Phase 2 N=62 Treatment

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

Neurofibromatosis Type 1

Bottom Line

View on ClinicalTrials.gov: NCT00634270 ↗

Enrolled (actual)

Serious AEs

41.4%

Results posted

Feb 2017

Primary outcome: Primary: Time to Disease Progression Based on Volumetric MRI — 15.4 Months

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Sirolimus (Drug)
Age: Pediatric, Adult, Older Adult · 3+ yrs
Sex: All
Sponsor: University of Alabama at Birmingham
Primary completion: Nov 2014

Outcome Measures

Outcome	Result	p-value
PRIMARY Time to Disease Progression Based on Volumetric MRI	15.4	—
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	12	—
PRIMARY Toxicity	49; 13	—
PRIMARY To Characterize the Pharmacokinetic Profile of Sirolimus Administered to This Patient Population (Clearance Liters/Hour (L/h))	11.8	—
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)	23.7	—
PRIMARY To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - (Clearance (L/h Per 1.85 m^2)	6.4	—
PRIMARY To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population- Therapeutic Dose (mg/m^2 Per Dose)	2.0	—
PRIMARY To Characterize the Pharmacokinetic Profile of Sirolimus in When Administered to This Patient Population - Therapeutic Dose (mg/kg Per Dose)	0.08	—
PRIMARY To Characterize the Pharmacokinetic Profile of Sirolimus When Administered to This Patient Population - Therapeutic Dose (mg/kg)^0.75	0.14	—
SECONDARY To Evaluate the Quality of Life During Treatment With Sirolimus by Assessing Preliminary Correlations of Response With Quality-of-life Outcomes	2.8	—
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	—	—
SECONDARY To Asses Preliminary Correlations of Radiographic Response With Changes in Pharmacodynamics Parameters Including p70s6 Kinase Activity in Peripheral Blood Mononuclear Cells.	—	—
SECONDARY To Evaluate the Effect of Sirolimus on Clinical Response by Reduction in Pain, or Improvement in Function or Performance Scale.	—	—
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.	9.37	—
SECONDARY To Evaluate the Role of Apolipoprotein E Genotypes as Predictors for Development of Hyperlipidemia During Therapy With Sirolimus.	1; 0	—

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.

Eligibility Criteria

Inclusion Criteria: all patients (stratum 1 and 2):

All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
Six or more café-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).
Freckling in the axilla or groin.
Optic glioma.
Two or more Lisch nodules.
A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex).
A first-degree relative with NF1.
Patients must have plexiform neurofibroma(s) 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. Patients with paraspinal plexiform neurofibromas will be eligible for this trial. 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.
Age: Patients must be greater than or equal to 3 years of age at the time of study entry.
Durable Power of Attorney: Adults evaluated for this study will be offered a durable power of attorney. Adults who are unable to provide informed consent will have to have a durable power of attorney in order to participate in this trial.
Disease status: Measurable disease: Patients must have measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. For the purpose of this study, a measurable lesion will be defined as a lesion of at least 3 cm measured in one dimension.
Performance Level: Karnofsky greater than or equal to 50% for patients > 10 years of age and Lansky greater than or equal to 50 for patients less than or equal to 10 years of age (Appendix IV). Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
Prior Therapy: 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. Patients are only eligible if complete resection of a plexiform neurofibroma with acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery. Patients may have been previously treated for a plexiform neurofibroma but must have fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy prior to entering this study.
a. Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study.
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor that supports platelet, red or white cell number or function.
c. Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. These patients must be discussed with the Study Chair on a case-by-case basis.
d. Investigational Drugs: Patients must not have received an investigational drug within 4 weeks.
e. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
f. CYP3A4 inhibitors: Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry. These include: Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin, trolea

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Data sourced from ClinicalTrials.gov (NCT00634270). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.