In Pediatric Patients With Recurrent Malignant Glioma

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).

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.

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.

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.

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.

Pediatric Brain Tumor Consortium

James M. Boyett/PBTC Operations and Biostatistics Center Executive Director

isolated perfusion

Jon Weingart, MD

RATIONALE: Immunotoxins can locate tumor cells and kill them without harming normal cells. This may be an effective treatment for malignant glioma.

PURPOSE: Phase I/II trial to study the effectiveness of immunotoxin therapy in treating patients who have malignant glioma.

OBJECTIVES:

* Determine the toxic effects and maximum tolerated dose (MTD) of interstitial interleukin-13 PE38QQR immunotoxin in patients with malignant glioma.
* Determine the response rate, duration of response, time to response, overall survival, and time to progression in patients treated with this regimen.
* Determine the toxic effects of this drug at the MTD in these patients.

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

Patients undergo stereotactic biopsy of brain tumor followed by CT guided stereotactic placement of 2 intratumoral catheters on day 0. Patients with histologically confirmed malignant glioma receive interleukin-13 PE38QQR immunotoxin interstitially over 96 hours beginning on day 1. Patients with a residual enhancing mass undergo repeat catheter placement on day 56 and then receive a second interstitial infusion beginning on day 57 in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of interleukin-13 PE38QQR immunotoxin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 patients experience dose-limiting toxicity. Additional patients are treated at the MTD.

Patients are followed every 8 weeks.

PROJECTED ACCRUAL: A maximum of 30 patients will be accrued for phase I of the study within 6 months and a total of 12-35 patients will be accrued for phase II of the study within 10-12 months.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotoxin Therapy Before and After Surgery in Treating Patients With Recurrent Malignant Glioma	NCT00036972	Brain and Centr...	cintredekin bes... adjuvant therap... conventional su... neoadjuvant the...	18 Years -	National Cancer Institute (NCI)
Immunotoxin Therapy in Treating Children With Recurrent Malignant Gliomas	NCT00053040	Brain and Centr...	cintredekin bes... conventional su...	3 Years - 21 Years	Pediatric Brain Tumor Consortium
Immunotoxin Therapy in Treating Children With Recurrent Malignant Gliomas	NCT00053040	Brain and Centr...	cintredekin bes... conventional su...	3 Years - 21 Years	Pediatric Brain Tumor Consortium
Immunotoxin Therapy in Treating Patients With Malignant Glioma	NCT00006268	Brain and Centr...	cintredekin bes... isolated perfus... conventional su...	18 Years -	National Cancer Institute (NCI)

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