Clinical Trial: A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas

Brief Summary:

Treatment Overview

This phase II study will evaluate the activity of sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas that have the potential to cause significant morbidity. The following disease strata will be studied:

Stratum 1: Progressive plexiform neurofibroma(s) that have the potential to cause significant morbidity. The endpoint will be time to tumor progression based on volumetric tumor measurements.

Stratum 2: Plexiform neurofibromas without documented radiographic progression at trial entry. The endpoint will be radiographic response. As of May 2009, Stratum 2 was closed to enrollment. Stratum 1 is active.

Detailed Summary:

ABSTRACT/SCHEMA

Sirolimus will be provided as oral solution 1 mg/ml to allow for precise dose adjustments. The tablet and oral solution forms are clinically equivalent (2003). Sirolimus will be administered orally twice daily (approximately every 12 hours) for a 28 day course with no rest period between courses. Sirolimus should be taken by the patient consistently either with or without food. Sirolimus should NOT be taken with grapefruit juice or with other effectors of CYP3A4 (see section 4.1.7). Dietary habits around the time of sirolimus intake should be as consistent as possible throughout the study, and in particular, during those periods when samples are being taken for pharmacokinetic analyses (if applicable). Limited exposure to sunlight and wearing sunscreen is recommended while taking this drug. If you miss a dose, treatment should continue without making up the missed dose.

The starting dose will be 0.8 mg/m2 BSA per dose. Each patient's dose will be rounded to the nearest 0.1 mg (adult average 1.6 mg per dose). The BSA should be calculated based on an accurate height and weight measurement performed according to institutional guidelines, or using the following formula:

Square root of: (Height[cm] X Weight[kg]/3,600)

Dosing will be pharmacokinetically adjusted to maintain trough sirolimus levels within the target range of 10-15 ng/ml. (Appendix IV-A). The first sirolimus level will not be measured until week 2 to allow for loading to occur and to approach steady state concentrations. If patients are unable to achieve target trough sirolimus levels within 4 weeks, patients may be asked to have mini-pharmacokinetics of 3 blood draws, in addition to a trough level, in order to better estimate patient's dose. The ext
Sponsor: University of Alabama at Birmingham

Current Primary Outcome:

• Time to Disease Progression Based on Volumetric MRI [ Time Frame: 24 Months Stratum 1 ]
  Median time to progression in Stratum 1 as defined as an increase of at least 20% of the volume of the primary lesion. Note: Since Stratum 2 looked at response rate only, median time to progression was not reviewed for this outcome.
• Results in Objective Radiographic Responses Based on Volumetric MRI Measurements in Children and Adults With NF1 and Inoperable PN in the Absence of Documented Radiographic Progression at Trial Entry [ Time Frame: 48 weeks Stratum 2 ]
  Stratum 2 outcome - Response
• Toxicity [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  Number of participants experiencing adverse events
• To Characterize the Pharmacokinetic Profile of Sirolimus Administered to This Patient Population (Clearance Liters/Hour (L/h)) [ Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours ]
  An iterative 2-stage Bayesian method was used for the PK parameter analyses
• To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population Using Liters/Hour Per Population Median Weight of 70kg (L/h70kg) [ Time Frame: Pre-dose; Day 1 at 0.5 hours, 1.0 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, and 10.0 to 12.0 hours ]
  An iterative 2-stage Bayesian method was used for the PK parameter analyses
• To Evaluate the Quality of Life During Treatment With Sirolimus by Assessing Preliminary Correlations of Response With Quality-of-life Outcomes [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  Self-reported, age-appropriate PedsQL Scale. Assessments included: Inventory for physical function, emotional function, social function and school function - number system 0-4 was used with 4 being the worse maximum threshold); inventory for chronic illness used a 5-point likert scale - 5 being the worst maximum threshold; Skindex-Teen used a scale of 0 to 100 - the higher the number the more frequent the experience; Pain intensity was measured using a line with a happy and sad face - marks toward the sad face indicated more intense pain; and, the McGill Pain Questionnaire - higher values indicating worse pain of a scale from 0-3. All assessments were combined for an overall PedsQL score by rating each item 0-4, then reverse transforming each to a 0 - 100 scale. The total scores were calculated by averaging the item scores, with higher scores being better.
• To Assess the Value of Three-dimensional MRI (3-D MRI) in the Evaluation of Plexiform Neurofibromas and Paraspinal Neurofibromas, and to Compare 3-D MRI to Conventional Two-dimensional MRI (2-D MRI) and One Dimensional MRI (1-D MRI) Data Analysis [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  The study provided central review of all MRIs using a three-dimensional volumetric protocol. As the STOPN protocol began, research had already demonstrated the superiority of this approach to 1-D or 2-D analyses, so these were not used in the STOPN study.
• To Asses Preliminary Correlations of Radiographic Response With Changes in Pharmacodynamics Parameters Including p70s6 Kinase Activity in Peripheral Blood Mononuclear Cells. [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  Response by Volumetric MRI.
• To Evaluate the Effect of Sirolimus on Clinical Response by Reduction in Pain, or Improvement in Function or Performance Scale. [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  There were no data collected for this outcome measure.
• To Evaluate Pharmacogenetic Polymorphisms of Cytochrome P450 3A4 & 3A5 Alleles and P-glycoprotein/MDR for Their Influence on the Metabolism of Sirolimus in This Patient Population. [ Time Frame: 24 weeks Stratum 1 Only ]
  Trough concentration of sirolimus is reported in nanograms per mL.
• To Evaluate the Role of Apolipoprotein E Genotypes as Predictors for Development of Hyperlipidemia During Therapy With Sirolimus. [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]
  Number of patients who experienced hyperlipidemia is being reported.

Original Secondary Outcome: feasibility and toxicity [ Time Frame: same as above ]

Information By: University of Alabama at Birmingham

Dates:
Date Received: February 20, 2008
Date Started: April 2008
Date Completion:
Last Updated: February 16, 2017
Last Verified: February 2017