R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Condition: Neurofibroma, Plexiform; Neurofibromatosis Type I
MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibroma, Plexiform
Intervention: tipifarnib; placebo
Intervention description: Given orally, 200 mg/m^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days; Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.
Intervention MeSH terms: Tipifarnib
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 62.0
Sex: All
Minimum age: 3 Years
Maximum age: 25 Years
Healthy volunteers: No
Keywords: Surrogate Markers; 3-Dimensional Magnetic Resonance Imaging (MRI); Natural History of Neurofibromatosis Type 1 (NF1); Tumor Tissue Bank; Neurofibromatosis; NF1; Neurofibromatosis Type 1; Plexiform Neurofibroma; Neurofibroma

Summary:

      This study will examine whether the experimental drug R115777 (Tipifarnib) can shrink or slow
      the growth of plexiform neurofibromas in children and young adults with neurofibromatosis
      type 1 (NF1) and determine what side effects are related to treatment. Plexiform tumors arise
      from nerves; the only effective treatment is surgical removal. Often, however, not all the
      tumors can be removed, because of their number or location.

      Patients with NF1 have a reduced amount of the protein neurofibromin. Neurofibromin is
      thought to help control the activity of another protein, called ras, which regulates cell
      growth. Too little neurofibromin, therefore, may allow for uncontrolled cell growth and tumor
      formation. R115777 interferes with the function of the ras and other proteins. In test tube
      and animal studies, R115777 has blocked the growth of cancer cells. This study will examine
      whether the drug is effective against plexiform tumors.

      Patients with NF1 and progressive plexiform neurofibromas between 3 and 25 years of age may
      be eligible for this study. Patients whose tumors can be successfully removed surgically may
      not participate in this study. Candidates are screened with a medical history and physical
      and eye examinations, blood and urine tests, and magnetic resonance imaging (MRI).
      Photographs are taken of tumors visible on the body surface.

      Study participants are randomly assigned to receive either R115777 or placebo (an inactive
      substance). They take R115777 or placebo tablets every 12 hours for 21 days, followed by a
      7-day rest period. This constitutes one 28-day treatment cycle. Treatment continues for as
      long as the tumors remain stable or shrink and side effects are tolerable. The treatment is
      switched (for example, from placebo to R115777) or stopped if the tumors grow or if side
      effects become unacceptable. Patients (or their parents) keep a record of side effects.

      For the first 3 treatment cycles, patients have a physical examination and blood tests every
      other week. Blood tests are also done before starting treatment, and at one time point after
      at least 14 days of treatment to measure the effect of R115777 on proteins in blood cells. A
      blood sample is obtained before starting treatment and before cycles 4, 7 and 10 and then
      after every 6 cycles to measure the level of a substance called nerve growth factor. The
      analysis of nerve growth factor is used to determine if it can predict which patients might
      be at risk of developing side effects from R115777.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Age: 3 years and 25 years of age.

        Diagnosis: Patients with neurofibromatosis type 1 (NF1) and progressive plexiform
        neurofibromas 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), lesions of the
        extremity that cause limb hypertrophy or loss of function, and painful lesions.

        Histologic confirmation of tumor is not necessary in the presence of consistent clinical
        and radiographic findings, clinically suspected.

        In addition to plexiform neurofibroma(s), all study subjects must have at least one other
        diagnostic criteria for NF1 listed below (National Institutes of Health (NIH) Consensus
        Conference[9]):

          1. Six or more cafe-au-lait spots (0.5 cm in prepubertal subjects or 1.5 cm in
             postpubertal subjects).

          2. Freckling in the axilla or groin;

          3. Optic glioma;

          4. Two or more Lisch nodules;

          5. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
             long bone cortex);

          6. A first degree relative with NF1.

        In this study a plexiform neurofibroma is defined as a neurofibroma that has grown along
        the length of a nerve and may involve multiple fascicles and branches.

        A spinal plexiform neurofibroma involves two or more levels with connection between the
        levels or extending laterally along the nerve.

        Measurable disease: Patients must have measurable plexiform neurofibroma(s). For the
        purpose of this study a measurable lesion will be defined as a lesion of at least 3 cm
        measured in one dimension.

