ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)

Byoung Chul Cho, Dong Wan Kim, Alessandra Bearz, Scott A. Laurie, Mark McKeage, Gloria Borra, Keunchil Park, Sang We Kim, Marwan Ghosn, Andrea Ardizzoni, Evaristo Maiello, Alastair Greystoke, Richard Yu, Karen Osborne, Wen Gu, Jeffrey W. Scott, Vanessa Q. Passos, Yvonne Y. Lau, Anna Wrona

Research output: Contribution to journalArticle

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Abstract

Introduction Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. Methods ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. Results As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration–time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. Conclusion Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

Original languageEnglish
Pages (from-to)1357-1367
Number of pages11
JournalJournal of Thoracic Oncology
Volume12
Issue number9
DOIs
StatePublished - Sep 2017

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Non-Small Cell Lung Carcinoma
Meals
Fats
Food
Pharmacokinetics
Safety
ceritinib
anaplastic lymphoma kinase
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Nausea
Vomiting
Diarrhea
Therapeutics
Drug Therapy
Genes

Keywords

  • Anaplastic lymphoma kinase
  • Ceritinib
  • Food-effect study
  • NSCLC

Cite this

Cho, Byoung Chul ; Kim, Dong Wan ; Bearz, Alessandra ; Laurie, Scott A. ; McKeage, Mark ; Borra, Gloria ; Park, Keunchil ; Kim, Sang We ; Ghosn, Marwan ; Ardizzoni, Andrea ; Maiello, Evaristo ; Greystoke, Alastair ; Yu, Richard ; Osborne, Karen ; Gu, Wen ; Scott, Jeffrey W. ; Passos, Vanessa Q. ; Lau, Yvonne Y. ; Wrona, Anna. / ASCEND-8 : A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC). In: Journal of Thoracic Oncology. 2017 ; Vol. 12, No. 9. pp. 1357-1367.
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title = "ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)",
abstract = "Introduction Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. Methods ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. Results As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration–time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25{\%} higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2{\%}], nausea [29.5{\%}], and vomiting [18.2{\%}]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. Conclusion Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.",
keywords = "Anaplastic lymphoma kinase, Ceritinib, Food-effect study, NSCLC",
author = "Cho, {Byoung Chul} and Kim, {Dong Wan} and Alessandra Bearz and Laurie, {Scott A.} and Mark McKeage and Gloria Borra and Keunchil Park and Kim, {Sang We} and Marwan Ghosn and Andrea Ardizzoni and Evaristo Maiello and Alastair Greystoke and Richard Yu and Karen Osborne and Wen Gu and Scott, {Jeffrey W.} and Passos, {Vanessa Q.} and Lau, {Yvonne Y.} and Anna Wrona",
year = "2017",
month = "9",
doi = "10.1016/j.jtho.2017.07.005",
language = "English",
volume = "12",
pages = "1357--1367",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "9",

}

Cho, BC, Kim, DW, Bearz, A, Laurie, SA, McKeage, M, Borra, G, Park, K, Kim, SW, Ghosn, M, Ardizzoni, A, Maiello, E, Greystoke, A, Yu, R, Osborne, K, Gu, W, Scott, JW, Passos, VQ, Lau, YY & Wrona, A 2017, 'ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)', Journal of Thoracic Oncology, vol. 12, no. 9, pp. 1357-1367. https://doi.org/10.1016/j.jtho.2017.07.005

ASCEND-8 : A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC). / Cho, Byoung Chul; Kim, Dong Wan; Bearz, Alessandra; Laurie, Scott A.; McKeage, Mark; Borra, Gloria; Park, Keunchil; Kim, Sang We; Ghosn, Marwan; Ardizzoni, Andrea; Maiello, Evaristo; Greystoke, Alastair; Yu, Richard; Osborne, Karen; Gu, Wen; Scott, Jeffrey W.; Passos, Vanessa Q.; Lau, Yvonne Y.; Wrona, Anna.

In: Journal of Thoracic Oncology, Vol. 12, No. 9, 09.2017, p. 1357-1367.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ASCEND-8

T2 - A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non–Small Cell Lung Cancer (NSCLC)

AU - Cho, Byoung Chul

AU - Kim, Dong Wan

AU - Bearz, Alessandra

AU - Laurie, Scott A.

AU - McKeage, Mark

AU - Borra, Gloria

AU - Park, Keunchil

AU - Kim, Sang We

AU - Ghosn, Marwan

AU - Ardizzoni, Andrea

AU - Maiello, Evaristo

AU - Greystoke, Alastair

AU - Yu, Richard

AU - Osborne, Karen

AU - Gu, Wen

AU - Scott, Jeffrey W.

AU - Passos, Vanessa Q.

AU - Lau, Yvonne Y.

AU - Wrona, Anna

PY - 2017/9

Y1 - 2017/9

N2 - Introduction Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. Methods ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. Results As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration–time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. Conclusion Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

AB - Introduction Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. Methods ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. Results As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration–time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. Conclusion Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

KW - Anaplastic lymphoma kinase

KW - Ceritinib

KW - Food-effect study

KW - NSCLC

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