Early-Phase Study to Evaluate MEK and MDM2 Inhibition in Patients with Neurofibromatosis Type 1 and Premalignant and Malignant Peripheral Nerve Sheath Tumors
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are a type of cancer called a sarcoma. While rare in the general population, they occur more commonly in people with NF1, and about half of all MPNST diagnosed are in people with NF1. Complete surgical removal is the only known treatment to cure MPNST, but many cannot be removed by surgery because they are too large or within important structures or spread to other parts of the body. In people with NF, MPNST often develop within benign tumors called plexiform neurofibromas and, in particular, atypical neurofibromas called atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP). The ANNUBP tumors often have some but not all of the microscopic and molecular changes of MPNST and are considered precursor tumors to MPNST. ANNUBP tumors are often recommended for removal by surgery, and this may prevent them from turning into MPNST even if the surgery is not complete. Scientists have been looking at the signaling within both pre-cancerous ANNUBP and cancerous MPNST. Animal models looking at blocking specific signaling targets against MEK and MDM2 thought to be important in the development and growth of these tumors showed the tumors getting smaller in these animal models when treated with drugs that inhibit MEK and MDM2. Selumetinib is an available drug that is taken by mouth that targets MEK and approved by the Food and Drug Administration for treatment of inoperable plexiform neurofibroma for patients with NF1. APG-115 is a drug taken by mouth that is currently being evaluated in patients with cancers that have not responded or have come back. Recommended doses of this drug by itself and in combination with other drugs are available but have not been studied in combination with selumetinib. We are proposing a clinical trial looking at the combination of these drugs in patients with NF1 and pre- cancerous ANNUBP and MPNST. The drugs will be available to all patients who enroll on study. The first part of the study, which we call Phase 1, will be looking at this combination in patients with MPNST that are not able to be removed by surgery, have spread to other parts of the body, or come back after initial treatment. We will give both drugs at their recommended doses. If this is not found to be tolerable, we will decrease the doses of drugs to see whether this is more tolerable. Once a dose is determined in Phase 1, we will open the Phase 2 portion of the study, where we will be seeing whether the combination shrinks or stabilizes MPNST in patients with NF1. For the Phase 1 and Phase 2 studies, patients can remain on the study drugs as long as they are tolerating the drugs and their tumors are not growing for up to 1 year of treatment. Patients will be closely followed by interval physical exams, laboratory assessments, and imaging with a treating provider. At the same time, as we open Phase 2, we will open the Phase 0 portion of the study where patients who are identified to have ANNUBP that will be undergoing resection will be treated with the drugs for 2 weeks before their surgery. We will be looking to see whether the drugs cause tumor cell death and also exploring how the targets are inhibited by looking at the tumor before and after resection. The study will also look how treatment affects pain and symptoms and the genetics of the tumors with treatment. This study will be open at multiple institutions across the country coordinated Children’s National in collaboration with the Department of Defense Neurofibromatosis Clinical Trials Consortium. The trial is uniquely designed for evaluate for target inhibition of novel drugs by looking at signals that may help in determining tumor response and help plan for future studies in prevention and treatment in this rare, but terrible cancer. We believe this work will provide people with NF1 and MPNST potentially helpful treatments and increase the knowledge for all people with NF1 and at r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211120
Entities
People
- Aerang Kim
Organizations
- United States Army