Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy

A phase II trial

James C. Yao, Catherine Lombard-Bohas, Eric Baudin, Larry K. Kvols, Philippe Rougier, Philippe Ruszniewski, Sakina Hoosen, Jessica St. Peter, Tomas Haas, David Lebwohl, Eric Van Cutsem, Matthew H. Kulke, Timothy James Hobday, Thomas M. O'Dorisio, Manisha H. Shah, Guillaume Cadiot, Gabriele Luppi, James A. Posey, Bertram Wiedenmann

Research output: Contribution to journalArticle

473 Citations (Scopus)

Abstract

Purpose: No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Patients and Methods: This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results: By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion: Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalJournal of Clinical Oncology
Volume28
Issue number1
DOIs
StatePublished - Jan 1 2010

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Neuroendocrine Tumors
Octreotide
Drug Therapy
Disease-Free Survival
Chromogranin A
Phosphopyruvate Hydratase
Everolimus
Sirolimus
Radiology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy : A phase II trial. / Yao, James C.; Lombard-Bohas, Catherine; Baudin, Eric; Kvols, Larry K.; Rougier, Philippe; Ruszniewski, Philippe; Hoosen, Sakina; St. Peter, Jessica; Haas, Tomas; Lebwohl, David; Van Cutsem, Eric; Kulke, Matthew H.; Hobday, Timothy James; O'Dorisio, Thomas M.; Shah, Manisha H.; Cadiot, Guillaume; Luppi, Gabriele; Posey, James A.; Wiedenmann, Bertram.

In: Journal of Clinical Oncology, Vol. 28, No. 1, 01.01.2010, p. 69-76.

Research output: Contribution to journalArticle

Yao, JC, Lombard-Bohas, C, Baudin, E, Kvols, LK, Rougier, P, Ruszniewski, P, Hoosen, S, St. Peter, J, Haas, T, Lebwohl, D, Van Cutsem, E, Kulke, MH, Hobday, TJ, O'Dorisio, TM, Shah, MH, Cadiot, G, Luppi, G, Posey, JA & Wiedenmann, B 2010, 'Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: A phase II trial', Journal of Clinical Oncology, vol. 28, no. 1, pp. 69-76. https://doi.org/10.1200/JCO.2009.24.2669
Yao, James C. ; Lombard-Bohas, Catherine ; Baudin, Eric ; Kvols, Larry K. ; Rougier, Philippe ; Ruszniewski, Philippe ; Hoosen, Sakina ; St. Peter, Jessica ; Haas, Tomas ; Lebwohl, David ; Van Cutsem, Eric ; Kulke, Matthew H. ; Hobday, Timothy James ; O'Dorisio, Thomas M. ; Shah, Manisha H. ; Cadiot, Guillaume ; Luppi, Gabriele ; Posey, James A. ; Wiedenmann, Bertram. / Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy : A phase II trial. In: Journal of Clinical Oncology. 2010 ; Vol. 28, No. 1. pp. 69-76.
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abstract = "Purpose: No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Patients and Methods: This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results: By central radiology review, in stratum 1, there were 11 partial responses (9.6{\%}), 78 patients (67.8{\%}) with stable disease (SD), and 16 patients (13.9{\%}) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4{\%}), 36 patients (80{\%}) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion: Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.",
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T2 - A phase II trial

AU - Yao, James C.

AU - Lombard-Bohas, Catherine

AU - Baudin, Eric

AU - Kvols, Larry K.

AU - Rougier, Philippe

AU - Ruszniewski, Philippe

AU - Hoosen, Sakina

AU - St. Peter, Jessica

AU - Haas, Tomas

AU - Lebwohl, David

AU - Van Cutsem, Eric

AU - Kulke, Matthew H.

AU - Hobday, Timothy James

AU - O'Dorisio, Thomas M.

AU - Shah, Manisha H.

AU - Cadiot, Guillaume

AU - Luppi, Gabriele

AU - Posey, James A.

AU - Wiedenmann, Bertram

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N2 - Purpose: No established treatment exists for pancreatic neuroendocrine tumor (NET) progression after failure of chemotherapy. Everolimus (RAD001), an oral inhibitor of mammalian target of rapamycin, in combination with octreotide has demonstrated encouraging antitumor activity in patients with NETs. Patients and Methods: This open-label, phase II study assessed the clinical activity of everolimus in patients with metastatic pancreatic NETs who experienced progression on or after chemotherapy. Patients were stratified by prior octreotide therapy (stratum 1: everolimus 10 mg/d, n = 115; stratum 2: everolimus 10 mg/d plus octreotide long-acting release [LAR], n = 45). Tumor assessments (using Response Evaluation Criteria in Solid Tumors) were performed every 3 months. Chromogranin A (CgA) and neuron-specific enolase (NSE) were assessed monthly if elevated at baseline. Trough concentrations of everolimus and octreotide were assessed. Results: By central radiology review, in stratum 1, there were 11 partial responses (9.6%), 78 patients (67.8%) with stable disease (SD), and 16 patients (13.9%) with progressive disease; median progression-free survival (PFS) was 9.7 months. In stratum 2, there were two partial responses (4.4%), 36 patients (80%) with SD, and no patients with progressive disease; median PFS was 16.7 months. Patients with an early CgA or NSE response had a longer PFS compared with patients without an early response. Coadministration of octreotide LAR and everolimus did not impact exposure to either drug. Most adverse events were mild to moderate and were consistent with those previously seen with everolimus. Conclusion: Daily everolimus, with or without concomitant octreotide LAR, demonstrates antitumor activity as measured by objective response rate and PFS and is well tolerated in patients with advanced pancreatic NETs after failure of prior systemic chemotherapy.

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