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)
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2,349 citations
Cites background from "ASCEND-8: A Randomized Phase 1 Stud..."
...Considering the safety profile of ceritinib, the influence of food on its oral bioavailability and the fact that food may improve gastrointestinal tolerability, a trial was conducted with a lower dose of ceritinib taken with a low-fat meal (ASCEND-8) [201]....
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276 citations
198 citations
Cites background from "ASCEND-8: A Randomized Phase 1 Stud..."
...The second-generation ALK inhibitors ceritinib and alectinib have also shown robust antitumour efficacy, along with intracranial activity, in patients with ALK-rearranged NSCLC in the ASCEND [198, 199] and J-ALEX [200] trials....
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187 citations
Cites background from "ASCEND-8: A Randomized Phase 1 Stud..."
...Alternative ceritinib dosing with food may help ameliorate these side effects going forward.(78) In the ASCEND-8 study, 450-mg daily dosing of ceritinib with meals was much better tolerated than 750-mg daily dosing fasting, yet it reached similar steady-state plasma levels according to pharmacokinetic studies....
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...In the ASCEND-8 study, 450-mg daily dosing of ceritinib with meals was much better tolerated than 750-mg daily dosing fasting, yet it reached similar steady-state plasma levels according to pharmacokinetic studies.(78) Confirmation that antitumor efficacy is comparable between the two dosing regimens remains to be established....
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158 citations
References
4,826 citations
"ASCEND-8: A Randomized Phase 1 Stud..." refers background in this paper
...The disease characteristics of patients in this study were representative of the population of patients with ALK-positive NSCLC....
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...ALK receptor tyrosine kinase gene (ALK) rearrangements serve as a key oncogenic driver and occur in 3% to 7% of patients with NSCLC.1,2 Ceritinib, a nextgeneration selective oral anaplastic lymphoma kinase (ALK) inhibitor, is approved at a dose of 750 mg/d under fasted conditions for the treatment of patients with metastatic ALK-positive NSCLC.3 In phase 1 and 2 studies, ceritinib, 750 mg/d fasted, demonstrated clinically meaningful and durable responses in ALK inhibitor–pretreated and ALK inhibitor–naive patients with advanced ALK-positive NSCLC.4–6 Further, in randomized, global phase 3 trials, ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-positive NSCLC who were treatment naive (ASCEND-4 study)7 or previously treated with crizotinib and one or two prior chemotherapy regimens (ASCEND-5 study).8 Data from phase 1 to phase 3 studies in patients with advanced ALK-positive NSCLC have shown that the gastrointestinal (GI) toxicities diarrhea, nausea, and vomiting are the most frequent adverse events (AEs) after ceritinib treatment4–8; these toxicities generally occur early in treatment.4 In the ASCEND-4 study, the most frequently reported AEs (all grades, all causality) in the ceritinib arm (n ¼ 189) were diarrhea (85%), nausea (69%), and vomiting (66%), predominantly of grade 1/2....
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...In another study of ceritinib (A2108) in healthy subjects, compared with the fasted state, a light snack (w100–300 cal and 1.5 g of fat) increased Cmax and AUCinf of a single oral 750-mg dose of ceritinib by 45% and 54%, respectively.11 On the basis of observations from both studies, the improved absorption of ceritinib in the fed state is hypothesized to be due to the enhanced bile salt secretion in the postprandial intestine even with minimal fat intake, which leads to increased micellar solubilization and wetting of the drug, both of which can enhance the dissolution rate.12–14 Thus, a low-fat meal with either 1.5 g or 9 g of fat increased the systemic exposure of ceritinib to a similar extent.11 On the basis of these pharmacokinetics (PK) data, it was determined that avoiding food during dosing of ceritinib at the labeled dose of 750 mg/d is essential, as the intake of food at that dose may increase the occurrence of exposure-dependent toxicities.11 Given the known safety profile of ceritinib, the effect of food on its bioavailability, and the observation that food improved the GI tolerability of other multikinase inhibitors, the ongoing, multicenter, randomized openlabel study ASCEND-8 (NCT02299505) intends to evaluate the systemic exposure and safety profile of 450mg or 600 mg of ceritinib taken daily with a low-fat meal versus 750 mg daily fasted in patients with ALK-positive NSCLC. Part 1 of the study aimed to determine whether ceritinib with a low-fatmealmay enhance GI tolerability in patients with ALK-positive NSCLC while maintaining similar steady-state exposure....
