TP-38 Toxin in Treating Young Patients With Recurrent or Progressive Supratentorial High-Grade Glioma

Study Overview
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Brief Summary
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RATIONALE: The TP-38 toxin can locate tumor cells and kill them without harming normal cells. Giving TP-38 toxin directly into the tumor may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of TP-38 toxin administered directly into the brain and to see how well it works in treating young patients with recurrent or progressive supratentorial high-grade glioma.

Detailed Description
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OBJECTIVES: Primary Phase I Determine the maximum safe volume rate and maximum tolerated infusion concentration of TGFa-PE38 toxin (TP-38) infused through 2 or 3 catheters in pediatric patients with recurrent or progressive supratentorial high-grade glioma. Describe the toxic effects of this drug in these patients. Phase II Estimate the efficacy of this drug, in terms of post-infusion survival, in these patients. Secondary Phase I and II Determine the prevalence of epidermal growth factor receptor (EGFR) expression and phosphorylation (activity) in patients treated with this drug. Correlate EGFR expression with qualitative measures (e.g., histology, grade, and other tumor characteristics) and tumor response, survival, and progression-free survival in patients treated with this drug. Phase II Only Estimate the objective response rate in patients treated with this drug. Estimate the progression-free survival of patients treated with this drug. OUTLINE: This is a dose-escalation, multicenter study. Patients in the phase I portion of the study are stratified according to the number of successfully placed catheters (3 catheters vs 2 catheters). Patients in the phase II portion of the study are stratified according to time of recurrence of high-grade glioma (first vs second or greater) and by surgery extent (surgical resection vs stereotactic biopsy) for those with first recurrence only. Phase I: Patients undergo stereotactic biopsy or resection of the tumor followed by intratumoral (or tumor bed) catheter placement for treatment infusion. Within 12-48 hours after intratumoral (or tumor bed) catheter placement, patients receive TGFa-PE38 toxin (TP-38) intratumorally through 2 or 3 catheters over 33 to 124 hours. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients (in each stratum) receive escalating volumes until the maximum safe volume (MSV) is determined. Cohorts of 3-6 patients (in each stratum) receive escalating concentrations at the MSV until the maximum tolerated infusion concentration (MTIC) is determined. The MSV and MTIC are defined as the volume and concentration preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive treatment as in phase I at the MSV and MTIC. Phase I patients are followed post catheter placement, daily during TP-38 infusion, at 30 days, and then every 2 months for 1 year. Phase II patients will be followed for an additional year. PROJECTED ACCRUAL: A total of 6-105 patients (6-60 for phase I and 45 for phase II) will be accrued for this study.

Official Title
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A Phase I/II Study Of A Recombinant Chimeric Protein Composed Of Transforming Growth Factor (TGF)-a And A Mutated Pseudomonas Exotoxin Termed PE38 (TP-38) In Pediatric Patients With Recurrent Or Progressive Supratentorial High Grade Gliomas

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Biological: TGFa-PE38 immunotoxin
* Procedure: conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed supratentorial malignant glioma Recurrent or progressive disease Amenable to gross total resection, clinically indicated partial resection, or biopsy Tumor must have a single solid portion at least 1 cm and no greater than 5 cm in maximum diameter No tumor crossing midline Tumors invading the corpus callosum that do not extend beyond to midline or into the contralateral hemisphere allowed No more than 1 focus of tumor No tumors involving the brainstem or cerebellum No tumor dissemination (i.e., subependymal or leptomeningeal) Must be on steroids ≥ 3 days prior to surgery Must have received prior external beam radiotherapy (tumor dose at least 45 Gy) and completed therapy at least 8 weeks before study entry No impending herniation, including midline shift greater than 0.5 cm No requirement for immediate palliative treatment PATIENT CHARACTERISTICS: Age 3 to 21 Performance status Karnofsky 60-100% (patients over 16 years of age) OR Lansky 60-100% (patients age 16 and under) Life expectancy Not specified Hematopoietic Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3* Hemoglobin at least 9 g/dL* NOTE: *Transfusion independent Hepatic ALT and AST less than 2.5 times upper limit of normal (ULN) PT and PTT no greater than ULN Renal Creatinine less than 1.5 times normal OR Glomerular filtration rate greater than 70 mL/min Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 30 days after study participation No uncontrolled seizures No active infection requiring treatment No unexplained febrile illness No known or suspected allergies to local anesthetics No systemic disease or other condition that may be associated with unacceptable anesthetic/operative risk and/or that would preclude study completion No other malignancy within the past 5 years except curatively treated carcinoma in situ or basal cell skin cancer PRIOR CONCURRENT THERAPY: Biologic therapy At least 8 weeks since prior hematopoietic stem cell transplantation Chemotherapy At least 6 months since prior polifeprosan 20 with carmustine implant (Gliadel® wafer) At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas and 2 weeks for vincristine) At least 2 weeks since prior non-cytotoxic chemotherapy No other prior intracerebral chemotherapy No concurrent chemotherapy Endocrine therapy Concurrent steroids allowed Radiotherapy See Disease Characteristics No prior focal radiotherapy (e.g., gamma knife radiosurgery, stereotactic radiosurgery, or brachytherapy) No concurrent radiotherapy Surgery Not specified Other Recovered from prior therapy At least 4 weeks since prior anticancer investigational agents No prior localized antitumor therapy for malignant glioma No other concurrent investigational agent No other concurrent anticancer (including alternative anticancer medicines/treatment) agent or therapy

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: TGFa-PE38 immunotoxin|nan|
|Procedure: conventional surgery|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum safe volume rate of TP-38 infused through three catheters (Stratum A) or through two catheters (Stratum B). |  |  | 
| Maximum tolerated infusion concentration of TP-38 infused through three catheters (Stratum A) or through two catheters (Stratum B). |  |  | 
| Toxicities of TP-38 |  |  | 
| Post-infusion survival (phase II) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EGFR expression and phosphorylation (activity) |  |  | 
| Correlation of EGFR expression with tumor histology, tumor grade, tumor response (phase I and phase II) and survival and progression-free survival (phase II). |  |  | 
| Post-infusion progression-free survival (phase II) |  |  | 
| Objective response (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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childhood high-grade cerebral astrocytoma, recurrent childhood cerebral astrocytoma, childhood oligodendroglioma, childhood supratentorial ependymoma, recurrent childhood ependymoma, recurrent childhood brain tumor