Background: MPNST is a type of cancer tumor called a sarcoma, which arises from nerves. 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 MPNST. Many MPNST cannot be completely removed by surgery, and the survival of MPNST in people with NF1 is worse compared to people who do not have NF1. There is an urgent need for the development of effective treatments for MPNST. The knowledge of how MPNST develop and grow has increased. A protein called mTOR was recently shown to regulate NF1. When drugs blocking mTOR were given to NF1 mice with rapidly growing MPNST, the tumors stopped growing for prolonged time periods, and the mice survived substantially longer compared to mice who did not receive the drug blocking mTOR. The formation of new tumor blood vessels has also been shown to contribute to the growth of MPNST. When mice with MPNST received a drug blocking mTOR together with a drug blocking new blood vessel formation, the tumors stopped growing for even longer.
Planned Clinical Trial: We hope that administration of a drug blocking mTOR alone or in combination with a drug blocking new blood vessel formation will shrink, slow down, or stop the growth of MPNST, for which chemotherapy has stopped working. We are therefore proposing a clinical trial for MPNST with the mTOR blocking drug RAD001 alone or in combination with the drug bevacizumab, which blocks new blood vessel formation. Both drugs have been given combined for other conditions to children and adults, and we believe we know how to safely dose these drugs. Children and adults with MPNST for which chemotherapy has stopped working will be able to participate in the trial. Patients with NF1 MPNST and patients with non NF1 MPNST will be treated in separate groups, as their tumors may respond differently. In each of the 2 groups, patients will be assigned to receive treatment with RAD001 alone or in combination with bevacizumab. This will help us learn the effect of RAD001 alone on tumor growth. RAD001 will be given as tablets once daily every day, and bevacizumab will be given as intravenous infusion over 30-90 minutes every 14 days. One treatment cycle will be 28 days. Patients who start treatment with RAD001 alone, and experience growth of their MPNST during treatment will be able to continue treatment with RAD001 with the addition of bevacizumab. We will monitor all patients carefully for side effects of these drugs by physical exam and lab tests, and also measure the MPNST regularly with imaging studies called CT and MRI 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. RAD001 and bevacizumab will be considered as potentially helpful for the treatment of MPNST if 30% or more patients have a stop in tumor growth for 4 months or longer or have tumor shrinkage. Approximately 40-80 patients will be enrolled on this trial, depending on how well RAD001 and bevacizumab work. The treatment options for MPNST are very few. We believe that there are good data to support the conduct of this trial, that this trial will provide people with MPNST with a potentially helpful treatment option, and that the trial will increase the knowledge for future MPNST trials.