Neurofibroma, Plexiform, Neurofibromatosis 1
Conditions
Keywords
Side Effect, Oral Administration, Nerve Sheath Tumor, Antifibrotic Agent, Volumetric Tumor Measurement, Plexiform Neurofibroma, Neurofibromatosis Type 1, Volumetric MRI Analysis, Time to Progression, NF1
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.
Interventions
DRUGPirfenidone
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).
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: 1. Age: greater than or equal to 3 years and Less than or equal to 21 years of age. Required body surface area (BSA): greater than or equal to 0.31 m\^2. 2. Diagnosis: Patients with NF1 and progressive plexiform neurofibromas that have 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 necessary in the presence of consistent clinical and radiographic findings, but should be considered if malignant degeneration of a plexiform neurofibroma is clinically suspected. In addition to plexiform neurofibroma(s), all study subjects must have at least one other diagnostic criteria for NF1 listed below (National Institutes of Health (NIH) Consensus Conference): <!-- --> 1. Six or more cafe-au-lait spots (greater than or equal to 0.5 cm in prepubertal subjects or greater than or equal to 1.5 cm in postpubertal subjects) 2. Freckling in the axilla or groin 3. Optic glioma 4. Two or more Lisch nodules 5. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex) 6. A first-degree relative with NF1 In this study a plexiform neurofibroma is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal plexiform neurofibroma involves two or more levels with connection between the levels or extending laterally along the nerve. 3\. Measurable disease: Patients must have measurable plexiform neurofibroma(s). For the purpose of this study a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension. There must be evidence of recurrent or progressive disease as documented by an increase in size or the presence of new plexiform neurofibromas on MRI. Progression at the time of study entry is defined as: A. A measurable increase of the plexiform neurofibroma (greater than or equal to 20% increase in the volume, or a greater than or equal to 13% increase in the product of the two longest perpendicular diameters, or a greater than or equal to 6% increase in the longest diameter) over the last two consecutive scans (magnetic resonance imaging (MRI) or computed tomography (CT), or over the time period of approximately one year prior to evaluation for this study. B. Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible to enter the study after the surgery, provided the plexiform neurofibroma was incompletely resected and is measurable. 4\. Prior therapy: Patients with NFI are eligible at the time of recurrence or progression of an inoperable plexiform neurofibroma. Patients will only be eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery. Since there is no standard effective chemotherapy for patients with NF1 and progressive plexiform neurofibromas, patients may be treated on this trial without having received prior medical therapy. Patients who received prior medical treatment for their plexiform neurofibroma(s) must have recovered from the toxic effects of all prior therapy before entering this study. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTCAE-3) Version 3.0 will be used for toxicity assessment. A copy of the CTCAE version 3.0 can be downloaded from the CTEP home page (http:// ctep.cancer.gov). Recovery is defined as a toxicity grade less than 2, unless otherwise specified in the Inclusion and
Exclusion criteria
. Patients must have had their last dose of radiation therapy at least six weeks prior to study entry, and their last dose of chemotherapy at least four weeks prior to study entry. Patients who received G-CSF after the prior cycle of chemotherapy must be off G-CSF for at least one week prior to entering this study. 5\. Performance Status: Performance Status: Patients should have a life expectancy of at least 12 months. Patients greater than 10 years must have a Karnofsky performance level greater than or equal to 50, and children less than or equal to 10 years must have a Lansky performance level 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. 6\. Hematologic Function: Patients must have an absolute granulocyte count greater than or equal to 1,500/uL, a hemoglobin greater than or equal to 9.0 gm/dl, and a platelet count greater than or equal to 150,000/microliter at study entry (all transfusion independent). 7\. Hepatic Function: Patients must have a bilirubin within normal limits and serum glutamic pyruvic transaminase (SGPT) less then or equal to 2x upper limit of normal. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin. (Gilbert syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). 8\. Renal Function: Patients must have an age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73 m\^2. Age Maximum Serum Creatinine (years) (mg/dl) less than or equal to 5 0.8 5 less than age less than or equal to 10 1.0 10 less than age less than or equal to 15 1.2 greater than 15 1.5 9\. Informed Consent: All patients or their legal guardians (if the patients is less than 18 years old) must sign an Institutional Review Board (IRB) approved document of informed consent (screening protocol) prior to performing studies to determine patient eligibility. After confirmation of patient eligibility all patients or their legal guardians must sign the protocol specific informed consent to document their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (other than the studies which were performed to determine patient eligibility). When appropriate, pediatric patients will be included in all discussions. Age appropriate assent forms for children from 7 through 12 years, and for children from 13 through 17 years have been developed and will be signed by the pediatric patients, when appropriate, in order to obtain written assent. 