RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. Tipifarnib may be effective in preventing the development of cancer in patients who have neurofibromatosis type 1 and plexiform neurofibromas.

PURPOSE: Randomized phase II trial to study the effectiveness of tipifarnib in preventing cancer in young patients who have neurofibromatosis type 1 and progressive plexiform neurofibromas.

Condition	Treatment or Intervention	Phase
childhood neurofibrosarcoma childhood soft tissue sarcoma	Drug: tipifarnib  Procedure: cancer prevention intervention  Procedure: chemoprevention of cancer	Phase II

Further Study Details: 

OBJECTIVES:

• Determine the effect of tipifarnib on the time to disease progression in pediatric patients with neurofibromatosis type 1 and progressive plexiform neurofibromas.
• Determine the objective response rate in patients treated with this regimen.
• Determine the toxic effects of this regimen in these patients.
• Assess the quality of life of patients treated with this regimen.
• Determine the circulating levels of nerve growth factor and correlate these levels with the development of clinical neurotoxicity in patients treated with this regimen.

OUTLINE: This is a randomized, cross-over, double-blind, placebo-controlled, multicenter study. Patients are randomized to 1 of 2 arms.

• Arm I: Patients receive oral tipifarnib every 12 hours on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral placebo every 12 hours on days 1-21. Courses repeat as in arm I. After documentation of disease progression, patients on both arms cross over to the other arm and (after a 2-week washout period) receive treatment as above in the absence of further disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, prior to courses 4, 7, and 10, and then after every 6 courses thereafter.

PROJECTED ACCRUAL: A total of 60 patients (30 per arm) will be accrued for this study within 3 years.

Ages Eligible for Study:  3 Years   -   25 Years,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of neurofibromatosis type 1 (NF1) AND
• Progressive plexiform neurofibromas
• Neurofibromas that have grown along the length of a nerve and may involve multiple fascicles and branches (spinal neurofibromas involve 2 or more levels with connection between the levels or extending laterally along the nerve)
• Potential to cause significant morbidity such as:
• Head and neck lesions that could compromise 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 limb that cause limb hypertrophy or loss of function
• Painful lesions
• Meets at least 1 other diagnostic criteria for NF1
• 6 or more cafe-au-lait spots (at least 0.5 cm in prepubertal patients or at least 1.5 cm in postpubertal patients)
• Freckling in the axilla or groin
• Optic glioma
• 2 or more Lisch nodules
• Distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
• First-degree relative with NF1
• Measurable plexiform neurofibromas
• At least 3 cm in one dimension
• Evidence of recurrent or progressive disease as documented by an increase in size or the presence of new plexiform neurofibromas on MRI
• No evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring chemotherapy or radiotherapy
• Prior surgery for progressive plexiform neurofibroma allowed provided neurofibroma was incompletely resected and is measurable
• Complete tumor resection not feasible or patient refused surgery

PATIENT CHARACTERISTICS: Age:

• 3 to 25

Performance status:

• ECOG 0-2

Life expectancy:

• At least 12 months

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Hemoglobin at least 9.0 g/dL
• Platelet count at least 150,000/mm^3
• Fibrinogen normal

Hepatic:

• Bilirubin normal unless due to Gilbert's syndrome
• SGPT no greater than 2 times upper limit of normal
• No significant hepatic dysfunction

Renal:

• Creatinine normal for age OR
• Creatinine clearance at least 70 mL/min

Cardiovascular:

• No significant cardiac dysfunction

Pulmonary:

• No significant pulmonary dysfunction

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No clinically significant unrelated systemic illness that would preclude study participation
• No serious infections
• No significant organ dysfunction
• No metal implanted prostheses (e.g., vascular clamps or pacemakers) that would contraindicate an MRI

PRIOR CONCURRENT THERAPY: Biologic therapy:

• At least 1 week since prior filgrastim (G-CSF)
• No concurrent anticancer immunotherapy

Chemotherapy:

• See Disease Characteristics
• No more than 1 prior myelosuppressive chemotherapy regimen
• At least 4 weeks since prior chemotherapy and recovered
• No concurrent anticancer chemotherapy

Endocrine therapy:

• No concurrent anticancer hormonal therapy

Radiotherapy:

• See Disease Characteristics
• At least 6 weeks since prior radiotherapy and recovered
• No concurrent anticancer radiotherapy

Surgery:

• See Disease Characteristics

Other:

• No prior tipifarnib
• At least 30 days since prior investigational agents
• No concurrent proton pump inhibitors (e.g., omeprazole, lansoprazole, pantoprazole, rabeprazole, or esomeprazole)
• No other concurrent investigational anticancer agents

Alabama
      University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham,  Alabama,  35294-3300,  United States; Recruiting
Maryland
      Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,  Maryland,  21231-2410,  United States; Recruiting
      Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda,  Maryland,  20892-1182,  United States; Recruiting
Missouri
      Siteman Cancer Center at Barnes-Jewish Hospital, Saint Louis,  Missouri,  63110,  United States; Recruiting
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
Canada, Ontario
      Hospital for Sick Children, Toronto,  Ontario,  M5G 1X8,  Canada; Recruiting

Study chairs or principal investigators

Brigitte C. Widemann, MD,  Study Chair,  NCI - Pediatric Oncology Branch   

Study ID Numbers:  CDR0000068922; NCI-01-C-0222G; NCI-T99-0090; NCT00029354
Record last reviewed:  June 2004
Last Updated:  January 6, 2005
Record first received:  January 10, 2002
ClinicalTrials.gov Identifier:  NCT00029354
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08