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

Phase 2
3 Years
Not Enrolling
Neurofibromatosis Type 1, Plexiform Neurofibromas, Paraspinal Plexiform Neurofibromas

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Trial Information

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


Patients with Neurofibromatosis 1 (NF1) have an increased risk of developing tumors of the
central and peripheral nervous system, including plexiform neurofibromas (PN), which are
benign nerve sheath tumors that are among the most debilitating complications of NF1.
Plexiform neurofibromas appear to have the fastest growth rate in young children. There are
no standard treatment options for PN other than surgery, which is often difficult due to the
extensive growth and invasion of surrounding tissues. Mammalian Target of rapamcyin (mTOR),
a serine/threonine kinase regulated by the phosphoinositol 3 kinase (PI3K), acts as a master
switch of cellular catabolism and anabolism and controls protein translation, angiogenesis,
cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the
mTOR pathway activity, with increased mTOR activation observed in NF1-deficent cells and
tumors from NF1 patients. Sirolimus is a macrolide antibiotic that inhibits mTOR activity,
preventing phosphorylation (and activation) of p70S6K, 4E-BP1, and other proteins involved
in cell motility, angiogenesis, and cell growth control.

Primary Objectives

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.

To evaluate the feasibility and toxicity of chronic sirolimus administration in this patient

To characterize the pharmacokinetic profile (profile includes pharacodynamics and
pharmacogenetics) of sirolimus when administered to this patient population.


Patients greater than or equal to 3 years old with NF1 AND

Inoperable, measurable, radiographically PROGRESSIVE PN that have the potential to cause
significant morbidity.


Inoperable, measurable PN WITHOUT documented progression that have the potential to cause
significant morbidity.


Rapamycin oral solution will be administered orally BID on a continuous dosing schedule (28
days equals 1 treatment cycle) with pharmacokinetically-guided dosing.

Disease status will be evaluated using volumetric MRI analysis at regular intervals.

The plasma pharmacokinetics and pharmacodynamics of sirolimus will be evaluated, as will
pharmacogenetic polymorphisms and their influence on the metabolism of sirolimus in this
patient population.

Pain reduction and quality of life outcomes will also be assessed.

Toxicity of chronic siolimus administered will be evaluated using physical and laboratory

Inclusion Criteria



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

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

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

- Macrolide Antibiotics: clarithromycin, telithromycin, erythromycin,

- 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

- 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)

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

- Greater than 15 years old Maximum Serum Creatinine (mg/dL) 1.5

OR a creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m(2)

- Adequate Liver Function Defined As:

- Bilirubin (sum of conjugated plus unconjugated) less than or equal to1.5 times
upper limit of normal (ULN) for age, and

- SGPT (ALT) less than or equal to 5 times upper limit of normal (ULN) for age,

- Serum albumin greater than or equal to 2 g/dL.

- Fasting LDL Cholesterol:

- Patients must have a fasting LDL cholesterol of less than or equal to 160 mg/dL

- Patients taking a cholesterol lowering agent must be on a single medication and
on a stable dose for at least 4 weeks


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 (documented by comparison
with prior MRI or CT), OR

- A measurable increase of the plexiform neurofibroma (greater than or equal to 20
percent increase in the volume, or a greater than or equal to 13 percent
increase in the product of the two longest perpendicular diameters, or a greater
than or equal to 6 percent increase in the longest diameter) documented by
comparison of two scans (MRI or CT) in the time period of approximately one year
or less prior to evaluation for this study.


Disease status:

- No radiographic disease progression as defined for criteria stratum 1 (above) by
comparison of two scans (MRI or CT) in the time period of approximately one year +/-
one month.



- Chronic treatment with systemic steroids or another immunosuppressive agent. Patients
with endocrine deficiencies are allowed to receive physiologic or stress doses of
steroids if necessary.

- Evidence of an active optic glioma, malignant glioma, malignant peripheral nerve
sheath tumor, or other cancer requiring treatment with chemotherapy or radiation
therapy. Patients not requiring treatment are eligible for this protocol.

- Dental braces or prosthesis that interfere with volumetric analysis of the

- Other concurrent severe and/or uncontrolled medical disease which could compromise
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,
severe infection, severe malnutrition, chronic liver or renal disease, active upper
GI tract ulceration).

- A known history of HIV seropositivity or known immunodeficiency. HIV testing will not
be required as part of this trial, unless HIV is clinically suspected.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of sirolimus (e.g. ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection). A nasogastric tube (NG tube) is allowed.

- Women who are pregnant or breast feeding.

- Males or females of reproductive potential may not participate unless they have
agreed to use an effective contraceptive method during the period they are receiving
the study drug and for 3 months thereafter. Abstinence is an acceptable method of
birth control. Women of childbearing potential will be given a pregnancy test within
7 days prior to administration of sirolimus and must have a negative urine or serum
pregnancy test.

- Patients who have received prior treatment with an mTOR inhibitor.

- History of noncompliance to medical regimens.

- Patients unwilling to or unable to comply with the protocol, or who in the opinion of
the investigator may not be able to comply with the safety monitoring requirements of
the study.

- Patients who have an uncontrolled infection.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Time Frame:

48 months

Safety Issue:


Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

March 2008

Completion Date:

February 2013

Related Keywords:

  • Neurofibromatosis Type 1
  • Plexiform Neurofibromas
  • Paraspinal Plexiform Neurofibromas
  • Plexiform Neurofibroma Growth
  • Quality of Life
  • Pain
  • Parmacokinetics
  • Pharmacodynamics
  • Neurofibromatosis Type 1
  • NF1
  • Plexiform Neurofibroma
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
University of AlabamaBirmingham, Alabama