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Protocol # 01-C-0222

A Phase II Randomized, Cross-Over, Double-Blinded, Placebo-Controlled Trialof the Farnesyltransferase Inhibitor R115777 in Pediatric Patients with Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
 

Patients with neurofibromatosis type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system.
Plexiform neurofibromas are a major source of morbidity, with no standard treatment options, other than surgery, available. Neurofibromin, the
NF1 gene product, contains a domain with significant homology to ras GTPase-activating proteins. Patients with NF1 have decreased levels of
neurofibromin, which is associated with an activated ras-GTP status. Agents directed at inhibiting ras, therefore, are a rational choice for trials of
potential therapeutic agents in patients with NF1. R115777 is a farnesyltransferase inhibitor that inhibits the post-translational isoprenylation of
ras and other farnesylated proteins, which is essential for the function of both mutant and non-mutant ras proteins. R115777 has completed phase
I trials in adults, and in children with solid tumors and NF1. 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 disease progression. R115777 will
be administered orally at a dose of 200 mg/m 2 twice daily for 21 days followed by a 7 day rest .

Eligibility Criteria:
• Age >3 and <25 years, BSA >0.38 m 2 , ECOG 0, 1 or 2
• Diagnosis of NF1 (NIH Consensus Conference) and inoperable plexiform neurofibromas with potential to cause significant morbidity
• Measurable disease: A lesion of at least 3cm in 1 dimension
• Progressive disease: Evidence of recurrent or progressive disease documented by either a measurable increase in size (13% increase in product of longest perpendicular diameters, >20% increase in the volume or 6% increase in the longest diameter) over the last two consecutive
MRIs, or approximately 1 year prior to study entry. Patients with persistent plexiform neurofibroma after surgery for a previously progressive lesion are also eligible provided that the plexiform neurofibroma was incompletely resected and is measurable
• Patient must have recovered from the toxic effects of all prior therapy
• Last dose of radiation therapy at least 6 weeks prior to study entry
• Last dose of chemotherapy at least 4 weeks prior to study entry, off G-CSF at least 1 week prior to study entry
• Patients must have an ANC >1,500/µL, Hgb >9.0 gm/dl, Plt >150,000/µL, normal fibrinogen
• Adequate liver function (bilirubin within normal limits and SGPT <2x upper limit of normal)
• Adequate renal function (age adjusted normal serum creatinine or creatinine clearance >70 mL/min/1.73m 2 )
• Ability to undergo MRI examinations
• Exclusion Criteria:
• Pregnant or breast feeding females
• Clinically significant unrelated systemic illness
• Prior treatment with >1 prior myelosuppressive chemotherapy regimen
• An investigational agent within the past 30 days
• Patients with a history of malignant peripheral nerve sheath tumor or other cancer
• 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
• Concomitant use of proton pump inhibitors (e.g. omeprazole, lansoprazole, pantoprazole)
• Prior treatment with R115777
Pretreatment Evaluation:
• History and physical, including complete neurological exam, Quality of Life Assessment
• Photography of plexiform neurofibromas visible on the body surface
• Laboratory work (within 2 weeks prior to enrollment), including hematology, chemistries, pregnancy test, urinalysis.
• MRI of all measurable disease site(s) within 2 weeks of start of therapy, & volumetric (3D) MRI imaging of progressing plexiform
neurofibroma
• Ophthalmologic evaluation prior to or within 3 days of starting treatment
• Biopsy of easily accessible discrete neurofibromas or superficial plexiform neurofibromas - not mandatory
• Farnesyl-Protein Transferase (FPTase) activity in peripheral blood mononuclear cells; 10-20 ml blood
• Prelamin A in buccal mucosal cells collected on clean, charged microscope slides
• Nerve Growth Factor (NGF); 3 ml blood sample
General Treatment Plan:
• Patients will be randomized at study entry to receive either R115777 or placebo first (cycles of 200mg/m 2 q12h for 21 days followed by a 7
day rest period). After documentation of disease progression patients will be crossed over to receive R115777 (if placebo was first given) or
placebo (if R115777 was first given). There will be a 2 week washout period when crossing over. Disease progression is assessed by
volumetric MRI measurements that are performed centrally. Patients can expect to stay in the area for approximately 4 days for the initial
work-up. Treatment is outpatient unless otherwise clinically indicated.
Accrual:
• We anticipate the trial to be open to accrual in July.