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)

Brigitte C. Widemann, Yao Lu, Denise Reinke, Scott Heitaka Okuno, Christian F. Meyer, Gregory M. Cote, Rashmi Chugh, Mohammed M. Milhem, Angela C. Hirbe, Aerang Kim, Brian Turpin, Joseph G. Pressey, Eva Dombi, Nalini Jayaprakash, Lee J. Helman, Ndidi Onwudiwe, Karen Cichowski, John P. Perentesis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number7656747
JournalSarcoma
Volume2019
DOIs
StatePublished - Jan 1 2019

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Neurofibromatosis 1
Neurilemmoma
Bevacizumab
Everolimus
Sirolimus
Disease Progression
Neoplasms
Up-Regulation
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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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). / Widemann, Brigitte C.; Lu, Yao; Reinke, Denise; Okuno, Scott Heitaka; Meyer, Christian F.; Cote, Gregory M.; Chugh, Rashmi; Milhem, Mohammed M.; Hirbe, Angela C.; Kim, Aerang; Turpin, Brian; Pressey, Joseph G.; Dombi, Eva; Jayaprakash, Nalini; Helman, Lee J.; Onwudiwe, Ndidi; Cichowski, Karen; Perentesis, John P.

In: Sarcoma, Vol. 2019, 7656747, 01.01.2019.

Research output: Contribution to journalArticle

Widemann, BC, Lu, Y, Reinke, D, Okuno, SH, Meyer, CF, Cote, GM, Chugh, R, Milhem, MM, Hirbe, AC, Kim, A, Turpin, B, Pressey, JG, Dombi, E, Jayaprakash, N, Helman, LJ, Onwudiwe, N, Cichowski, K & Perentesis, JP 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)', Sarcoma, vol. 2019, 7656747. https://doi.org/10.1155/2019/7656747
Widemann, Brigitte C. ; Lu, Yao ; Reinke, Denise ; Okuno, Scott Heitaka ; Meyer, Christian F. ; Cote, Gregory M. ; Chugh, Rashmi ; Milhem, Mohammed M. ; Hirbe, Angela C. ; Kim, Aerang ; Turpin, Brian ; Pressey, Joseph G. ; Dombi, Eva ; Jayaprakash, Nalini ; Helman, Lee J. ; Onwudiwe, Ndidi ; Cichowski, Karen ; Perentesis, John P. / 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). In: Sarcoma. 2019 ; Vol. 2019.
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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 Heitaka} 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.}",
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TY - JOUR

T1 - 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)

AU - Widemann, Brigitte C.

AU - Lu, Yao

AU - Reinke, Denise

AU - Okuno, Scott Heitaka

AU - Meyer, Christian F.

AU - Cote, Gregory M.

AU - Chugh, Rashmi

AU - Milhem, Mohammed M.

AU - Hirbe, Angela C.

AU - Kim, Aerang

AU - Turpin, Brian

AU - Pressey, Joseph G.

AU - Dombi, Eva

AU - Jayaprakash, Nalini

AU - Helman, Lee J.

AU - Onwudiwe, Ndidi

AU - Cichowski, Karen

AU - Perentesis, John P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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DO - 10.1155/2019/7656747

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JO - Sarcoma

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