Mutations in the NF1 tumor suppressor gene, neurofibromin, cause the inherited syndrome Neurofibromatosis Type 1 (NF1). In 30-50% of NF1 patients plexiform neurofibromas develop, which are progressive slow growing nerve-based tumors that are refractory to traditional chemotherapy, radiation, and surgery. One particularly serious and urgent presentation of plexiform neurofibromas is symptomatic airway compression, most commonly observed in young children. As there are no effective therapies for these patients, they experience significant morbidity and mortality. Studies with a genetic mouse model of NF1 demonstrated that imatinib could inhibit plexiform tumor growth. The applicant reported that this observation was confirmed in the applicant's initial clinical trial where imatinib resulted in many patients responding with tumor shrinkage and improvement of symptoms. Of special note, a number of pediatric NF1 patients with symptomatic airway plexiform neurofibromas have responded to imatinib with improvement in airway symptoms, and most showing reduction in tumor size. Based on this experience with imatinib, the applicant hypothesizes that 1) NF1 associated pediatric airway-related plexiform neurofibromas represent a subset of plexiform neurofibromas with an inherent sensitivity to imatinib therapy and 2) that imatinib therapy will show efficacy by improving respiratory function as assessed by pulmonary function tests and sleep study evaluations in children with airway tumors. To test this hypothesis, the applicant proposes a Phase 2 efficacy trial using imatinib to treat children with symptomatic NF1 airway plexiform tumors. There are 3 study objectives: 1) Determine quantitative functional airway response to imatinib by sleep study and pulmonary function tests in pediatric patients with symptomatic airway plexiform neurofibromas. 2) Determine the response to imatinib of airway plexiform tumors compared to non-airway plexiform tumors in the same patients using volumetric MRI size determination. 3) Perform biomarker/biologic effect assessment in: circulating cytokine levels, circulating levels of inflammatory and angiogenic cells by flow cytometry, pharmacokinetics-pharmacodynamics of imatinib, and quality of life information. The goals of this study are to determine whether imatinib is clinically effective therapy for children with airway-associated plexiform neurofibromas presenting with impaired airway function by yielding significantly improved airway function and when compared to non-airway related plexiforms in the enrolled subjects, results in a significantly greater reduction in tumor volumetric measure.
Project Narative Phase 2 Study of Imatinib in Children with Neurofibromatosis and Airway Tumors Kent Robertson, PI Neurofibromatosis Type 1 (NF1) results in plexiform tumors that are refractory to conventional cancer treatment and occur in children producing life-threatening airway compression. Preliminary studies with oral Gleevec (imatinib) have demonstrated activity with dramatic relief of air-way symptoms in these patients. The goal of this proposal is to confirm the activity of imatinib and establish an effective therapy for these life-threatening tumors in children with NF1.
