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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

Phase 1/Phase 2
3 Years
21 Years
Not Enrolling
Brain and Central Nervous System Tumors

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Trial Information

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



- 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


- 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

- 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.

Inclusion Criteria


- 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



- 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


- 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


- ALT and AST less than 2.5 times upper limit of normal (ULN)

- PT and PTT no greater than ULN


- Creatinine less than 1.5 times normal OR

- Glomerular filtration rate greater than 70 mL/min


- 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


Biologic therapy

- At least 8 weeks since prior hematopoietic stem cell transplantation


- At least 6 months since prior polifeprosan 20 with carmustine implant (Gliadel®

- 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


- See Disease Characteristics

- No prior focal radiotherapy (e.g., gamma knife radiosurgery, stereotactic
radiosurgery, or brachytherapy)

- No concurrent radiotherapy


- Not specified


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Outcome Measure:

Maximum safe volume rate of TP-38 infused through three catheters (Stratum A) or through two catheters (Stratum B).

Safety Issue:


Principal Investigator

Roger J. Packer, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Children's Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

May 2004

Completion Date:

June 2006

Related Keywords:

  • Brain and Central Nervous System Tumors
  • childhood high-grade cerebral astrocytoma
  • recurrent childhood cerebral astrocytoma
  • childhood oligodendroglioma
  • childhood supratentorial ependymoma
  • recurrent childhood ependymoma
  • recurrent childhood brain tumor
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



Duke Comprehensive Cancer Center Durham, North Carolina  27710
Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania  19104-4283
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania  15213
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital Houston, Texas  77030-2399