Background: Malignant peripheral nerve sheath tumors (MPNSTs) are a type of cancer tumor called a sarcoma, which arises from nerves. There are approximately 1,200 new cases of MPNSTs diagnosed each year. While this tumor is rare in the general population, it develops in up to 8%-13% of people with NF1 during their lifetime. Complete surgical removal is the only known treatment to cure MPNSTs. Many MPNSTs cannot be completely removed by surgery. When MPNSTs cannot be controlled, survival is threatened. There is no effective medical treatment for MPNSTs, and thus there is an urgent need for the development of more effective treatments to control MPNSTs.
The knowledge of how MPNSTs develop and grow has increased. A protein called mTOR is known to have a role in MPNST cell growth. When drugs blocking mTOR were given to mice with rapidly growing MPNST, the tumors did not get smaller, but stopped growing for prolonged time periods. These mice lived substantially longer compared to mice that did not receive the drug blocking mTOR. Identifying additional targets to combine with drugs blocking mTOR to strengthen the effect were evaluated. A protein called Hsp90 was recently noted in laboratory studies to regulate MPNST cell growth. Blocking or inhibiting this protein, Hsp90 significantly disrupts cancer cells causing cell death. When mice with MPNSTs received a combination of the drug blocking Hsp90 together with a drug blocking mTOR, the tumors shrank on average 49%.
Planned Clinical Trial: We hope that administration of a drug blocking Hsp90 in combination with a drug blocking mTOR will shrink, slow down, or stop the growth of MPNSTs for which chemotherapy has stopped working. We are therefore proposing a clinical trial for MPNSTs with the Hsp90-blocking drug ganetespib in combination with the mTOR-blocking drug sirolimus. The first stage of the trial will focus on finding a safe dose of ganetespib and sirolimus when combined in patients with MPNSTs. The goal in the second stage of the study is to determine how many patients benefit from the combination treatment. Adults (those 18 years and older) with MPNSTs for whom chemotherapy has stopped working will be able to participate in the trial. Sirolimus is a tablet that will be taken once a day by mouth, and ganetespib is a medicine given by injection into the vein (intravenous infusion), which is given over 60 minutes on days 1, 8, and 15 of the treatment cycle. One treatment cycle will be 28 days. We will monitor all patients carefully for side effects of these drugs by physical exam and lab tests, and also measure the MPNSTs regularly with imaging studies called CT (computer tomography) and MRI (magnetic resonance imaging) to see the effect of the drugs on tumor size. Patients will be able to continue with these drugs for as long as they have no severe side effects and their tumor is not growing. Ganetespib and sirolimus will be considered as potentially helpful for the treatment of MPNSTs if 25% or more of the patients have a stop in tumor growth for 4 months or longer or have tumor shrinkage. Approximately 16-38 patients 18 years or older will be enrolled in this trial, depending on how well ganetespib and sirolimus work. The treatment options for MPNSTs are very few. We believe that there are good data to support the conduct of this trial. This trial will provide people with MPNSTs a potentially helpful treatment option and will increase the knowledge for future clinical trials for patients with MPNSTs.