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...Introduction ALK receptor tyrosine kinase gene (ALK) rearrangements serve as a key oncogenic driver and occur in 3% to 7% of patients with NSCLC.(1,2) Ceritinib, a nextgeneration selective oral anaplastic lymphoma kinase (ALK) inhibitor, is approved at a dose of 750 mg/d under fasted conditions for the treatment of patients with metastatic ALK-positive NSCLC....
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...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. 2017 International Association for the Study of Lung Cancer....
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1,733 citations
"ASCEND-8: A Randomized Phase 1 Stud..." refers background in this paper
...The disease characteristics of patients in this study were representative of the population of patients with ALK-positive NSCLC....
[...]
...ALK receptor tyrosine kinase gene (ALK) rearrangements serve as a key oncogenic driver and occur in 3% to 7% of patients with NSCLC.1,2 Ceritinib, a nextgeneration selective oral anaplastic lymphoma kinase (ALK) inhibitor, is approved at a dose of 750 mg/d under fasted conditions for the treatment of patients with metastatic ALK-positive NSCLC.3 In phase 1 and 2 studies, ceritinib, 750 mg/d fasted, demonstrated clinically meaningful and durable responses in ALK inhibitor–pretreated and ALK inhibitor–naive patients with advanced ALK-positive NSCLC.4–6 Further, in randomized, global phase 3 trials, ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-positive NSCLC who were treatment naive (ASCEND-4 study)7 or previously treated with crizotinib and one or two prior chemotherapy regimens (ASCEND-5 study).8 Data from phase 1 to phase 3 studies in patients with advanced ALK-positive NSCLC have shown that the gastrointestinal (GI) toxicities diarrhea, nausea, and vomiting are the most frequent adverse events (AEs) after ceritinib treatment4–8; these toxicities generally occur early in treatment.4 In the ASCEND-4 study, the most frequently reported AEs (all grades, all causality) in the ceritinib arm (n ¼ 189) were diarrhea (85%), nausea (69%), and vomiting (66%), predominantly of grade 1/2....
[...]
...In another study of ceritinib (A2108) in healthy subjects, compared with the fasted state, a light snack (w100–300 cal and 1.5 g of fat) increased Cmax and AUCinf of a single oral 750-mg dose of ceritinib by 45% and 54%, respectively.11 On the basis of observations from both studies, the improved absorption of ceritinib in the fed state is hypothesized to be due to the enhanced bile salt secretion in the postprandial intestine even with minimal fat intake, which leads to increased micellar solubilization and wetting of the drug, both of which can enhance the dissolution rate.12–14 Thus, a low-fat meal with either 1.5 g or 9 g of fat increased the systemic exposure of ceritinib to a similar extent.11 On the basis of these pharmacokinetics (PK) data, it was determined that avoiding food during dosing of ceritinib at the labeled dose of 750 mg/d is essential, as the intake of food at that dose may increase the occurrence of exposure-dependent toxicities.11 Given the known safety profile of ceritinib, the effect of food on its bioavailability, and the observation that food improved the GI tolerability of other multikinase inhibitors, the ongoing, multicenter, randomized openlabel study ASCEND-8 (NCT02299505) intends to evaluate the systemic exposure and safety profile of 450mg or 600 mg of ceritinib taken daily with a low-fat meal versus 750 mg daily fasted in patients with ALK-positive NSCLC. Part 1 of the study aimed to determine whether ceritinib with a low-fatmealmay enhance GI tolerability in patients with ALK-positive NSCLC while maintaining similar steady-state exposure....
[...]