10\. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired. 11\. Patients must be able to take pirfenidone by mouth. Capsules can be opened and content mixed with food for easier consumption in small children. 12\. Patients (both male and female) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of a child-bearing age. For purposes of the protocol, all patients greater than 9 years of age or those showing pubertal development will be considered of childbearing age. 13\. Ability to undergo magnetic resonance imaging (MRI) and no contraindication for MRI examinations following the MRI protocol outlined.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Number of Participants Who Contributed to the Tissue Bank | 5 years | Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons. |
| 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. |
| 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 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. |
Countries
United States
Participant flow
Recruitment details
36 participants were enrolled in this study
Participants by arm
| Arm | Count |
|---|---|
| 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). | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Clinical progression | 1 |
| Overall Study | plexiform neurofibroma surgery | 1 |
| Overall Study | Progression in pre-existing brain tumor | 1 |
| Overall Study | refusal of further therapy | 2 |
Baseline characteristics
| Characteristic | Pirfenidone |
|---|---|
| Age, Categorical <=18 years | 34 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 9.81 years STANDARD_DEVIATION 4.52 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 36 |
| other Total, other adverse events | 36 / 36 |
| serious Total, serious adverse events | 3 / 36 |
Outcome results
Primary
Median Time to Disease Progression
Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pirfenidone | Median Time to Disease Progression | 13.2 Months |
Primary
Number of Participants With Adverse Events
Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pirfenidone | Number of Participants With Adverse Events | 36 Participants |
Primary
Percentage of Participants Who Had an Objective Response Rate
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.
Time frame: ≥4 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pirfenidone | Percentage of Participants Who Had an Objective Response Rate | Complete Response | 0 percentage of participants |
| Pirfenidone | Percentage of Participants Who Had an Objective Response Rate | Partial Response | 0 percentage of participants |
Secondary
Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale
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.
Time frame: prior to cycles 1, 4, 7 and 10.
Population: Of the 36 pts enrolled, 28 were within the age range of the IPI Scale at baseline. 2 pts did not have any QOL forms completed; 1 did not have a baseline \& 6 pts had missing f/u evals. QOL data is presented for 19 pts. Due to pts not completing forms at random f/u evals, some time points have fewer than 19 pts included in the longitudinal analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Pre Cycle 7 | 71.4 scores on a scale | Standard Deviation 12.3 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Baseline (to Cycle 4) | 71.1 scores on a scale | Standard Deviation 13.1 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Pre Cycle 4 | 71.8 scores on a scale | Standard Deviation 10.7 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Baseline (to Cycle 4) | 67.9 scores on a scale | Standard Deviation 12.9 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Pre Cycle 4 | 69.8 scores on a scale | Standard Deviation 10.8 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Baseline (to Cycle 7) | 71.7 scores on a scale | Standard Deviation 11.5 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Pre Cycle 7 | 70.6 scores on a scale | Standard Deviation 9 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Baseline (to Cycle 7) | 69.5 scores on a scale | Standard Deviation 12.8 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Baseline (to Pre Cycle 10) | 71.56 scores on a scale | Standard Deviation 12.6 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Parent Pre Cycle 10 | 72.1 scores on a scale | Standard Deviation 7.8 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Baseline (to Pre Cycle 10) | 67.5 scores on a scale | Standard Deviation 13 |
| Pirfenidone | Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale | Child Pre Cycle 10 | 68.3 scores on a scale | Standard Deviation 14.1 |
Comparison: F=0.25 under the null hypothesisp-value: 0.6263ANOVA
Comparison: F= 0.87 under the null hypothesisp-value: 0.3625ANOVA
Comparison: F=0.31 under the null hypothesisp-value: 0.5877ANOVA
Comparison: F=1.27 under the null hypothesisp-value: 0.2767ANOVA
Comparison: F=0.04 under the null hypothesisp-value: 0.8466ANOVA
Comparison: F=0.18 under the null hypothesisp-value: 0.6774ANOVA
Secondary
Number of Participants Who Contributed to the Tissue Bank
Tumor specimens from patients who undergo tumor surgery or biopsies for clinical reasons.
