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A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)

This study has been completed.
Sponsor:
Collaborators:
Boston Children’s Hospital
Children's Hospital of Philadelphia
Children's Research Institute
Children's Hospital Medical Center, Cincinnati
National Cancer Institute (NCI)
University of Chicago
University of Utah
Washington University School of Medicine
Information provided by (Responsible Party):
Bruce Korf, MD, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT00634270
First received: February 20, 2008
Last updated: February 16, 2017
Last verified: February 2017
Results First Received: July 3, 2015  
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment;   Masking: No masking;   Primary Purpose: Treatment
Condition: Neurofibromatosis Type 1
Intervention: Drug: Sirolimus

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Existing and NF1 new patients at Consortium sites and partnering with the Children's Tumor Foundation.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Eligibility for Stratum 1 if evidence of progression and Stratum 2 if not evidence of progression.

Reporting Groups
  Description
Stratum 1

Design

  • Sirolimus oral solution will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment course) with pharmacokinetically-guided dosing.
  • Disease status will be evaluated using volumetric MRI analysis at regular intervals.

Sirolimus, Rapamycin: This phase II study will evaluate children and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with sirolimus. It is divided in two strata. The first stratum will evaluate time to progression (TTP) in children and adults with NF1 and progressive plexiform neurofibromas with the potential to cause sign

Stratum 2 Non-randomized, single arm interventional strata for inoperable Plexiform Neurofibromas with potential to cause significant morbidity WITHOUT evidence of progression

Participant Flow:   Overall Study
    Stratum 1   Stratum 2
STARTED   49 [1]   13 
COMPLETED   46   12 
NOT COMPLETED   3   1 
[1] February 12, 2008



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Of the 49 patients enrolled in Stratum 1; 46 were evaluable. Of the 13 enrolled in Stratum 2; 12 were evaluable. This information is also listed in the Analysis Population Descriptions and Additional Description.

Reporting Groups
  Description
Stratum 1

Design

  • Sirolimus oral solution will be administered orally BID on a continuous dosing schedule (28 days = 1 treatment course) with pharmacokinetically-guided dosing.
  • Disease status will be evaluated using volumetric MRI analysis at regular intervals.

Sirolimus, Rapamycin: This phase II study will evaluate children and adults with neurofibromatosis type-1 (NF1) and plexiform neurofibromas treated with sirolimus. It is divided in two strata. The first stratum will evaluate time to progression (TTP) in children and adults with NF1 and progressive plexiform neurofibromas with the potential to cause sign

Stratum 2 Non-randomized, single arm interventional strata for inoperable Plexiform Neurofibromas with potential to cause significant morbidity WITHOUT evidence of progression
Total Total of all reporting groups

Baseline Measures
   Stratum 1   Stratum 2   Total 
Overall Participants Analyzed 
[Units: Participants]
 49   13   62 
Age 
[Units: Years]
Mean (Full Range)
 9 
 (3 to 45) 
 16 
 (3 to 35) 
 10.46 
 (3 to 45) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      24  49.0%      8  61.5%      32  51.6% 
Male      25  51.0%      5  38.5%      30  48.4% 
Race/Ethnicity, Customized 
[Units: Participants]
     
American Indian or Alaskan Native   0   0   0 
Asian   3   1   4 
Native Hawaiian or Pacific Islander   0   0   0 
Black or African American   6   2   8 
White   35   10   45 
Unknown or Not Reports   5   0   5 
Region of Enrollment 
[Units: Participants]
     
United States   49   13   62 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Time to Disease Progression Based on Volumetric MRI   [ Time Frame: 24 Months Stratum 1 ]

2.  Primary:   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 ]

3.  Primary:   Toxicity   [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ]

4.  Primary:   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 ]

5.  Primary:   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 ]

6.  Primary:   To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - (Clearance (L/h Per 1.85 m^2)   [ 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 ]

7.  Primary:   To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population- Therapeutic Dose (mg/m^2 Per Dose)   [ 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 ]

8.  Primary:   To Characterize the Pharmacokinetic Profile of Sirolimus in When Administered to This Patient Population - Therapeutic Dose (mg/kg Per Dose)   [ 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 ]

9.  Primary:   To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - Therapeutic Dose (mg/kg)^0.75   [ 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 ]

10.  Secondary:   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 ]

11.  Secondary:   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 ]

12.  Secondary:   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 ]

13.  Secondary:   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 ]

14.  Secondary:   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 ]

15.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.  


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Bruce Korf, MD, PhD
Organization: The Univ of Alabama at Birmingham
phone: 205.934.5140
e-mail: kcole@uab.edu



Responsible Party: Bruce Korf, MD, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00634270     History of Changes
Other Study ID Numbers: F071019012
DOD: W81XWH-05-615. ( Other Identifier: Department of Defense )
UAB: 251558. ( Other Identifier: UAB Link Number )
Study First Received: February 20, 2008
Results First Received: July 3, 2015
Last Updated: February 16, 2017