...Introduction ALK receptor tyrosine kinase gene (ALK) rearrangements serve as a key oncogenic driver and occur in 3% to 7% of patients with NSCLC.(1,2) Ceritinib, a nextgeneration selective oral anaplastic lymphoma kinase (ALK) inhibitor, is approved at a dose of 750 mg/d under fasted conditions for the treatment of patients with metastatic ALK-positive NSCLC....
[...]
...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. 2017 International Association for the Study of Lung Cancer....
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855 citations
"ASCEND-8: A Randomized Phase 1 Stud..." refers background or result in this paper
...The disease characteristics of patients in this study were representative of the population of patients with ALK-positive NSCLC....
[...]
...ALK receptor tyrosine kinase gene (ALK) rearrangements serve as a key oncogenic driver and occur in 3% to 7% of patients with NSCLC.1,2 Ceritinib, a nextgeneration selective oral anaplastic lymphoma kinase (ALK) inhibitor, is approved at a dose of 750 mg/d under fasted conditions for the treatment of patients with metastatic ALK-positive NSCLC.3 In phase 1 and 2 studies, ceritinib, 750 mg/d fasted, demonstrated clinically meaningful and durable responses in ALK inhibitor–pretreated and ALK inhibitor–naive patients with advanced ALK-positive NSCLC.4–6 Further, in randomized, global phase 3 trials, ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-positive NSCLC who were treatment naive (ASCEND-4 study)7 or previously treated with crizotinib and one or two prior chemotherapy regimens (ASCEND-5 study).8 Data from phase 1 to phase 3 studies in patients with advanced ALK-positive NSCLC have shown that the gastrointestinal (GI) toxicities diarrhea, nausea, and vomiting are the most frequent adverse events (AEs) after ceritinib treatment4–8; these toxicities generally occur early in treatment.4 In the ASCEND-4 study, the most frequently reported AEs (all grades, all causality) in the ceritinib arm (n ¼ 189) were diarrhea (85%), nausea (69%), and vomiting (66%), predominantly of grade 1/2....
[...]
...In another study of ceritinib (A2108) in healthy subjects, compared with the fasted state, a light snack (w100–300 cal and 1.5 g of fat) increased Cmax and AUCinf of a single oral 750-mg dose of ceritinib by 45% and 54%, respectively.11 On the basis of observations from both studies, the improved absorption of ceritinib in the fed state is hypothesized to be due to the enhanced bile salt secretion in the postprandial intestine even with minimal fat intake, which leads to increased micellar solubilization and wetting of the drug, both of which can enhance the dissolution rate.12–14 Thus, a low-fat meal with either 1.5 g or 9 g of fat increased the systemic exposure of ceritinib to a similar extent.11 On the basis of these pharmacokinetics (PK) data, it was determined that avoiding food during dosing of ceritinib at the labeled dose of 750 mg/d is essential, as the intake of food at that dose may increase the occurrence of exposure-dependent toxicities.11 Given the known safety profile of ceritinib, the effect of food on its bioavailability, and the observation that food improved the GI tolerability of other multikinase inhibitors, the ongoing, multicenter, randomized openlabel study ASCEND-8 (NCT02299505) intends to evaluate the systemic exposure and safety profile of 450mg or 600 mg of ceritinib taken daily with a low-fat meal versus 750 mg daily fasted in patients with ALK-positive NSCLC. Part 1 of the study aimed to determine whether ceritinib with a low-fatmealmay enhance GI tolerability in patients with ALK-positive NSCLC while maintaining similar steady-state exposure....
[...]
...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. 2017 International Association for the Study of Lung Cancer....
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...Part 1 (primary PK analysis) investigated PK exposure to ceritinib, 450 mg fed and 600 mg fed, versus ceritinib, 750 mg fasted, and preliminary safety in previously treated or treatment-naive patients with advanced ALK-positive NSCLC. Part 2 (efficacy analysis) is currently randomly allocating only treatment-naive patients with advanced ALK-positive NSCLC by IHC and will assess efficacy as well as additional safety follow-up....
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616 citations
464 citations