        There must be evidence of recurrent or progressive disease as documented by an increase in
        size or the presence of new plexiform neurofibromas on MRI. Progression at the time of
        study entry is defined as:

          1. A measurable increase of the plexiform neurofibroma (20% increase in the volume, or a
             13% increase in the product of the two longest perpendicular diameters, or a 6%
             increase in the longest diameter) over the last two consecutive scans (magnetic
             resonance imaging (MRI) or computed tomography (CT)), or over the time period of
             approximately one year prior to evaluation for this study.

          2. 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.

             Prior therapy: Patients with NF1 are eligible at the time of recurrence or progression
             of inoperable plexiform neurofibroma.

             A surgical consultation should be obtained prior to enrollment on the study to
             evaluate if tumor resection is a feasible option.

             Patients will only be eligible if complete tumor resection is not feasible, or if a
             patient with surgical option refuses surgery.

             Since there is no standard effective chemotherapy for patients with NF1 and
             progressive plexiform neurofibromas, patients may be treated on this trial without
             having received prior therapy.

             Patients must have recovered from the toxic effects of all prior therapy before
             entering this study.

             The Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0 will
             be used for toxicity assessment.

             A copy of the CTC version 2.0 can be downloaded from the CTEP home page:
             http://ctep.cancer.gov. Recovery is defined as a toxicity grade less than 2, unless
             otherwise specified in the Inclusion and Exclusion Criteria.

             Patients must have had their last dose of radiation therapy at least six weeks prior
             to study entry, and their last dose of chemotherapy at least four weeks prior to study
             entry.

             Patients who received growth colony stimulating factor (G-CSF) after the prior cycle
             of chemotherapy must be off G-CSF for at least one week prior to entering this study.

             Performance Status: Patients should have a life expectancy of at least 12 months and
             an Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2.

             Patients who are wheelchair bound because of paralysis should be considered
             'ambulatory' when they are up in their wheelchair.

             Hematologic Function: Patients must have an absolute granulocyte count 1,500/ uL, 9.0
             gm/dl, and a platelet count 150,000/uL at study entry, and a normal fibrinogen.

             Hepatic Function: Patients must have a bilirubin within normal limits and serum
             glutamic pyruvic transaminase (SGPT) 2x upper limit of normal.

             Patients with Gilbert syndrome are excluded from the requirement of a normal
             bilirubin. (Gilbert syndrome is found in 3-10% of the general population, and is
             characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver
             disease or overt hemolysis).

             Renal Function: Patients must have an age-adjusted normal serum creatinine OR a
             creatinine clearance (70 mL / min / 1.73 m^2).

             Informed Consent: All patients or their legal guardians (if the patient is less than
             18 years old) must sign an institutional review board (IRB) approved document of
             informed consent (screening protocol) prior to performing studies obtained exclusively
             to determine patient eligibility.

             After confirmation of patient eligibility all patients or their legal guardians must
             sign the protocol specific informed consent to document their understanding of the
             investigational nature and the risk of this study before any protocol related studies
             are performed (other than the studies which were performed to determine patient
             eligibility).

             When appropriate pediatric patients will be included in all discussion. Per
             institutional guidelines, age appropriate assent forms for children from 7 through 12
             years, and for children may be developed and, when appropriate, will be signed by the
             pediatric patients in order to obtain written assent.

             Durable Power of Attorney (DPA):

             All patients 18 years of age will be offered the opportunity to assign DPA so that
             another person can make decisions about their medical care if they become
             incapacitated or cognitively impaired.

             Ability to undergo MRI examinations.

             EXCLUSION CRITERIA:

             Pregnant or breast feeding females are excluded, because the toxic effects and
             pharmacology of R115777 in the fetus and newborn are unknown.

             Clinically significant unrelated systemic illness (serious infections or significant
             cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgement of the
             Principal or Associate Investigator would compromise the patient's ability to tolerate
             R115777 or are likely to interfere with the study procedures or results.

             Prior treatment with greater than 1 prior myelosuppressive chemotherapy regimen.

             An investigational agent within the past 30 days.

             Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor
             or other cancer requiring treatment with chemotherapy or radiation therapy.

             Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, or
             immunotherapy.

             Inability to return for follow-up visits or obtain follow-up studies required to
             assess toxicity and response to therapy.

             Prior treatment with R115777.