Know Cancer

or
forgot password

A Phase II Trial of Peginterferon Alpha-2b (PEG-Intron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas


Phase 2
6 Months
21 Years
Open (Enrolling)
Both
Neurofibromatosis Type 1, Plexiform Neurofibroma

Thank you

Trial Information

A Phase II Trial of Peginterferon Alpha-2b (PEG-Intron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas


Background:

Neurofibromatosis 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized
by diverse cutaneous, neurological, skeletal and neoplastic manifestations. Approximately
25 percent of individuals with NF1 develop plexiform neurofibromas (PN), which are benign
nerve sheath tumors that are among the most debilitating complications of NF1. Plexiform
neurofibromas may be congenital and appear to have the fastest growth rate in young
children. There are no standard treatment options for PN other than surgery, which is often
difficult due to the extensive growth and invasion of surrounding tissues. Interferon-alpha
has shown immune modulatory and antiproliferative effects in a variety of malignancies, and
also inhibits angiogenesis. The pegylated preparation, peginterferon alfa-2beta (Pegintron)
lengthens the plasma half-life and allows for administration once a week. A phase I trial
of Pegintron for children and young adults with NF1and PN was completed, and defined the
maximum tolerated dose (MTD) as 1 microgram/kg by subcutaneous (SC) injection once weekly
for a maximum duration of 2 years. At this dose level, Pegintron was well tolerated, and
disease stabilization and minor PN shrinkage by volumetric MRI analysis were observed in
several patients. At doses exceeding the MTD fatigue and behavioral changes were dose
limiting. A phase II trial of Pegintron will be performed to define the activity of
Pegintron for inoperable PN in NF1.

Objectives:

To determine the radiographic and clinical response rate and/or progression free survival of
unresectable progressive, or symptomatic (i.e. interfering with performance status), or life
threatening NF1 associated PN to Pegintron given weekly SC.

To describe and define the toxicities of Pegintron given weekly SC for prolonged time
periods in this patient population.

To compare volumetric analysis of PN using three-dimensional MRI (3-D MRI) to conventional
two-dimensional MRI (2-D MRI) and one-dimensional MRI (1-D MRI) data analysis.

To evaluate the effects of Pegintron on serum cytokines and on induction of genes and
cytokines in peripheral blood mononuclear cells.

Eligibility:

Individuals (greater than or equal to 6 months to 21 years of age) with NF1 and an
inoperable plexiform neurofibroma that has the potential to cause significant morbidity.

Design:

Patients will be enrolled on one of three strata depending on disease status.

Stratum 1: Radiographic progression at trial entry cannot be documented. Patient has no
clinical symptoms from the PN. Radiographic response (PN volume decrease greater than or
equal to 20 percent) will be the primary endpoint.

Stratum 2: Radiographic progression at trial entry cannot be documented. Patient has
clinical symptoms from the PN, such as pain, or decrease in function. Radiographic response
(PN volume decrease greater than or equal to 20 percent), and clinical response rate will be
the primary endpoint.

Stratum 3: Patient has a progressive PN. Time to progression (TTP) (PN volume increase
greater than or equal to 20 percent) will be the primary endpoint, and activity will be
defined by comparing TTP on Pegintron to TTP on the placebo arm of the R115777 phase II
trial for NF1 PN (01-C-0222) performed at the NCI, POB.

Stratum 4: Age between 6 and 18 months of age and must have a symptomatic and/or life
threatening plexiform neurofibroma(s).

Pegintron will be administered SC at a dose of 1.0 mcg/kg/week until disease progression, or
development of unacceptable toxicity. In addition, treatment for patients on stratum 1 and 2
will be limited to a maximum of 1 year unless they respond to treatment with Pegintron
(partial or complete response), in which case they can continue treatment for a maximum of
two years.

Tumor evaluation for volumetric MRI analysis will be performed pre treatment, and prior to
months 4, 8, 12, and then after every six months on treatment with Pegintron. Response
analysis will be performed centrally at the NCI, POB.

Inclusion Criteria


- INCLUSION CRITERIA:

Age: Greater than or equal to 6 months to 21 years of age

Diagnosis: Patients with NF1 and an inoperable plexiform neurofibroma that has the
potential to cause significant morbidity, such as (but not limited to) head and neck
lesions that could compromise the airway or great vessels, brachial or lumbar plexus
lesions that could cause nerve compression and loss of function, lesions that could result
in major deformity (e.g., orbital lesions) or significant cosmetic problems, lesions of
the extremity that cause limb hypertrophy or loss of function, and painful lesions.
Histologic confirmation of tumor is not required in the presence of consistent clinical
and radiographic findings. However, if any clinical observation or scan suggests possible
malignant transformation, the tumor should be biopsied prior to therapy. Patients without
biopsy-proof of a plexiform neurofibroma must have at least one other diagnostic criteria
for NF1 as defined by the NIH Consensus Conference.

- Six or more cafe-au-lait spots (greater than 0.5 cm in prepubertal subjects or
greater than 1.5 cm in postpubertal subjects)

- Freckling in the axilla or groin

- Optic glioma

- Two or more Lisch nodules

- A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
long bone cortex)

- A first degree relative with NF1

Specific eligibility criteria stratum 1:

Disease status:

- Radiographic disease progression as defined for stratum 3 is not required for trial
entry.

