Phase II study of the mTOR inhibitor sirolimus for nonprogressive NF1-associated plexiform neurofibromas: A Neurofibromatosis Consortium study.

e13601 Background: Plexiform neurofibromas (PN) are a common and potentially debilitating complication of neurofibromatosis type 1 (NF1). These benign nerve sheath tumors cause significant morbidity through disfigurement and compression of vital structures. Surgery is the only standard treatment for PN, but complete resection is often not feasible. The NF1 gene regulates mTOR pathway activation. In in vitro and in vivo NF1 models Nf1 loss results in Ras- and PI3K-dependent mTOR pathway activation, which could be inhibited with sirolimus. We performed a multicenter, Department of Defense funded phase II trial to determine if sirolimus can induce objective radiographic response (PN volume decrease ≥20%) of PN. Methods: Subjects with NF1 and ≥ 1 inoperable PN with the potential to cause significant morbidity but without radiographic progression within one year prior to trial entry were eligible. Sirolimus (0.8 mg/m2/dose) was given orally q12h on a continuous dosing schedule (one course=28 days), and trough sirolimus levels were maintained between 10-15 ng/ml. Subjects received a maximum of 6 courses of sirolimus unless there was evidence of response, in which case treatment could be continued for up to 60 total courses. Volumetric MRI analysis was performed at baseline and after every 3 courses. Subjects with progressive disease or unacceptable toxicity were removed from sirolimus treatment. Using a two-stage Simon Optimal design (target response rate 20%, rule out 5%), enrollment would be expanded if ≥1 of the initial 12 enrolled subjects had a response. In the absence of response in the first 12 subjects, the stratum would close. Results: Seven females and 5 males with median age of 11 years (range, 3-35 yrs) and a median PN volume of 847 mL (range, 23-2,476 mL) were enrolled. All subjects were removed from sirolimus after 6 courses: one for PN progression, 11 for lack of response. Conclusions: Sirolimus was well tolerated, but not effective in shrinking nonprogressive NF1 PN. Evaluation of whether sirolimus can prolong the time to progression in subjects with NF1 and progressive PN at trial entry is ongoing in another stratum of this trial. No significant financial relationships to disclose.