A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

Edward Wolin, Alain Mita, Amit Mahipal, Tim Meyer, Johanna Bendell, John Nemunaitis, Pam N. Munster, Luis Paz-Ares, Ellen H. Filvaroff, Shaoyi Li, Kristen Hege, Hans de Haan, Monica Mita

Research output: Contribution to journalArticle

Abstract

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed 1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade 3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9–97.3%). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95% CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

Original languageEnglish (US)
Article numbere0221994
JournalPloS one
Volume14
Issue number9
DOIs
StatePublished - Jan 1 2019

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Neuroendocrine Tumors
Carcinoid Tumor
signs and symptoms (animals and humans)
Tumors
mouth
phosphotransferases (kinases)
Phosphotransferases
Disease control
neoplasms
Sirolimus
Somatostatin
somatostatin
TOR Serine-Threonine Kinases
duration
confidence interval
Diarrhea
diarrhea
disease control
Time and motion study
Pharmacokinetics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms. / Wolin, Edward; Mita, Alain; Mahipal, Amit; Meyer, Tim; Bendell, Johanna; Nemunaitis, John; Munster, Pam N.; Paz-Ares, Luis; Filvaroff, Ellen H.; Li, Shaoyi; Hege, Kristen; de Haan, Hans; Mita, Monica.

In: PloS one, Vol. 14, No. 9, e0221994, 01.01.2019.

Research output: Contribution to journalArticle

Wolin, E, Mita, A, Mahipal, A, Meyer, T, Bendell, J, Nemunaitis, J, Munster, PN, Paz-Ares, L, Filvaroff, EH, Li, S, Hege, K, de Haan, H & Mita, M 2019, 'A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms', PloS one, vol. 14, no. 9, e0221994. https://doi.org/10.1371/journal.pone.0221994
Wolin, Edward ; Mita, Alain ; Mahipal, Amit ; Meyer, Tim ; Bendell, Johanna ; Nemunaitis, John ; Munster, Pam N. ; Paz-Ares, Luis ; Filvaroff, Ellen H. ; Li, Shaoyi ; Hege, Kristen ; de Haan, Hans ; Mita, Monica. / A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms. In: PloS one. 2019 ; Vol. 14, No. 9.
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abstract = "Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed 1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26{\%} of patients remained on the starting dose. Most frequent grade 3 toxicities were diarrhea (38{\%}), fatigue (21{\%}), and stomatitis (11{\%}). By investigator, 3 of 41 evaluable patients (7{\%}) showed partial response (PR) and 34 (83{\%}) had stable disease (SD) for a disease control rate (DCR) of 90{\%} (95{\%} confidence interval [CI] 76.9–97.3{\%}). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95{\%} CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50{\%}, 41{\%}, and 39{\%} of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.",
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AU - Meyer, Tim

AU - Bendell, Johanna

AU - Nemunaitis, John

AU - Munster, Pam N.

AU - Paz-Ares, Luis

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