Pilot Study of Gleevec/Imatinib Mesylate (STI-571, NSC 716051) in Neurofibromatosis (NF1) Patients with Plexiform Neurofibromas

Principal Investigator: ROBERTSON, KENT
Program: NFRP
Proposal Number: NF080099
Award Number: W81XWH-09-1-0120
Funding Mechanism: Clinical Trial Award
Partnering Awards:
Award Amount: $1,060,991.00


Neurofibromatosis (NF1) is a common inherited disorder that occurs in 1 out of every 3,500 individuals and results from the loss of protein called neurofibromin that controls how cells grow. As a result, NF1 patients are at risk to develop a variety of tumors including one called plexiform neurofibromas (PNs). These PNs are, as their name implies, a complex mix of different kinds of cells including nerve cells, supportive tissue cells, blood cells, and cells that make up blood vessels. They can be disfiguring, painful, and life-threatening. Because of their slow growth and location near vital structures including nerves, vessels, and the airway, these PNs are resistant to most therapeutic approaches including chemotherapy, radiation, and surgery. Unfortunately, there are no good forms of therapy currently available to treat PNs. The way to make treatments for tumors that do not respond is to understand how the tumors grow and what controls their growth. Recent research has found several proteins that control growth of PN cells. The drug Gleevec is known to block these proteins from making cells grow. Testing in NF1 cells in the laboratory and in mice with NF1 has shown that Gleevec will stop the growth of PN cells and make the cells behave in a more normal way. Based on these findings, we treated a 3-year old girl with NFI and a large PN pressing on her airway making breathing and eating difficult. After 3 months of taking Gleevec, she had a very good reduction (by more than half) in the size of her PN tumor with improvement in her breathing and ability to eat. Based on this experience, we treated a small group of NF1 patients with PNs. Measuring the size of tumors by X-ray (MRI scans = magnetic resonance imaging), one patient showed a similar reduction in the size of the tumor and 12 patients showed their PNs had more modest reduction in their tumor or it stopped growing. Several patients showed improvement in their symptoms including less pain, better strength, and better sense of well-being, and three patients who had lost control of their bladder function because of spinal cord compression by their PNs were able to regain control of bladder function. The difficulty in measuring the response of PNs to therapy is that they are slow-growing and may be slow to shrink, yet a therapy may still potentially have benefits for patients. We propose to use the methods that have been developed to measure how these tumors grow as a way to measure how patients respond to therapy. NF1 patients with PNs will be treated with Gleevec for a minimum of 6 months. Their response to treatment will be measured by MRI scans measuring the diameter of the tumors and the volume of the tumors, PET (positron emission ) scans that use a low dose radioactive dye to measure how actively the PNs are growing, plus we will measure the effect of treatment on (1) cells in the blood stream that contribute to PNs, (2) levels of biochemicals in the blood that can make PNs grow, and (3) how a patient's blood changes in its ability to make PNs grow. Additionally, we will develop a method to measure how Gleevec (and other drugs) treatment affect how a patient feels and is able to function in their daily life. It is the hope that this approach will set out the best ways to measure an NF1 patient's response to therapy that can be used to ask whether a therapy is helpful or not. These results would be used in future studies with Gleevec and other therapies for PNs in NF1 patients.