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

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Brief Title

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

Official Title

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

Brief 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Time to Disease Progression Based on Volumetric MRI

Secondary Outcome

 To Evaluate the Quality of Life During Treatment With Sirolimus by Assessing Preliminary Correlations of Response With Quality-of-life Outcomes

Condition

Neurofibromatosis Type 1

Intervention

Sirolimus

Study Arms / Comparison Groups

 Sirolimus
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

58

Start Date

April 2008

Completion Date

December 2015

Primary Completion Date

November 2014

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,
             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.
      

Gender

All

Ages

3 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Bruce Korf, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00634270

Organization ID

F071019012

Secondary IDs

DOD: W81XWH-05-615.

Responsible Party

Principal Investigator

Study Sponsor

University of Alabama at Birmingham

Collaborators

 Boston Children's Hospital

Study Sponsor

Bruce Korf, MD, Principal Investigator, The University of Alabama at Birmingham


Verification Date

October 2017