Time frame: 5 years
Population: Participants declined to contribute specimens for the tissue bank.
Secondary
Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging
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.
Time frame: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression
Population: This outcome measure was not done because only 3D imaging was performed. Due to a detailed comparison of 1D-2D and 3D imaging for another study (Tipifarnib R115777) the investigator determined that a detailed comparison of 1D-2D and 3D analysis would really add no new knowledge. Therefore only 3D analysis was performed for this trial.
Secondary
Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging
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.
Time frame: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years
Population: Five patients were not analyzed due to clinical progression (n=1), plexiform neurofibroma surgery (n=1), progression in a pre-existing brain tumor (n=1), and refusal of further therapy (n=2).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pirfenidone | Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging | Progressive disease | 31 Participants |
| Pirfenidone | Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging | Complete response | 0 Participants |
| Pirfenidone | Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging | Partial response | 0 Participants |
| Pirfenidone | Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging | Stable disease | 0 Participants |
| Pirfenidone | Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging | MInor response | 0 Participants |
Secondary
Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging
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.
Time frame: Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression
Population: This outcome measure was not done because only 3D imaging was performed. Due to a detailed comparison of 1D-2D and 3D imaging for another study (Tipifarnib R115777) the investigator determined that a detailed comparison of 1D-2D and 3D analysis would really add no new knowledge. Therefore only 3D analysis was performed for this trial.
Secondary
Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at 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.
Time frame: Baseline
Population: Of the 36 patients enrolled, 28 were within the age range of the IPI Scale at baseline. Two patients did not have any QOL forms completed; one did not have a baseline evaluation, and six patients had missing follow-up evaluations. Thus, QOL data is presented for 19 subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Parent proxy-adaptive behavior | 72.1 Scores on a scale | Standard Deviation 10.2 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Parent proxy - emotional functioning | 72.4 Scores on a scale | Standard Deviation 13.4 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Total score parent | 72.7 Scores on a scale | Standard Deviation 10.7 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Total score child | 69.1 Scores on a scale | Standard Deviation 12 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Child Self-Report-adaptive behavior | 76.7 Scores on a scale | Standard Deviation 11.8 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Child Self-Report-emotional functioning | 63.7 Scores on a scale | Standard Deviation 14.7 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Parent proxy - medical/physical status | 77.6 Scores on a scale | Standard Deviation 15.1 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Child Self-Report - medical/physical status | 67.1 Scores on a scale | Standard Deviation 16.2 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Parent proxy - cognitive functioning | 62.9 Scores on a scale | Standard Deviation 19.6 |
| Pirfenidone | Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline | Child Self-Report- cognitive functioning | 69.4 Scores on a scale | Standard Deviation 18.5 |
Comparison: F=5.45 under the null hypothesisp-value: 0.0301ANOVA
Comparison: F = 6.56 under the null hypothesisp-value: 0.0186ANOVA
Comparison: F=11.23 under the null hypothesisp-value: 0.0032ANOVA