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Journal ArticleDOI

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)

TL;DR: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than cerit inib, 750 mg in fasted patients with ALK‐positive NSCLC.
About: This article is published in Journal of Thoracic Oncology.The article was published on 2017-09-01 and is currently open access. It has received 143 citations till now. The article focuses on the topics: Ceritinib & Anaplastic lymphoma kinase.
Citations
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Journal ArticleDOI
TL;DR: The ESMO Guidelines Committee concluded that current state-of-the-art oncology practices in France, Belgium, and the Netherlands are suitable for frontline use and recommend further research into these practices.

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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Journal ArticleDOI
TL;DR: Department of Medical Oncology, Thoracic Group, Gustave-Roussy Villejuif, France; Royal Marsden Hospital, London; Aberdeen Royal Infirmary, Aberdeen University Medical School, Aberdeen, UK; Department of Oncologists, University of Turin, San Luigi Hospital, Orbassano, Italy.

276 citations

Journal ArticleDOI
TL;DR: These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS) and were considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.

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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Journal ArticleDOI
TL;DR: The biology and diagnosis of ROS1‐rearranged NSCLC, and current and emerging treatment options for this disease are discussed and future challenges in the field are highlighted.

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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Journal ArticleDOI
TL;DR: This review introduces targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human Epidermal Growth Factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD
Abstract: Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Herein, we introduce targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD-1 L).

158 citations

References
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Journal ArticleDOI
02 Aug 2007-Nature
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
Abstract: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

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....

    [...]

  • ...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....

    [...]

Journal ArticleDOI
TL;DR: EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics and patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
Abstract: Purpose The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non–small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients and Methods Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Results Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and ...

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....

    [...]

Journal ArticleDOI
TL;DR: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.

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....

    [...]

  • ...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....

    [...]

Journal ArticleDOI
TL;DR: Case studies are presented in which postprandial changes in bioavailability are rationalized in terms of the sensitivity of the physicochemical properties of the administered drug to the altered GI environment.

616 citations

Journal ArticleDOI
TL;DR: The current status of information regarding interactions which may influence the gastrointestinal (GI) absorption of orally administered drugs is presented and regional differences in membrane permeability are discussed.
Abstract: Drug-drug, drug-formulation and drug-meal interactions are of clinical concern for orally administered drugs that possess a narrow therapeutic index. This review presents the current status of information regarding interactions which may influence the gastrointestinal (GI) absorption of orally administered drugs. Absorption interactions have been classified on the basis of rate-limiting processes. These processes are put in the context of drug and formulation physicochemical properties and oral input influences on variable GI physiology. Interaction categorisation makes use of a biopharmaceutical classification system based on drug aqueous solubility and membrane permeability and their contributions towards absorption variability. Overlaying this classification it is important to be aware of the effect that the magnitudes of drug dosage and volume of fluid administration can have on interactions involving a solubility rate limits. GI regional differences in membrane permeability are fundamental to the rational development of extended release dosage forms as well as to predicting interaction effects on absorption from immediate release dosage forms. The effect of meals on the regional-dependent intestinal elimination of drugs and their involvement in drug absorption interactions is also discussed. Although the clinical significance of such interactions is certainly dependent on the narrowness of the drug therapeutic index, clinical aspects of absorption delays and therapeutic failures resulting from various interactions are also important.

464 citations

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