Protocol Number: 02-C-0193

Title:

A Phase II Study Of Pegylated Interferon Alfa-2b (Peg-Intron (TM)) In Children With Diffuse Pontine Gliomas

Number:

02-C-0193

Summary:

Diffuse pontine gliomas are tumors on the pons portion of the brainstem. Their peak incidence is in children between 5 and 10 years old. Their location makes surgery impractical. Most patients are treated with radiation, which typically delays progress of the tumor for a median time of only about 6 months; median survival time is less than 1 year. The addition of chemotherapy has not improved the outcome.

Alpha, beta, and gamma interferons have been used to treat malignant brain tumors, with mixed results. Different doses and different methods of administration have been tried. Alpha interferon is usually given in high doses 2 or 3 times a week, but it has serious side effects at these doses. Recent studies have shown that administering chemotherapy more frequently at smaller doses may be both more effective and better tolerated.

PEG-Intron™ (Trademark) is a form of interferon alpha combined with monomethoxy polyethylene glycol (PEG). It has a longer half-life than interferon alone, so that it can be administered once a week, and it reduces the peaks and troughs in blood levels.

This study will enroll 32 patients under age 21. The primary goals of the study are to determine if there is a difference in the 2-year survival rate of patients treated with radiation alone and those treated with radiation followed by PEG-Intron™ (Trademark) and to define the toxicities of PEG-Intron™ (Trademark) in the study doses. Secondary goals are to evaluate various magnetic resonance imaging (MRI) techniques for noninvasive monitoring of changes in the brainstem and to evaluate neuropsychological function in the study patients.

In this study, PEG-Intron™ (Trademark) will be administered subcutaneously once a week at low doses (0.3 microgram per kilogram of body weight) for a 4-week cycle. The cycles will be repeated indefinitely until progression of disease or serious side effects develop. For less severe effects, the dose will be lowered and the patient may remain in the study. For more severe effects, the dose will be discontinued. Patients in the study may receive supportive medication but may not receive other forms of chemotherapy.

Patients or their caregivers will be instructed in how to inject the drug. Patients and/or caregivers will be asked to maintain a diary documenting the dose, site of administration, and any side effects. The diary will be reviewed at each National Cancer Institute (NCI) visit. Patients will return to NCI before cycles 2 and 3. If there are no significant side effects, patients may then return to NCI before every other cycle, indefinitely (i.e., before cycles 5, 7, 9, etc.).

Patients will undergo the following tests and procedures:

- Physical examination, including neurologic exam, monthly

- Complete blood count, differential, and platelet count weekly during cycle 1 and every 2 weeks thereafter if no severe side effects occur

- Blood chemistries weekly during cycle 1 and every 2 weeks thereafter if no severe side effects occur

- Endocrine function tests before each cycle

- Urinalysis before each cycle

- MRI of the brain before cycles 1, 2, 3, 5, 7, and every other month; patients may also have proton magnetic spectroscopic imaging performed at the time of the MRI

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA

Age: Patients must be less than or equal to 21 years of age.

Histological diagnosis: Histologic confirmation is not required for this study. Patients must have a diffuse pontine glioma as diagnosed by MRI criteria below.

Radiographic Appearance: Patients must have a diffuse intrinsic tumor with the epicenter presumed to be in the pons. The T-2 weighted sequence must reveal a diffuse signal abnormality involving at least 50 percent of the pons.

Prior therapy: The patient must have received adequate radiation therapy. (Radiation must be completed between 2-10 weeks prior to the start of treatment with Peg-Intron (TM).

Performance status: Patients should have an ECOG performance status of 0, 1, 2, or 3 (see below). Patients who are unable to walk because of paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose of calculating the performance score.

ECOG Performance Status:

Score--Clinical Status

0--Asymptomatic

1--Symptomatic, fully ambulatory

2--Symptomatic, in bed less than 50 percent of the day

3--Symptomatic, in bed greater than 50 percent of the day but not bedridden

4--Bedridden

Hematological function: Patients must have adequate bone marrow function defined as a peripheral absolute granulocyte count of greater than 1000/mm3, hemoglobin greater than 8 gm/dL, and platelet count greater than 100,000/mm3. Patients may be transfused with RBC's or platelets to achieve these parameters.

Hepatic function: Patients must have adequate liver function, defined as total bilirubin less than 2.5 times the upper limit of normal, direct bilirubin within normal limits, and SGPT less than 2.0 times the upper limit of normal.

Renal function: Patients must have an age-adjusted normal serum creatinine (see below) OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m2.

Age (Years)---Maximum Serum Creatinine (mg/dl)

less than or equal to 5---0.8

greater than 5 and less than or equal to 10---1.0

greater than 10 less than or equal to 15---1.2

greater than 15---1.5

Steroids: Patients on steroids must be on a stable or decreasing dose of steroids for greater than or equal to 1 week prior to study entry.

Informed consent: All patients or their legal guardians (if the patient is less than 18 years old) or DPA must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study. When appropriate, pediatric patients will be included in all discussions in order to obtain verbal assent.

Durable Power of Attorney (DPA): Assignment of DPA to a family member or guardian should be offered to all patients 18 to 21 years of age.

EXCLUSION CRITERIA

Patients with known or suspected neurofibromatosis-1

Patients who have received prior chemotherapy,including radiosensitizers, or who are currently receiving other investigational chemotherapeutic agents

Patients with a known hypersensitivity to interferon-alpha.

Pregnant or breast-feeding females are excluded because the effects of pegylated interferon alfa-2b (PEG-Intron (TM)) on the unborn fetus are unknown

Patients with clinically significant unrelated systemic illness (including autoimmune disease, serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment of the Principal or Associate Investigators would compromise the patient's ability to tolerate this therapy or are likely to interfere with the study procedures or results.

Special Instructions: Currently Not Provided

Keywords:

Brainstem Glioma

Pediatric

Interferon

MR Imaging

Angiogenesis

Recruitment Keywords:

Brain Tumor

Glioma

Pediatric Brain Tumor

Conditions:

Glioma

Investigational Drug(s):

Peg-Intron (TM)

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Packer RJ, Nicholson HS, Vezina LG, Johnson DL Brainstem gliomas Neurosurg Clin N Am 1992 Oct;3(4):863-79 Review PMID: 1392581

Freeman CR, Farmer JP Pediatric brain stem gliomas: a review Int J Radiat Oncol Biol Phys 1998 Jan 15;40(2):265-71 Review PMID: 9457808

Barkovich AJ, Krischer J, Kun LE, Packer R, Zimmerman RA, Freeman CR, WaraWM, Albright L, Allen JC, Hoffman HJ Brain stem gliomas: a classification system based on magnetic resonance imaging Pediatr Neurosurg 1990-91;16(2):73-83 PMID: 2132928

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