Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
- Registration Number
- NCT00076102
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure \[AUC\] not more than 1 standard deviation below the mean drug exposure \[AUC\] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.
Objectives:
To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.
To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.
To describe and define the toxicities of pirfenidone.
Eligibility:
Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform neurofibromas that have the potential to cause substantial morbidity.
Design:
The phase II dose will be used in a single stage, single arm phase II trial The natural history of the growth of plexiform neurofibromas is unknown. For this reason, time to disease progression on the placebo arm of an ongoing National Cancer Institute (NCI) Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and progressive plexiform neurofibromas.
Funding source - Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD)
- Detailed Description
Background:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure \[AUC\] not more than 1 standard deviation below the mean drug exposure \[AUC\] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.
Objectives:
To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.
To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.
To describe and define the toxicities of pirfenidone.
Eligibility:
Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform neurofibromas that have the potential to cause substantial morbidity.
Design:
The phase II dose will be used in a single stage, single arm phase II trial The natural history of the growth of plexiform neurofibromas is unknown. For this reason, time to disease progression on the placebo arm of an ongoing National Cancer Institute (NCI) Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and progressive plexiform neurofibromas will be used as historical control to determine if pirfenidone increases time to disease progression. Eligibility criteria and method of tumor measurements are identical for both trials.
Pirfenidone will be administered orally as capsules at a dose of 500 mg/m\^2 three times a day (q8h) for cycles of 28 days with no rest period between cycles based on the results of our pediatric phase I trial.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 36
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Pirfenidone Pirfenidone Pirfenidone orally as capsules three times a day approximately every 8 hours for cycles of 28 days with no rest period between cycles (28 day treatment cycles); 500 mg/m\^2 every 8 hours (1500 mg/m2/day).
- Primary Outcome Measures
Name Time Method Median Time to Disease Progression 5 years Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).
Number of Participants With Adverse Events 5 years Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Percentage of Participants Who Had an Objective Response Rate ≥4 weeks Objective response rate is defined as a complete response (CR) or partial response (PR). Complete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks.
- Secondary Outcome Measures
Name Time Method Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline Baseline Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL. Baseline comparisons between child and parent total and domain scores were performed.
Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale prior to cycles 1, 4, 7 and 10. Quality of life was assessed by the Impact of Pediatric Illness scale for children 6-18 years of age. The child's primary caregiver completed the proxy Parent Form and children answered either the self-report Child or Adolescent (11-18 years) Form prior to cycles 1, 4, 7 and 10. The parallel IPI Scale forms assess four domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 3-or5-point Likert scale (1 to 5 for Parent and Adolescent Form and 1, 3, 5 for the Child Form) ranging from "not at all" to "a lot". Item scores are transformed to a scale of 0-100, and then mean scores are calculated for the four domains and total scale with higher scores indicating better QOL.
Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years Index lesions will be followed for progression by 3D magnetic resonance imaging. Compete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment. Stable disease is a \<20% increase, and \<25% decrease in the sum of the volume of all index lesions for ≥4 weeks. Minor response is a ≥25% but \<50% reduction in the sum of the volume of all index lesions for ≥4 weeks.
Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression Index lesions will be followed for progression by 1D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.
Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression Index lesions will be followed for progression by 2D magnetic resonance imaging. Progression is defined as a ≥20% increase in the volume of at least one of the index plexiform neurofibromas compared to the pretreatment volume measured prior to the start of treatment.
Number of Participants Who Contributed to the Tissue Bank 5 years Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons.
Trial Locations
- Locations (15)
Johns Hopkins Oncology Center
🇺🇸Baltimore, Maryland, United States
Childrens Hospital, Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
St. Louis Children's Hospital
🇺🇸Saint Louis, Missouri, United States
Childrens Hospital, Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
Mayo Clinic, Rochester
🇺🇸Rochester, Minnesota, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
Beth Israel Medical Center
🇺🇸New York, New York, United States
Oregon Health Sciences University
🇺🇸Portland, Oregon, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Childrens Hospital, Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Childrens Memorial Hospital, Chicago
🇺🇸Chicago, Illinois, United States
Childrens National Medical Center
🇺🇸Washington, District of Columbia, United States
University of Alabama
🇺🇸Birmingham, Alabama, United States