Clinical trial NCT00021541: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2001-07-23
Enrollment: 62
Sex: ALL
Minimum age (years): 3
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Median Time to Progression
timeFrame: 8 years
measure: Number of Participants With Adverse Events
timeFrame: 8 years
Secondary outcomes:
measure: Quality of Life (QOL)
timeFrame: Baseline to pre cycle 4
Other outcomes:
measure: Median Time to Progression Using the Conventional 1-Dimensional Response Evaluation Criteria in Solid Tumors (RECIST) Method
timeFrame: 8 years
measure: Median Time to Progression Using the 2-Dimensional World Health Organization (WHO) Solid Tumor Method
timeFrame: 8 years
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (M1149)
state: Alabama
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles, CA (M1118)
state: California
city: Chicago
country: United States
facility: Children's Memorial Hospital, Chicago, IL (M1484)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Oncology Center (M1011)
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Boston
country: United States
facility: The Children's Hospital, Dana-Farber Cancer Institute, Boston, MA (M1034)
state: Massachusetts
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital, St. Louis, MO (M1123)
state: Missouri
city: Syracuse
country: United States
facility: SUNY Upstate Medical University, NY (M1303)
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital (FWA 00002988)
state: Ohio
city: Philadelphia
country: United States
facility: Childrens Hospital of Philadelphia, PA (M1257)
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital, Houston, TX (M1060)
state: Texas
city: Hamburg
country: Germany
facility: Klinikum Nord, Hamburg, Germany (FWA 00003228)
Study officials:
affiliation: National Insitutes of Health, National Cancer Institute
name: Brigitte Widemann, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.