Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I

• Register: ClinicalTrials.gov
• Last refreshed on: 19 February 2015
• Main ID: NCT00652990
• Date of registration: 03/04/2008
• Prospective Registration: No
• Primary sponsor: University of Alabama at Birmingham
• Public title: Sirolimus to Treat Plexiform Neurofibromas in Patients With Neurofibromatosis Type I
• Scientific title: A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
• Date of first enrolment: March 2008
• Target sample size: 18
• Recruitment status: Active, not recruiting
• URL: http://clinicaltrials.gov/show/NCT00652990
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
• Phase: Phase 2

Countries of recruitment

United States

Contacts

• Name: Brigitte C Widemann, M.D.
• Affiliation: National Cancer Institute (NCI)

Key inclusion & exclusion criteria

- INCLUSION CRITERIA:

INCLUSION CRITERA FOR ALL PATIENTS (STRATUM 1 AND 2):

All patients must have the clinical diagnosis of NF1 using the NIH Consensus Conference
criteria. In addition to a plexiform neurofibroma, one or more of the following diagnostic
criteria for NF1 must be present:

- 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).

- 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 percent for patients greater than
10 years of age and Lansky greater than or equal to 50 for patients less than or equal to
10 years of age. 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.

- Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
this study.

- 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.

- 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.

- Investigational Drugs: Patients must not have received an investigational drug within
4 weeks.

- Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or
stress doses of steroids if necessary.

- 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,
troleandomycin.

- Gastrointestinal prokinetic agents: cisapride, metoclopramide.

- Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole

- Calcium channel blockers: verapamil, diltiazem, nicardipine

- Other drugs: rifampin, bromocriptine, cimetidine (tagamet), danazol,
cyclosporine oral solution, lansoprazole (prevacid)

- Grapefruit juice.

- CYP3A4 inducers: Patients must also avoid strong inducers of CYP3A4, and may not have
received these medications within 1 week of entry. These include:

- Anticonvulsants: carbamazepine, phenobarbital, phenytoin

- Antibiotics: rifabutin, rifapentine

- Herbal preparations: St. John's wort (Hypericum perforatum, hypericine).

- Enzyme inducing anticonvulsants: Patients may not be taking enzyme -inducing
anticonvulsants, and may not have received these medications within 1 week of entry,
as these patients may experience different drug disposition. These medications
include:

- Carbamazepine (Tegretol)

- Felbamate (Felbtol)

- Phenobarbitol

- Phenytoin (Dilantin)

- Primidone (Mysoline)

- Oxcarbazepine (Trileptal)

- XRT: Greater than or equal to 6 months from involved field radiation to index
plexiform neurofibroma(s); greater than or equal to 6 weeks must have elapsed if
patient has received radiation to areas outside index plexiform neurofibroma(s).

- Surgery: At least 2 weeks since undergoing any major surgery.

Organ Function Requirements

- Adequate Bone Marrow Function Defined as:

- Peripheral absolute neutrophil count (ANC) greater than or equal to 1500/miroL

- Platelet count greater than or equal to 100,000/micorL (transfusion independent)

- Hemoglobin greater than or equal to 10.0 gm/dL (may receive RBC transfusions)

- Adequate Renal Function Defined as:

A serum creatinine based on age as follows:

- Less than or equal to 5 years old, Maximum Serum Creatinine (mg/dL) 0.8

- 5 years old to less than or equal to 10 years old, Maximum Serum Creatinine (mg/dL)
1.0

- 10 years old to less than or equal to 15 years old, Maximum Serum Creatinine (mg/dL)
1.2

- Greater than 15 years old Maximum Serum Creatinine (mg/dL


Age minimum: 3 Years
Age maximum: N/A
Gender: Both

Health Condition(s) or Problem(s) studied

Neurofibromatosis Type 1

Plexiform Neurofibromas

Paraspinal Plexiform Neurofibromas

Intervention(s)

Drug: Sirolimus

Primary Outcome(s)

Time to tumor progression as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of treatment (stratum 1) [Time Frame: 48 months]

Objective radiographic response as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of the treatment (stratum 2 [closed to accrual as of 5/27/09]) [Time Frame: 48 months]

Toxicity [Time Frame: 48 months]

Secondary Outcome(s)

Comparison of volumetric 3-D MRI measurements with conventional 2-D and 1-D MRI measurements in determining tumor response [Time Frame: 48 months]

Time to tumor progression as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and at the end of treatment 9stratum 2 [closed to accrual as of 5/27/09]) [Time Frame: 48 months]

Clinical response, defined as improvement in function and performance status or decrease in plexiform neurofibroma-related pain [Time Frame: 48 months]

Objective radiographic response as assessed by volumetric MRI analysis at baseline, after courses 3, 6, 9, and 15, after every 6 courses, and then at the end of treatment (stratum 1) [Time Frame: 48 months]

Secondary ID(s)

08-C-0096

080096

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

National Cancer Institute (NCI)