Clinical trial NCT00036569: A Phase II Study of Pegylated Interferon Alfa 2b (PEG-Intron(Trademark)) in Children With Diffuse Pontine Gliomas
Official title: A Phase II Study of Pegylated Interferon Alfa-2b (Peg-Intron (TM)) in Children With Diffuse Pontine Gliomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Intrinsic Pontine Glioma
Keywords: Brainstem Glioma
Pediatric
Interferon
MR Imaging
Angiogenesis
Brain Tumor
Glioma
Pediatric Brain Tumor
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2002-05-13
Enrollment: 32
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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 surgical resection impossible. Most patients are treated with radiation, which typically delays progression 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 studied. 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 (metronomic) may have a better effect against the tumor.

PEG-Intron(Trademark) is a form of interferon alpha combined with monomethoxy polyethylene glycol (PEG). It has a longer half-life than interferon alone, is administered once a week, and the long half-life 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 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

Detailed description: Background:

Children with diffuse pontine gliomas have a dismal prognosis. Because surgery in this area is difficult, radiation therapy has been the mainstay of treatment. Although some children may improve clinically after radiation therapy, the effect is short-lived and almost all progress within several months. Chemotherapy has not had a significant impact on survival. Interferon-alpha is a cytokine that has been studied in patients with gliomas and has demonstrated some activity in prior clinical trials.

Objectives:

* To compare the 2-year survival of pediatric patients with diffuse pontine gliomas receiving weekly subcutaneous low-dose pegylated interferon alfa-2b (PEG-Intron\[TM\]) injections after standard radiation therapy versus historical controls who have received radiation therapy alone.
* To define the toxicities of weekly low-dose pegylated interferon alfa-2b (PEG-Intron(Trademark)) in pediatric patients.

Eligibility:

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.

Radiologic 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\[TM\].

Design:

In this study, we plan to administer pegylated interferon alfa-2b (PEG-Intron\[TM\]) subcutaneously once a week to pediatric patients with diffuse pontine gliomas who have completed radiation therapy. The endpoint of the trial will be 2-year survival compared to historical controls.

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 magnetic resonance imaging (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 Cooperative Oncology Group (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/mm\^3, hemoglobin greater than 8 gm/dL, and platelet count greater than 100,000/mm\^3. Patients may be transfused with red blood cells (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 serum glutamic pyruvic transaminase (SGPT) less than 2.0 times the upper limit of normal. Patients with Gilbert Syndrome are excluded from both the total and direct bilirubin requirements. (Gilbert Syndrome is found in 3-10 percent of the general population and is characterized by mild, chronic hyperbilirubinemia in the absence of liver disease or overt hemolysis.)

   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 m\^2.

   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.

Primary outcomes:
measure: Two Year Survival of Pediatric Patients With Diffuse Pontine Gliomas
timeFrame: 8 yrs 6 mo 0 days
Secondary outcomes:
measure: Median Time to Progression
timeFrame: 8 yrs 11 mo 22 days
measure: Number of Participants With Adverse Events
timeFrame: 8 yrs 11 mo 22 days
measure: Mean Quality of Life (QOL) Score at Baseline and Follow-Up
timeFrame: once a week for 4 weeks beginning 2-10 weeks after completion of radiation therapy and continued until disease progression or one of the other off study criteria.
measure: Number of Participants With a Metabolic and Biological Change in the Brainstem Through Magnetic Resonance Imaging (MRI) Techniques
timeFrame: once a week for 4 weeks beginning 2-10 weeks after completion of radiation therapy and continued until disease progression or one of the other off study criteria.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Kathy Warren, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Packer RJ, Nicholson HS, Vezina LG, Johnson DL. Brainstem gliomas. Neurosurg Clin N Am. 1992 Oct;3(4):863-79.
citation: Freeman CR, Farmer JP. Pediatric brain stem gliomas: a review. Int J Radiat Oncol Biol Phys. 1998 Jan 15;40(2):265-71. doi: 10.1016/s0360-3016(97)00572-5.
citation: Barkovich AJ, Krischer J, Kun LE, Packer R, Zimmerman RA, Freeman CR, Wara WM, Albright L, Allen JC, Hoffman HJ. Brain stem gliomas: a classification system based on magnetic resonance imaging. Pediatr Neurosurg. 1990-1991;16(2):73-83. doi: 10.1159/000120511.