Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults
|First Received Date ICMJE||May 14, 2008|
|Last Updated Date||March 14, 2014|
|Start Date ICMJE||May 2008|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT00678951 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Clinical and radiographic response (stratum3) [ Designated as safety issue: No ]|
|Original Secondary Outcome Measures ICMJE
||Clinical and radiographic response (stratum 3) [ Designated as safety issue: No ]|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Pegintron to Treat Plexiform Neurofibromas in Children and Young Adults|
|Official Title ICMJE||A Phase II Trial of Peginterferon Alpha-2b (PEG-Intron) for Neurofibromatosis Type 1 Related Unresectable, Symptomatic or Life-Threatening Plexiform Neurofibromas|
-Patients between 18 months and 21 years of age with NF1 and an inoperable plexiform neurofibroma that can cause serious medical problems.
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.
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.
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.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Intervention ICMJE||Drug: PEG-interferon alfa-2b
|Study Arm (s)||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE||90|
|Estimated Completion Date||March 2015|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
Specific eligibility criteria stratum 1:
Patient does not have clinical symptoms from the plexiform neurofibroma.
Specific eligibility criteria stratum 2:
Specific eligibility criteria stratum 3:
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:
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.
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
|Ages||6 Months to 21 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00678951|
|Other Study ID Numbers ICMJE||080130, 08-C-0130|
|Has Data Monitoring Committee||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )|
|Study Sponsor ICMJE||National Cancer Institute (NCI)|
|Collaborators ICMJE||Not Provided|
|Information Provided By||National Institutes of Health Clinical Center (CC)|
|Verification Date||September 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP