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

Learn more about:
Related Clinical Trial
Phase I Study to Assess the Effect of Food on the PK and Gastrointestinal Toxicity of Selumetinib in Adolescent Children With Neurofibromatosis Type 1 Related Plexiform Neurofibromas NFX-179 Topical Gel Treatment for Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF) Mechanism of Action of Transcranial Direct Current Stimulation in Neurofibromatosis Type 1 Study to Evaluate the Safety, Tolerability, PK Characteristics and Anti-tumor Activity of FCN-159 in Adult and Pediatric Participants With Neurofibromatosis Type 1 Evaluating Genetic Modifiers of Cutaneous Neurofibromas in Adults With Neurofibromatosis Type 1 Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas Systematically Assessing Changes in Plexiform Neurofibroma Related Disfigurement From Photographs of Subjects With Neurofibromatosis Type 1 on a Phase 2 Clinical Trial Pilot Randomized Control Trial of Telehealth Group for Improving Peer Relationships (PEERS) in NF1 Open Trial of Telehealth Group for Improving Peer Relationships (PEERS) in NF1 Identification of Pre-Malignant Lesions In Pediatric Patients With Neurofibromatosis Type 1 Using Novel Magnetic Resonance Imaging Techniques Paired With Artificial Intelligence A Study of Selumetinib in Chinese Paediatric and Adult Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN) Innovation in the Treatment of Persistent Pain in Adults With NF1: Implementation of the iCanCope Mobile Application- Clinical Trial Antioxidant Therapy With N-acetylcysteine for Children With Neurofibromatosis Type 1 Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1 A Long-term Study of NPC-12G Gel in Neurofibromatosis Type I NFX-179 Topical Gel Treatment in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF) Analysis of Data Collected From Individuals Administered Neurobehavioral Assessments Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia Comparison of Gastrointestinal Motility in Healthy Children and Children With Constipation AZD6244 Hydrogen Sulfate for Children With Nervous System Tumors Photodynamic Therapy for Benign Dermal Neurofibromas- Phase II Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NCS 716051) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas Medical Treatment of “High-Risk” Neurofibromas Fludeoxyglucose F 18 Positron Emission Tomography and Magnetic Resonance Perfusion Imaging in Patients With Neurofibromatosis 1 and Plexiform Neurofibroma Whole Body MRI to Identify Atypical Neurofibromas in Patients With NF1 Use of Topical Liquid Diclofenac Following Laser Microporation of Cutaneous Neurofibromas in Patients With NF1 Development and Validation of Patient Reported Outcome (PRO) Measures for Individuals With Neurofibromatosis 1 (NF1) and Plexiform Neurofibromas (PNs) Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patient With Plexiform Neurofibromas Treatment of NF1-related Plexiform Neurofibroma With Trametinib Subtle Myocardial Deformation Abnormalities in Asymptomatic Nf-1 Patients R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas Study of Tasigna®/Nilotinib (AMN107) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas Ranibizumab for Neurofibromas Associated With Neurofibromatosis 1 AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas Neurofibromatosis Type 1 Brain Tumor Genetic Risk Acceptance and Commitment Therapy for Adolescents and Young Adults With Neurofibromatosis and Chronic Pain Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas Adaptation and Quality of Life Among Adults With Neurofibromatosis Type I Reliability of Functional Outcome Measures in Neurofibromatosis 1 Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults Medication Adherence in Children, Adolescents and Adults With Neurofibromatosis Type 1 (NF1) on Clinical Treatment Trials Targeting the Mechanisms Underlying Cutaneous Neurofibroma Formation in NF1: A Clinical Translational Approach. Sorafenib to Treat Children and Young Adults With Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST) Quality of Friendships in Children With Neurofibromatosis Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1) MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas Interventions for Reading Disabilities in NF1 Everolimus for Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis1 CRAD001CUS232T Clinical Trial of Pirfenidone in Adult Patients With Neurofibromatosis 1 Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain Neurobiology and Treatment of Reading Disability in NF-1 From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1 Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1) Efficacy of Computerized Cognitive Training and Stimulant Medication in Neurofibromatosis Type 1 Analysis of Plasma for Diagnosis and Follow-up of Neurofibromatosis Type 1 Study About Annoucement of the Diagnosis of Neurofibromatosis 1 in de Novo Forms MicroRNAs in Patients With Neurofibromatosis Type 1 Pirfenidone in Treating Young Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas Stem Cells in NF1 Patients With Tumors of the Central Nervous System Function of the Pigment Epithelium in Patients With Type 1 Neurofibromatosis NF1-Attention: Study of Children With Neurofibromatosis Type 1 Treated by Methylphenidate Trial to Evaluate the Safety of Lovastatin in Individuals With Neurofibromatosis Type I (NF1) Internet Support Group for Parents of a Child With Neurofibromatosis Type 1 Reading Disability in Children With NF1 Multi-center Project: Spinal Abnormalities in Neurofibromatosis Type1 (NF1) Patients Functional Imaging and Reading Deficit in Children With NF1 Effects of Physical Training on Bone and Muscle Quality, Muscle Strength, and Motor Coordination in Children With NF1 Effect of Lamotrigine on Cognition in NF1 A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1 Neurofibromatosis Type 1 (NF1) and Tibial Dysplasia Non-invasive Stimulation in Neurofibromatosis Type 1 Modifying Genes in Neurofibromatosis 1 Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1 Vision, Attention and Reading in Neurofibromatosis Type 1 (NF1) Children Neuropsychological Impairment and Quality of Life in Neurofibromatosis Type 1 Spinal Abnormalities in Neurofibromatosis Type 1 (NF1) Neurofibromatosis Type 1 Patient Registry Frameshift Peptides of Children With NF1 Prevalence of Constitutional Mismatch-repair Deficiency Among Suspected Neurofibromatosis Type 1/Legius Syndrome Children Without a Malignancy and Without a NF1 or SPRED1 Mutation How Neurofibromatosis Type 1 (NF1) Affects Schoolwork and Self-Esteem

Brief Title

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

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

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.
    

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Median Time to Progression

Secondary Outcome

 Quality of Life (QOL)

Condition

Neurofibroma, Plexiform

Intervention

tipifarnib

Study Arms / Comparison Groups

 Tipifarnib (R11577)-Arm I
Description:  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.

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

62

Start Date

July 17, 2001

Completion Date

February 19, 2009

Primary Completion Date

February 19, 2009

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.
      

Gender

All

Ages

3 Years - 25 Years

Accepts Healthy Volunteers

No

Contacts

Brigitte Widemann, M.D., , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT00021541

Organization ID

010222

Secondary IDs

01-C-0222

Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Brigitte Widemann, M.D., Principal Investigator, National Insitutes of Health, National Cancer Institute


Verification Date

March 2018