Neurofibromatosis 1 (NF1) Clinical Trial
Official title:
Phase II Trial of the MEK1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
Background: Neurofibromatosis type 1 (NF1) is a disorder that can cause plexiform neurofibromas (PNs). These are tumors that grow along nerves. Some PNs cause serious health problems. PNs often can t be operated on because of their large size, location, or number. There are no effective treatments known for people with NF1 and PNs. Researchers want to test if the drug selumetinib (AZD6244 hydrogen sulfate) causes PNs to shrink or slows down their growth. Objectives: To test if selumetinib helps treat PNs. To test how the body handles selumetinib and how it affects peoples symptoms. Eligibility: People ages 18 and older with NF1, with an inoperable PN that causes morbidity or is growing Design: Participants will be screened with: Medical history and physical exam Blood, urine, and heart tests Eye exam MRI: They lie in a machine that takes pictures of the body. PN biopsy: A small piece of the tumor is removed by a large needle. Questionnaires Participants will swallow selumetinib capsules every 12 hours for several 28-day cycles. The capsules are taken with a full glass of water on an empty stomach. Participants may have only water for 2 hours before and 1 hour after each dose. Participants will keep a drug diary. They will continue taking the drug as long as they tolerate it and their disease doesn t progress. Participants will have several visits throughout the study. These will include repeats of the screening tests. Participants will have a final visit after they stop taking selumetinib.
Background: - Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3500 in the US. One of the cardinal features of NF1 is the development of histologically benign peripheral nervesheath tumors called plexiform neurofibromas (PN) in 25-40% of individuals with NF1. Unlike discrete neurofibromas, PN grow along the length of nerves and involve multiple branches of a nerve. They are a major source of morbidity, causing disfigurement, impairment of nerve function, pain, and in some cases development of malignant peripheral nerve sheath tumors. - Selumetinib (AZD6244) is a novel orally bioavailable mitogen activated protein kinase inhibitor, is a specific inhibitor of MEK 1/2, which may mediate anti-tumor effects in PN by inhibition of downstream signaling of Ras. Selumetinib is currently undergoing evaluation in adult cancers and children with brain tumors and NF1-related plexiform neurofibromas. - In an NCI phase I trial of selumetinib for children and young adults with NF1 and inoperable PN we have observed preliminary activity with PN volume decrease in >50% of patients enrolled. This degree of activity has not been observed in prior trials directed at PN. While preliminary activity has been seen in most patients enrolled to date, in several patients who required (Bullet) 1 dose reduction for toxicity, after an initial volume decrease, the PN volumes appear to be increasing slowly, and in one patient a nodular appearing lesion is not responding to selumetinib. These findings suggest that not all PN types may be responsive to selumetinib and that a certain selumetinib tissue concentration may be required for target inhibition and anti-tumor activity. Objective: -Determine the objective response rate (PN volume decrease greater than or equal to 20% compared to baseline) to selumetinib in adult patients with inoperable PN. Eligibility: - Patients must be at least 18 years of age with a diagnosis of NF1, with an inoperable, measureable PN that causes morbidity or is growing, which is amenable to percutaneous biopsy, and must be willing to undergo two biopsies. - Up to 10 patients who meet all criteria, but have PN, which cannot be biopsied safely, will be eligible for the treatment portion of the study. - Patients must have adequate organ function, be able to undergo serial MRI scans and have recovered from acute toxicity of all prior treatment. Design: - This is a single site open label phase II study in which all subjects will receive selumetinib orally approximately every 12 hours until patient develops progression of disease, unacceptable toxicity or, in patients with non-progressive, symptomatic PN at enrollment, a maximum of 2 years (unless they experience a partial response, or an improvement in symptoms or function in which case they may continue until progression of disease). - Selumetinib will be administered at a dose of 50 mg BID on a continuous dosing schedule (1 cycle=28 days), which is the recommended adult dose. A maximum accrual of 35 evaluable patients to meet the primary objective; while a maximum of 60 patients in total may be enrolled to allow for a small number of screen failures, inevaluable patients and up to 10 patients who cannot safely undergo two biopsies of PNs. Enrollment will proceed over approximately 24 months. ;