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R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas

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ClinicalTrials.gov Identifier: NCT00021541
Recruitment Status : Completed
First Posted : July 23, 2001
Results First Posted : September 17, 2012
Last Update Posted : April 17, 2018
Information provided by (Responsible Party):
Brigitte Widemann, M.D., National Institutes of Health Clinical Center (CC)

Brief 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.

Condition or disease Intervention/treatment Phase
Neurofibroma, Plexiform Neurofibromatosis Type I Drug: tipifarnib Other: placebo Phase 2

Detailed Description:
R115777 (Tipifarnib) is a farnesyltransferase inhibitor that blocks the post-translational isoprenylation of ras and other farnesylated proteins. The ras proteins are integral in cell signaling pathways, and farnesylation is essential for the function of both mutant and non-mutant ras proteins. Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, and there are no standard treatment options, other than surgery, available for these tumors. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins (GAP). Although NF1 patients lack germline ras mutations, the decreased levels of neurofibromin have been shown to be associated with a constitutively activated ras-GTP status. Thus, upstream inhibition of ras farnesylation may inhibit growth of tumors in NF1 patients. A randomized, cross-over, double-blinded, placebo-controlled pediatric phase II trial of oral R115777 will be performed in children and young adults with NF1, who have progressive, plexiform neurofibroma(s) to determine the effect of this novel anticancer drug on the rate of growth of neurofibromas. The endpoint of the trial is time to progression. R115777 will be administered orally at a dose of 200 mg/m(2) twice daily for cycles of 21 days followed by a 7 day rest period based on the results of our prior pediatric phase I trial.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trial of the Farnesyltransferase Inhibitor R115777 in Pediatric Patients With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
Actual Study Start Date : July 17, 2001
Actual Primary Completion Date : February 19, 2009
Actual Study Completion Date : February 19, 2009

Arm Intervention/treatment
Experimental: Tipifarnib (R11577)-Arm I
Patients receive oral R115777 (Tipifarnib) first followed by placebo. 200 mg/m^2/dose BSA every 12 hours by mouth (po)on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: tipifarnib
Given orally, 200 mg/m^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days
Other Name: R115777

Placebo Comparator: Placebo-Arm II
Patients receive oral placebo first followed by R115777 (Tipifarnib). 200 mg/m^2/dose BSA every 12 hours by mouth (po)every 12 hours on days 1-21. Courses repeat as in arm I.
Other: placebo
Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

Primary Outcome Measures :
  1. Median Time to Progression [ Time Frame: 8 years ]
    Median time to progression is defined as a greater than or equal to 20% increase increase in the sum of the volume of all index lesions based on volumetric analysis utilizing magnetic resonance imaging (MRI).Start of phase A or phase B to time of progression.

  2. Number of Participants With Adverse Events [ Time Frame: 8 years ]
    Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Secondary Outcome Measures :
  1. Quality of Life (QOL) [ Time Frame: Baseline to pre cycle 4 ]
    Parents of participants aged 6-18 years completed the Impact of Pediatric Illness (IPI) Scale about their child prior to the start of cycles 1, 4, 7, and 10 and then after every 6 cycles. The IPI Scale assesses QOL in 4 domains: adaptive behavior, emotional functioning, medical/physical status, and cognitive functioning. Responses to the 43 items are made on a 5-point Likert scale (1-5) ranging from "not al all" to "a lot". Higher mean scores indicate better QOL. Parent total scores for participants on placebo were compared with scores from participants receiving tipifarnib on phase A.

Other Outcome Measures:
  1. Median Time to Progression Using the Conventional 1-Dimensional Response Evaluation Criteria in Solid Tumors (RECIST) Method [ Time Frame: 8 years ]
    Median time to progression is defined as ≥20% increase in diameter based on volumetric analysis using the 1-dimensional RECIST method. Start of phase A or phase B to time of progression.

  2. Median Time to Progression Using the 2-Dimensional World Health Organization (WHO) Solid Tumor Method [ Time Frame: 8 years ]
    Median time to progression is defined as ≥25% increase in area based on volumetric analysis using the 2-dimensional WHO solid tumor method.

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.


    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00021541

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United States, Alabama
University of Alabama at Birmingham (M1149)
Birmingham, Alabama, United States, 35233
United States, California
Children's Hospital Los Angeles, CA (M1118)
Los Angeles, California, United States, 90027
United States, Illinois
Children's Memorial Hospital, Chicago, IL (M1484)
Chicago, Illinois, United States, 60614
United States, Maryland
Johns Hopkins Oncology Center (M1011)
Baltimore, Maryland, United States, 21231
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Massachusetts
The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034)
Boston, Massachusetts, United States, 02115
United States, Missouri
St. Louis Children's Hospital, St. Louis, MO (M1123)
Saint Louis, Missouri, United States, 63110
United States, New York
SUNY Upstate Medical University, NY (M1303)
Syracuse, New York, United States, 13210
United States, Ohio
Cincinnati Children's Hospital (FWA 00002988)
Cincinnati, Ohio, United States, 45229
United States, Pennsylvania
Childrens Hospital of Philadelphia, PA (M1257)
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Texas Children's Hospital, Houston, TX (M1060)
Houston, Texas, United States, 77030
Klinikum Nord, Hamburg, Germany (FWA 00003228)
Hamburg, Germany, D-22419
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Brigitte Widemann, M.D. National Insitutes of Health, National Cancer Institute
  Study Documents (Full-Text)

Documents provided by Brigitte Widemann, M.D., National Institutes of Health Clinical Center (CC):
Publications of Results:
Other Publications:
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Responsible Party: Brigitte Widemann, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00021541    
Obsolete Identifiers: NCT00029354
Other Study ID Numbers: 010222
First Posted: July 23, 2001    Key Record Dates
Results First Posted: September 17, 2012
Last Update Posted: April 17, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Brigitte Widemann, M.D., National Institutes of Health Clinical Center (CC):
Surrogate Markers
3-Dimensional Magnetic Resonance Imaging (MRI)
Natural History of Neurofibromatosis Type 1 (NF1)
Tumor Tissue Bank
Neurofibromatosis Type 1
Plexiform Neurofibroma
Additional relevant MeSH terms:
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Neurofibromatosis 1
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Antineoplastic Agents