@article{d2f9f41e0b6f4f6bae77122a865ae776,
title = "Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016)",
abstract = "Purpose. There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). Patients and Methods. Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results. Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1-16). Adverse events were similar to those known for this combination. Conclusion. With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory MPNST.",
author = "Widemann, {Brigitte C.} and Yao Lu and Denise Reinke and Okuno, {Scott H.} and Meyer, {Christian F.} and Cote, {Gregory M.} and Rashmi Chugh and Milhem, {Mohammed M.} and Hirbe, {Angela C.} and Aerang Kim and Brian Turpin and Pressey, {Joseph G.} and Eva Dombi and Nalini Jayaprakash and Helman, {Lee J.} and Ndidi Onwudiwe and Karen Cichowski and Perentesis, {John P.}",
note = "Funding Information: )is research was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Neurofibromatosis Research Program under Award No. W81XWH-10-1-0681 and, in part, by the NCI Center for Cancer Research Intramural Research Program. Funding Information: patients aged ≥18 years with histologically confirmed unresectable, refractory, or metastatic high-grade NF1 or sporadic MPNST; presence of measurable disease; progressive disease after ≥1 prior cytotoxic chemotherapy (unless the patient refused chemotherapy or chemotherapy was felt not to be in the best interest of the patient by the treating physician); Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; adequate bone marrow, liver, and renal function; fasting serum cholesterol ≤300 mg/dL and triglycerides ≤2.5x the upper limit of normal; urine protein creatinine ratio ≤0.5; left ventricular ejection fraction ≥50% in patients who previously received an anthracycline; recovery from toxic effects of prior therapy to ≤grade 1 (CTCAE version 4); a minimum of 3 weeks from prior chemotherapy, 7 days from a biologic agent, 4 weeks from radiation, and 4 weeks from major surgery; willingness to use birth control, and for patients with NF1, documentation of diagnostic criteria [7]. Key exclusion criteria were as follows: patients receiving chronic systemic administration of a corticosteroid or another immunosuppressive agent; presence of severe or uncontrolled medical condition that could affect study participation including brain or leptomeningeal metastases, heart failure, severely impaired lung function, and active or uncontrolled hepatitis; prior treatment with an mTOR inhibitor for MPNST or bev-acizumab; concurrent use of anticoagulant drugs at treatment doses, strong CYP3A4 inhibitors, St. John{\textquoteright}s Wort, grapefruit, or enzyme inducing anticonvulsants. )is multi-institutional trial was coordinated through the Sarcoma Alliance for Research through Collaboration (SARC) and funded by a Department of Defense Clinical Trial Award W81XWH-10-1-0681. )e trial was IND exempt. Everolimus was supplied by Novartis and bevacizumab by Genentech. )e study was conducted after approval from the Department of Defense Protocol Review, and institutional review boards from all participating sites and all patients provided written informed consent before participating. )e trial was registered with ClinicalTrials.gov (NCT01661283). Funding Information: D. Reinke reports grant from the Department of Defense and other support from Novartis and Genentech. G. M. Cote reports personal fees from Agios Pharmaceuticals and other from Otsuka, Amgen, Epizyme, Eisai, MacroGenics, Boston Biomedical, PharmaMar, Plexxikon, Merck KGaA, EMD Serono, CBA Inc, and Bavarian-Nordic outside the submitted work. R. Chugh reports grants from AADi, Novartis, Lilly, Medivation, Plexxikon, Pfizer, Advenchen, Morpho-tek, and MabVax; grants and personal fees from Epizyme and Janssen; and personal fees from Immune Design outside the submitted work. K. Cichowski is an advisor to Gen-entech. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2019 Brigitte C. Widemann et al.",
year = "2019",
doi = "10.1155/2019/7656747",
language = "English (US)",
volume = "2019",
journal = "Sarcoma",
issn = "1357-714X",
publisher = "Hindawi Publishing Corporation",
}