Phase 2 Study of AZD2014, a Dual mTORC1/mTORC1 Inhibitor, for NF2 Patients with Progressive or Symptomatic Meningiomas
Abstract
Patients with neurofibromatosis 2 (NF2) are at increased risk for multiple types of benign nervous system tumors, including schwannomas, meningiomas, and ependymomas. Meningiomas are common in NF2 patients, affecting about 80% of patients by 70 years of age. NF2 patients with meningioma are at increased risk of death compared to patients without meningioma. Furthermore, these tumors can reduce quality of life due to the presence of neurologic symptoms or due to complications of treatment. Surgery is currently the standard treatment for these tumors, with radiation reserved for meningiomas that cannot be safely removed or for meningiomas that recur despite surgery. Treatment of symptomatic or growing meningiomas is an important unmet medical need for NF2 patients. To date, no chemotherapy has demonstrated efficacy against NF2-related meningiomas and, therefore, novel medical treatments are greatly needed. Over the past decade, our laboratory has studied the mTOR signaling pathway involved in meningioma growth. This work has led to a clinical study of everolimus, an inhibitor of the mTOR pathway, for patients with NF2. Unfortunately, preliminary clinical results suggest that everolimus does not shrink meningiomas in NF2 patients. Our subsequent work suggests that the reason for this finding is that everolimus (and related drugs like rapamycin) only inhibit one of the two growth signals in the mTOR pathway. AZD2014 is a novel drug that blocks both cellular signals in the mTOR pathway that are involved in meningioma cell growth. Importantly, our laboratory data show that AZD2014 is significantly more effective than everolimus in inhibiting tumor growth in meningioma cell lines. Currently, AZD2014 is being studied in patients with advanced cancers by itself or in combination with a number of well-known anticancer therapies. Various studies in animals and in humans with cancer have shown that AZD2014 can slow the growth of cancer. Previous studies have also allowed investigators to determine the best dose and frequency of AZD2014 to achieve antitumor effects while reducing the likelihood of side effects. Potential side effects have been mild in most patients and include mouth sores, high cholesterol, nausea, fatigue, and liver inflammation. Our group has partnered with AstraZeneca to provide AZD2014 for a clinical trial for NF2 patients with meningiomas. This study is a Phase 2 clinical trial designed to establish the efficacy, safety, and tolerability of AZD2014 in NF2 patients with growing or symptomatic meningiomas. Patients will receive AZD2014 by mouth 2 days per week. Patients will continue treatment for as long as their meningioma does not grow and they do not experience significant side effects. Patients response to treatment will be carefully monitored by the study team using clinical exams and MRIs of the brain. In addition, we will study the effect of AZD2014 on quality of life and on the size of vestibular schwannomas. Finally, we will determine whether the activity level of the mTOR pathway in tumors predicts the clinical response to AZD2014. If so, investigators might be able to predict which patients are likely to respond to treatment. Successful completion of the proposed trial will provide information about the effectiveness and safety profile of AZD2014 in neurofibromatosis 2 patients with progressive or symptomatic meningiomas. Information from the proposed project will hopefully lead to larger clinical trials of AZD2014 to confirm its ability to stop meningiomas from growing and/or to improve quality of life. If successful, these trials could lead to the first medical treatment of NF2-related meningiomas. Regardless of the outcome, this study will provide valuable information about the importance of the two mTOR pathways in human meningiomas and will improve our understanding of treating meningiomas in NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610103
Entities
People
- Scott R. Plotkin
Organizations
- Massachusetts General Hospital
- United States Army