Patient does not have clinical symptoms from the plexiform neurofibroma.

Specific eligibility criteria stratum 2:

Disease status:

- Radiographic disease progression as defined for stratum 3 is not required for trial
entry.

- Patient has clinical symptoms from the plexiform neurofibroma.

Specific eligibility criteria stratum 3:

Disease status:

- Patients must have a radiographically progressive plexiform neurofibroma(s) with or
without clinical symptoms. Progression at the time of study entry is defined as:

- Presence of new plexiform neurofibromas on MRI within the last 12 months OR

- A measurable increase of the plexiform neurofibroma (greater than or equal to 20
percent increase in the volume, or a greater than or equal to 13 percent increase in
the product of the two longest perpendicular diameters, or a greater than or equal to
6 percent increase in the longest diameter) over the last two consecutive scans (MRI
or CT), or over the time period of approximately one year prior to evaluation for
this study.

Surgery/Residual disease: Patients are only eligible if complete tumor resection is not
feasible, or if a patient with a surgical option refuses surgery. Patients must have
measurable residual tumor present. For the purpose of this study a measurable lesion will
be defined as a lesion of at least 3 cm measured in one dimension. Evidence of recurrent
or progressive disease is NOT necessary. Patients must be at least 21 days from surgery,
if performed, prior to receiving their first dose of study drug.

Prior therapy: Since there is no standard effective chemotherapy for patients with
progressive plexiform neurofibromas, patients may be treated on this trial without having
received prior therapy. If patients have received prior therapy, they must have recovered
from all toxic effects prior to entering this study.

Performance Status: Patients should have a life expectancy of at least 12 months and a
Karnofsky or Lansky performance score of greater than or equal to 50. Patients who are
wheelchair bound because of paralysis should be considered ambulatory when they are up
in their wheel chair.

Organ Function: Subjects must have adequate hepatic, renal and bone marrow function as
defined by the following parameters:

- An absolute granulocyte count greater than 1500/microL, a hemoglobin greater than 10
gm/dl, and a platelet count greater than 100,000/microL at study entry.

- Bilirubin less than 1.5 mg/dl and SGPT less than or equal to 2 times upper limit of
normal.

- An age-adjusted normal serum creatinine (see below) OR a creatinine clearance greater
than or equal to 70 mL/min/1.73 m(2).

- Age less than or equal to 5, Maximum Serum Creatinine - 0.8 (mg/dl)

- Age greater than 5 to less than or equal to 10, Maximum Serum Creatinine - 1.0
(mg/dl)

- Age greater than 10 to less than or equal to 15, Maximum Serum Creatinine - 1.2
(mg/dl)

- Age greater than 15, Maximum Serum Creatinine - 1.5 (mg/dl)

Baseline Clinical and Radiographic Evaluations: MRI scan of the target plexiform
neurofibroma(s), performed according to study requirements, including axial and coronal
STIR images within 4 weeks of enrollment on study. Patients with orbital PNF's must have a
baseline ophthalmologic evaluation as per Appendix G performed prior to study enrollment
by an ophthalmologist familiar with the protocol guidelines. Patients with pain associated
with the target PNF must be able to fill out the Pain Medication Diary with at least one
week of documentation prior to study enrollment.

Informed Consent: All patients or their legal guardians (if the patients is less than 18
years old) must sign an IRB approved document of informed consent indicating their
understanding of the investigational nature and the risks of this study BEFORE any
protocol related studies are performed (this does not include routine laboratory tests or
imaging studies required to establish eligibility). When appropriate, pediatric patients
will be included in all discussion in order to obtain verbal assent.

EXCLUSION CRITIERIA:

Clinically significant unrelated systemic illness (serious infections or significant
cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment of the
Principal or Associate Investigator would compromise the patient's ability to tolerate
Pegintron or are likely to interfere with the study procedures or results.

An investigational agent within the past 30 days

Evidence of an optic glioma requiring treatment with chemotherapy or radiation therapy at
the time of study entry

History of malignant peripheral nerve sheath tumor or other cancer other than surgically
cured non-melanoma skin cancer or cervical carcinoma in situ

Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, or
immunotherapy

Inability to return for follow-up visits or obtain follow-up studies required to assess
toxicity and response to therapy

Severe cardiovascular disease, i.e., arrhythmias requiring chronic treatment, congestive
heart failure or symptomatic ischemic heart disease

Pre-existing severe psychiatric condition or a history of a psychiatric disorder requiring
hospitalization or a history of suicidal ideation or attempt

Thyroid dysfunction not responsive to therapy

Uncontrolled diabetes mellitus

History of seropositivity for HIV

Subjects who are pregnant, lactating, or of reproductive potential and not practicing an
effective means of contraception

Subjects with a medical condition requiring chronic systemic corticosteroids

Subjects who are known to be actively abusing alcohol or drugs

Subjects who have not recovered from the effects of recent surgery

Prior administration of interferon alfa-2b or Pegintron

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Radiographic response (stratum 1)

Safety Issue:

No

Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

080130

NCT ID:

NCT00678951

Start Date:

May 2008

Completion Date:

March 2015

Related Keywords:

  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Neurofibromatosis Type 1
  • Plexiform Neurofibroma
  • Volumetric MRI Analysis
  • NF1
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Childrens Hospital, PittsburghPittsburgh, Pennsylvania  15213