Window of Opportunity Study Assessing Nivolumab and Ipilimumab in People with Neurofibromatosis Type 1 and Newly Diagnosed Malignant and Premalignant Peripheral Nerve Sheath Tumors
Abstract
Background: The leading cause of death in people with neurofibromatosis type I (NF1) is an aggressive cancer called a malignant peripheral nerve sheath tumor (MPNST). This is a type of sarcoma or soft tissue cancer. Although MPNST is very rare in the general population, people with NF1 have a cumulative lifetime risk of 8-26% for developing MPNST. NF1 associated MPNSTs are also more resistant to the treatments commonly used to treat sarcomas. As a result, even when patients with NF1 associated MPNST complete maximally aggressive anti-cancer therapy (including chemotherapy, radiation and surgery), only an estimated 20-50% of patients will be alive at 5 years. Because of this dire situation, finding and developing effective treatments for NF1-associated MPNST is a critical priority. Recently, a tumor type called atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP) was shown to be a precursor tumor to MPNST. Although it is known that ANNUBP predicts progression to the aggressive sarcoma, MPNST, there is not yet agreement in the medical field about how to best care for a person with NF1 and newly diagnosed ANNUBP and there are no specific drug therapies for ANNUBP. Study Objectives: The primary objective of this study is to determine whether it is safe and feasible for people with NF1 and a new diagnosis of either ANNUBP or MPNST to receive two doses of drugs called nivolumab and ipilimumab. Nivolumab and ipilimumab are both monoclonal antibodies that target proteins involved in immune system’s response to a cancer and hence, are termed immunotherapies. Nivolumab is a monoclonal antibody targeting the protein programmed death 1 (PD-1). Ipilimumab is a monoclonal antibody targeting the protein cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These drugs are each approved by the Food and Drug Administration (FDA) for multiple cancers. The combination of nivolumab (the anti-PD-1 antibody) and ipilimumab (the anti-CTLA-4 antibody) has also been approved by the FDA for multiple cancers, including metastatic melanoma and hepatocellular carcinoma. In this study, up to 18 people with NF1 and a new diagnosis of ANNUBP and MPNST will be invited to participate across five expert sites within the Neurofibromatosis Clinical Trials Consortium. People with NF1 who have MRI and FDG-PET findings suggestive of ANNUBP or MPNST are referred for biopsy. If ANNUBP or MPNST are confirmed, nivolumab 4.5mg/kg IV (maximum dose 360mg) in combination with ipilimumab 1mg/kg will be given every three weeks x two doses prior to conventional therapy. The primary endpoint is the proportion of patients who complete two doses of nivolumab and ipilipumab and start of conventional therapy within eight weeks of diagnosis. Additional endpoints are to see if there is evidence on imaging of tumor response to nivolumab and ipilimumab and to assess tumor-associated pain before and after treatment with nivolumab and ipilimumab. Finally, tumor tissue samples collected at the time of standard biopsy/surgery and blood samples will be collected to study the biologic effect of these drugs on people with NF1 and ANNUBP or MPNST. Impact: This is the first clinical trial to assess PD-1 and CTLA-4 inhibitors in people with NF1 and ANNUBP or MPNST. There is a desperate need for new, effective therapies for these tumors. This study will fill the critical gap in knowledge about whether immunotherapies like nivolumab and ipilimumab are safe and feasible in people with NF1 associated ANNUBP or MPNST. If this is proven to be the case, this study will be the first step in developing immunotherapies like nivolumab and ipilimumab for people with NF1. Nivolumab and ipilimumab have been revolutionary for other cancers labeled as untreatable in the past and it is possible that they will also have unprecedented activity in NF1 associated ANNUBP and MPNST. If they are not safe and feasible in people with NF1, this is also a criti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210580
Entities
People
- Jaishri O Blakeley
Organizations
- Johns Hopkins University
- United States Army