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
Intervention: Sirolimus
Intervention description: 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.
Intervention MeSH terms: Sirolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 3 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Plexiform, Neurofibromatosis Type 1, Sirolimus, Phase II

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.
    

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.