Phase I/II Trial of Intracerebral IL13-PE38QQR Infusions in Pediatric Patients With Recurrent Malignant Glioma
Phase I/II Trial of Intracerebral IL13-PE38QQR Infusions in Pediatric Patients With Recurrent Malignant Glioma
IL13-PE38QQR is an oncology drug product consisting of IL13 (interleukin-13) and PE38QQR (a
 bacteria toxin). IL3-PE38QQR is a protein that exhibits cell killing activity against a
 variety of IL13-receptor positive tumor cell lines indicating that it may show a therapeutic
 benefit. In reciprocal competition experiments, the interaction between IL13-PE38QQR and the
 IL13 receptors was shown to be highly specific for human glioma cells.
PHASE I OBJECTIVES:

 I. To describe toxicities and estimate the maximum safe flow rate and maximum tolerated
 infusion concentration, of IL13-PE38QQR delivered after surgical resection by peritumoral
 infusion via 2 to 4 catheters positioned in the brain adjacent to the resection cavity, from
 the start of infusion through the DLT observation period.

 II. To determine the IL13 receptor alpha-2 chain expression status and distribution in
 pediatric recurrent or progressive malignant gliomas.

 III. To describe the overall safety and tolerability of IL13PE38QQR infusion from the start
 of infusion through disease progression or initiation of alternative treatment.

 PHASE II OBJECTIVES:

 I. To estimate the survival distribution post initial progression, at the maximum safe total
 flow rate and MTiC established in phase I.

 II. To estimate the progression-free survival distribution for patients post-initial
 progression or recurrence at the maximum safe total flow rate and MTiC established in phase
 I.

 III. To determine the serum levels of IL13-PE38QQR and distribution in pediatric recurrent or
 progressive malignant gliomas.

 IV. To describe the overall safety and tolerability of IL13-PE38QQR infusion from the start
 of infusion through disease progression or initiation of alternative treatment.

 PROTOCOL OUTLINE: At study entry, all patients will be registered prior to planned gross
 total resection (> 95% resection of the solid, contrast enhancing tumor component). On the
 day of catheter placement (CP, 2-7 days after resection), if the patient is neurologically
 stable, 2-4 catheters will be stereotactically placed. On day 1 after catheter placement,
 infusion of IL3-PE38QQR will begin if the patient is neurologically stable and will continue
 for 96 hours. In Phase I, the total flow rate and the concentration of IL3-PE38QQR will be
 determined by the dose escalation plan. In the Phase II evaluations of safety and efficacy,
 patients will be treated at the flow rate and concentration identified in Phase I.

 PROJECTED ACCRUAL: Approximately 24 patients will participate in the Phase I portion of the
 study. During the Phase I portion, the rate-limiting factor is the time the study must be
 closed during the toxicity assessment period. Although it is estimated that 1.5 patients per
 month will enroll in the Phase I portion, the observed rate may be lower due to temporary
 suspensions in accrual. It is not possible to estimate the time required to complete the
 Phase I portion of the trial. It is estimated that approximately 26 patients will contribute
 to the Phase II portion. Using the same rough estimate of accrual, the Phase II portion may
 last about 3 years.
-Disease Characteristics-

 Must be at least 3 years but not more than 21 years of age.

 Must have had surgery (or biopsy) of a supratentorial brain tumor with pathologic diagnosis
 of malignant (grade 3 or 4) glioma, including anaplastic astrocytoma, mixed anaplastic
 astrocytoma, or glioblastoma multiforme.

 Must have radiographic evidence of recurrent or progressive supratentorial malignant glioma
 compared with a prior imaging study. The baseline tumor measurements must be determined
 within 2 weeks prior to study entry.

 The tumor must have a solid component at least 1.0 cm in diameter.

 Gross total resection must be planned, with the intent of removing all contrast-enhancing
 components of the tumor.

 Must have received external beam radiotherapy, with tumor dose of at least 48 Gy; and must
 be completed at least 8 weeks prior to study entry.

 -Patient Characteristics-

 Karnofsky Performance Score for patients older than 16 years, or the Lansky Performance
 Scale for patients 16 years old or younger, must be at least 60.

 Hematologic status: Absolute neutrophils at least 1,500/mm3; Hemoglobin at least 10 gm/dL
 (transfusion independent); Platelets at least 100,000/mm3 (transfusion independent); PT &
 aPTT less than or equal to the institutional upper limit of normal.

 Must have recovered from toxicity of prior therapy: at least 6 months after Gliadel® wafer;
 at least 8 weeks after hematopoietic stem cell transplant; at least 4 weeks after any
 cytotoxic chemotherapy or any systemic investigational agent; at least 6 weeks after
 nitrosoureas; at least 2 weeks after vincristine or non-cytotoxic chemotherapy.

 Patient's legal guardian must understand the investigational nature of this study and its
 potential risks and benefits; must sign informed consent.

 No pregnant or breast-feeding patients. All patients of child-bearing age, male and female,
 must practice an effective method of birth control during the study.

 No patients with multi-focal tumor not amenable to gross total resection or tumor
 dissemination (subependymal or leptomeningeal).

 No patients with clinically significant increased intracranial pressure (e.g., impending
 herniation) uncontrolled seizures, or requirement for immediate palliative treatment.

 No patients who received any localized antitumor therapy for the malignant glioma, either
 intracerebral chemotherapy (other than Gliadel®) or focal radiation therapy (e.g.,
 stereotactic radiosurgery or brachytherapy).

 No patients who are receiving concurrent chemotherapy (other than steroids) or any other
 investigational agent.

 No patients unwilling to follow protocol requirements.