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Sarcoma. 2019 Jul 24;2019:7656747. doi: 10.1155/2019/7656747. eCollection 2019.

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).

Author information

1
National Cancer Institute, Center for Cancer Research, Pediatric Oncology Branch, 10 Center Drive, Building 10, Room 1-3752, Bethesda, MD 20892, USA.
2
SARC Statistics, Weill Cornell Medicine Healthcare and Policy Research, 402 East 67th Street, New York, NY 10065, USA.
3
SARC, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48105, USA.
4
Mayo Clinic, 200 First St, SW, Rochester, MN 55905, USA.
5
Johns Hopkins Hospital, 1650 Orleans St., CRB1/Room G89, Baltimore, MD 21231, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School, 10 North Grove Street, POB-2, Boston, MA 02114, USA.
7
University of Michigan, 1500 E. Medical Center Dr, SPC 5912, Ann Arbor, MI 48109, USA.
8
University of Iowa, 200 Hawkins Drive, C32 GH, Iowa, IA 52242, USA.
9
Washington University of St. Louis, 660 S, Euclid Ave, St. Louis, MO 63110, USA.
10
Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010, USA.
11
Cincinnati Children's Hospital, 3333 Burnet Ave, Cincinnati, OH 45229, USA.
12
Cincinnati Children's Hospital Medical Center, University of Alabama, 1600 7th Avenue South, Lowder 512, Birmingham, AL 35233, USA.
13
Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.

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.

Conflict of interest statement

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, Morphotek, 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 Genentech. No potential conflicts of interest were disclosed by the other authors.

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