A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas (Protocol 102)
|First Received Date ICMJE||February 20, 2008|
|Last Updated Date||February 11, 2014|
|Start Date ICMJE||April 2008|
|Estimated Primary Completion Date||August 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Increased time to disease progression based on volumetric MRI [ Time Frame: 24 weeks Stratum 1 / 48 weeks Stratum 2 ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00634270 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||feasibility and toxicity [ Time Frame: same as above ] [ Designated as safety issue: Yes ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas|
|Official Title ICMJE||A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas|
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.
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 extra trough sirolimus levels will be at: 1 hour, 3 hours, and 4-6 hours after a sirolimus dose.
Sirolimus doses will be adjusted pharmacokinetically and will account for changes in body surface area.
Dose modifications for patients who experience toxicities are outlined in Section 8.0.
Sirolimus should be re-taken if vomiting occurs within 15 minutes of taking the dose, but not if vomiting occurs more than 15 minutes after taking sirolimus. Patients or their parents/guardians will keep a diary to document the intake of each dose of sirolimus and potential side effects. The patient diary should be reviewed with the patient's family at each required clinical study evaluation. In addition, leftover study medication should be collected at each on study evaluation, and drug should be accounted for at this time (Appendix V).
A treatment course will consist of 4 weeks of therapy. For stratum 1 treatment may continue until disease progression or unacceptable toxicity occurs. Patients entered on stratum 2 may receive up to a maximum of 6 courses (i.e. 24 weeks) of therapy unless there is evidence of objective radiographic response, as defined in Section 13.0 (> to 20% decrease in PN volume), tumor progression, or unacceptable toxicity. Patients who experience unacceptable toxicity or disease progression will be removed from treatment with sirolimus. Patients with documented radiographic response may continue treatment with sirolimus for up to 6 treatment courses after the maximum response.
• To determine whether the mTOR inhibitor sirolimus, administered using pharmacokinetically-guided dosing: Increases time to disease progression based on volumetric MRI measurements in children and adults with neurofibromatosis type 1 (NF1) and progressive plexiform neurofibromas (PN).
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.
• Inoperable, measurable PN WITHOUT documented progression that have the potential to cause significant morbidity.
EXPERIMENTAL DESIGN SCHEMA
GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
To determine whether the mTOR inhibitor sirolimus, administered orally twice daily on a continuous dosing schedule (1 course = 28 days) using pharmacokinetically-guided dosing:
Increases time to disease progression based on volumetric MRI measurements in children and young adults with neurofibromatosis type 1 (NF1) and inoperable progressive plexiform neurofibromas (PN),
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
To evaluate the feasibility and toxicity of chronic sirolimus administration in this patient population.
To characterize the pharmacokinetic profile of sirolimus when administered to this patient population.
To evaluate quality of life during treatment with sirolimus and to assess preliminary correlations of response with quality-of-life outcomes.
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.
To assess preliminary correlations of radiographic response with changes in pharmacodynamic parameters including p70s6 kinase activity in peripheral blood mononuclear cells.
To evaluate the effect of sirolimus on clinical response by reduction in pain, or improvement in function or performance scale.
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.
To evaluate the role of Apolipoprotein E genotypes as predictors for development of hyperlipidemia during therapy with sirolimus.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Neurofibromatosis Type 1|
|Intervention ICMJE||Drug: 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 significant morbidity treated with sirolimus. The second stratum will evaluate objective radiographic response to sirolimus in children and adults with NF1 and inoperable plexiform neurofibromas with the potential to cause significant morbidity that do not have documented progression of the PN at time of trial entry.
Other Name: Sirolimus, Rapamune, Rapamycin
|Study Arm (s)||Experimental: 1
Intervention: Drug: Sirolimus, Rapamycin
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Completion Date||August 2014|
|Estimated Primary Completion Date||August 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Inclusion Criteria: all patients (stratum 1 and 2):
Specific eligibility criteria stratum 1 Disease status:
- Patients must have a progressive plexiform neurofibroma(s). Progression at the time of study entry is defined as: Presence of new plexiform neurofibromas on MRI or CT, OR A measurable increase of the plexiform neurofibroma (> or equal to 20% increase in the volume, or a > or equal to 13% increase in the product of the two longest perpendicular diameters, or a > or equal to 6% increase in the longest diameter) over the last two consecutive scans (MRI or CT), or over the time period of approximately one year prior to evaluation for this study.
Specific eligibility criteria stratum 2 Disease status:
- Radiographic disease progression as defined in Section 4.2.1 is not required for trial entry.
Exclusion Criteria:(Both Strata):
|Ages||3 Years to 75 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00634270|
|Other Study ID Numbers ICMJE||F071019012, DOD: W81XWH-05-615., UAB: 251558.|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Bruce Korf, MD, University of Alabama at Birmingham|
|Study Sponsor ICMJE||University of Alabama at Birmingham|
|Information Provided By||University of Alabama at Birmingham|
|Verification Date||February 2014|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP