Accelerated Clinical Development of Rational Therapies for Malignant Peripheral Nerve Sheath Tumors

Principal Investigator: KIM, AERANG
Program: NFRP
Proposal Number: NF150092
Award Number: W81XWH-17-1-0695
Funding Mechanism: Clinical Trial Award
Partnering Awards:
Award Amount: $1,021,259.00


Malignant peripheral nerve sheath tumors (MPNST) are a type of cancer called a

sarcoma. While this tumor is rare in the general population, it develops in up to 8% to 13% of people with NF1 during their lifetime. MPNST is the most common cancer associated with NF1 and the leading cause of death in NF1. Complete surgical removal is the only known treatment to cure MPNST. Many MPNST cannot be completely removed by surgery because the tumor is too large or within important structures of the body. There is no effective medical treatment for MPNST and thus there is an urgent need for the development of more effective treatments to control MPNST.

The knowledge of how MPNST develop and grow has increased. Mice that have been programmed to rapidly grow MPNST are being used to discover new possible treatments for MPNST. Several combinations of drugs targeting specific pathways known to have a role in MPNST growth have shown tumors to shrink in these mouse models. We believe that finding the best approaches to most safely and quickly bring the science to clinical studies is important in developing effective treatments for MPNST. Combining a drug that blocks a protein called MEK with a drug that blocks a protein called mTOR, both of which have been shown to have a role in MPNST cell growth, caused tumors to dramatically shrink in the mouse models. MEK inhibitors shrink plexiform neurofibromas in children and adults with NF1, but in MPNST they will likely work best in combination with an mTOR inhibitor. We are proposing a clinical trial of these agents for patients with MPNST. As more combinations that effectively treat MPNST in mouse models are discovered, we will build on this clinical trial using the design of the study and infrastructure to run the clinical trial to study additional combinations.

We hope that giving patients a drug blocking MEK called selumetinib in combination with a drug blocking mTOR called AZD2014 will shrink, slow down, or stop the growth of MPNST. Patients 13 years and older with MPNST that cannot be surgically removed will be able to participate in the trial. Both drugs can be taken by mouth and 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 MPNST regularly with imaging studies 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. These drugs will be considered as potentially helpful for the treatment of MPNST if 30% or more of the patients have a stop in tumor growth for 4 months or longer or have tumor shrinkage. Approximately 7-21 patients will be enrolled in this trial.

The study will be open at multiple institutions and coordinated by SARC, an organization dedicated to finding cures for sarcomas and led by investigators with expertise in NF1, sarcomas, and clinical trials. The treatment options for MPNST are very few. We believe there are good data to support the conduct of this trial. We hope this trial will serve as the basis to build a structure and organization to bring other combinations of drugs found to be beneficial in the mouse models to clinical trials and ultimately to patients safely and quickly. We believe this work will provide people with MPNST with potentially helpful treatment options and will increase the knowledge for all future patients with NF1 and MPNST.