A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
Condition: Neurofibromatosis Type 1
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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),

      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 evaluate the effect of sirolimus on clinical response by reduction in pain, or improvement
      in function or performance scale.
    

Intervention name(s): Sirolimus
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Rapamune; Rapamycin
Intervention MeSH terms: Sirolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Plexiform, Neurofibromatosis Type 1, Sirolimus, Phase II