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


Phase 2
3 Years
75 Years
Open (Enrolling)
Both
Neurofibromatosis Type 1

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Trial Information

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


ABSTRACT/SCHEMA

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.

Background

- 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 rapamycin (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-deficient 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 population.

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

Eligibility

- Patients ≥ 3 years old with NF1 AND

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

OR

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

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.

- 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 sirolimus administered will be evaluated using physical and
laboratory evaluations.

EXPERIMENTAL DESIGN SCHEMA

GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

Primary 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.

Secondary Aims

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.


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,
troleandomycin; Gastrointestinal prokinetic agents: cisapride, metoclopramide;
Antifungals: itraconazole, ketoconazole, fluconazole, voriconazole, clotrimazole;
Calcium channel blockers: verapamil, diltiazem, nicardipine; and, Other drugs:
rifampin, bromocriptine, cimetidine, danazol, cyclosporine oral solution.

- Grapefruit juice.

- g. 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).

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

- i. 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).

- j. 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/μL; Platelet count
greater than or equal to 100,000/μL (transfusion independent); and 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, OR a creatinine
clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2

- Adequate Liver Function Defined As: Bilirubin (sum of conjugated + unconjugated) < or
equal to 1.5 x upper limit of normal (ULN) for age, and SGPT (ALT)< or equal to 5 x
upper limit of normal (ULN) for age, and Serum albumin > or equal to 2 g/dL.

- Fasting LDL Cholesterol: Patients must have a fasting LDL cholesterol of < 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

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):

- 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
neurofibroma(s).

- 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:

Interventional

Study Design:

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

Outcome Measure:

Increased time to disease progression based on volumetric MRI

Outcome Time Frame:

24 weeks Stratum 1 / 48 weeks Stratum 2

Safety Issue:

Yes

Principal Investigator

Bruce Korf, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The University of Alabama at Birmingham

Authority:

United States: Institutional Review Board

Study ID:

F071019012

NCT ID:

NCT00634270

Start Date:

April 2008

Completion Date:

August 2013

Related Keywords:

  • Neurofibromatosis Type 1
  • Plexiform, Neurofibromatosis Type 1, Sirolimus, Phase II
  • Neurofibroma
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica
  • Neurofibroma, Plexiform

Name

Location

The University of Alabama at BirminghamBirmingham, Alabama  35294
National Cancer Institute (NCI)Bethesda, Maryland  20892
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's National Medical CenterWashington, District of Columbia  20010-2970
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
University of UtahSalt Lake City, Utah  
Children's Hospital BostonBoston, Massachusetts  02115
University of ChicagoChicago, Illinois  60637
Washington UniversitySt. Louis, Missouri  63110