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

NCT00021541 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 01022201-C-0222
• Study Type: interventional
• Target: 62
• Locations: 2 countries
• Sites: 12

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.

Conditions

Neurofibroma, Plexiform; Neurofibromatosis Type I

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

Outcome Measures

Primary Outcomes (2)

• Median Time to Progression

  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.

  8 years

• Number of Participants With Adverse Events

  Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

  8 years

Secondary Outcomes (1)

• Quality of Life (QOL)

  Baseline to pre cycle 4

Other Outcomes (2)

• Median Time to Progression Using the Conventional 1-Dimensional Response Evaluation Criteria in Solid Tumors (RECIST) Method

  8 years

• Median Time to Progression Using the 2-Dimensional World Health Organization (WHO) Solid Tumor Method

  8 years

Study Arms (2)

Tipifarnib (R11577)-Arm I

EXPERIMENTAL

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

Placebo-Arm II

PLACEBO COMPARATOR

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

Interventions

tipifarnib DRUG

Given orally, 200 mg/m\^2/dose BSA every 12 hours by mouth (po) daily x 21 days, Course is every 28 days

Also known as: R115777

Tipifarnib (R11577)-Arm I

placebo OTHER

Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I.

Placebo-Arm II

Eligibility Criteria

• Age: 3 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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\[9\]):
• Six or more cafe-au-lait spots (0.5 cm in prepubertal subjects or 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.
• 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:
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (12)

University of Alabama at Birmingham (M1149)

Birmingham, Alabama, 35233, United States

Location

Children's Hospital Los Angeles, CA (M1118)

Los Angeles, California, 90027, United States

Location

Children's Memorial Hospital, Chicago, IL (M1484)

Chicago, Illinois, 60614, United States

Location

Johns Hopkins Oncology Center (M1011)

Baltimore, Maryland, 21231, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034)

Boston, Massachusetts, 02115, United States

Location

St. Louis Children's Hospital, St. Louis, MO (M1123)

St Louis, Missouri, 63110, United States

Location

SUNY Upstate Medical University, NY (M1303)

Syracuse, New York, 13210, United States

Location

Cincinnati Children's Hospital (FWA 00002988)

Cincinnati, Ohio, 45229, United States

Location

Childrens Hospital of Philadelphia, PA (M1257)

Philadelphia, Pennsylvania, 19104, United States

Location

Texas Children's Hospital, Houston, TX (M1060)

Houston, Texas, 77030, United States

Location

Klinikum Nord, Hamburg, Germany (FWA 00003228)

Hamburg, D-22419, Germany

Location

Related Publications (4)

• Bernards A. Neurofibromatosis type 1 and Ras-mediated signaling: filling in the GAPs. Biochim Biophys Acta. 1995 Jul 28;1242(1):43-59. doi: 10.1016/0304-419x(95)00003-x. No abstract available.

  PMID: 7626654 BACKGROUND

• De Santis S, Pace A, Bove L, Cognetti F, Properzi F, Fiore M, Triaca V, Savarese A, Simone MD, Jandolo B, Manzione L, Aloe L. Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor. Clin Cancer Res. 2000 Jan;6(1):90-5.

  PMID: 10656436 BACKGROUND

• Goldberg Y, Dibbern K, Klein J, Riccardi VM, Graham JM Jr. Neurofibromatosis type 1--an update and review for the primary pediatrician. Clin Pediatr (Phila). 1996 Nov;35(11):545-61. doi: 10.1177/000992289603501101.

  PMID: 8953130 BACKGROUND

• Widemann BC, Dombi E, Gillespie A, Wolters PL, Belasco J, Goldman S, Korf BR, Solomon J, Martin S, Salzer W, Fox E, Patronas N, Kieran MW, Perentesis JP, Reddy A, Wright JJ, Kim A, Steinberg SM, Balis FM. Phase 2 randomized, flexible crossover, double-blinded, placebo-controlled trial of the farnesyltransferase inhibitor tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. Neuro Oncol. 2014 May;16(5):707-18. doi: 10.1093/neuonc/nou004. Epub 2014 Feb 4.

  PMID: 24500418 RESULT

MeSH Terms

Conditions

Neurofibroma, Plexiform; Neurofibromatosis 1; Neurofibromatoses; Neurofibroma

Interventions

tipifarnib

Condition Hierarchy (Ancestors)

Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Brigitte Widemann, M.D.
• Organization: National Institutes of Health, National Cancer Institute

widemanb@mail.nih.gov

301-496-7387

Study Officials

• Brigitte Widemann, M.D.

  National Insitutes of Health, National Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 19, 2006
• First Posted: July 23, 2001
• Study Start: July 17, 2001
• Primary Completion: February 19, 2009
• Study Completion: February 19, 2009
• Last Updated: April 17, 2018
• Results First Posted: September 17, 2012

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (11); DE (1)