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Systemic Therapy (Targeted Therapy and Immunotherapy) for Thyroid Cancers
Published in Madan Laxman Kapre, Thyroid Surgery, 2020
Ceritinib: This is a second-generation ALK inhibitor that overcomes secondary resistance due to acquired ALK mutations or amplification or activation of alternative ALK-independent survival pathways (such as EGF, IGF, RAS/SRC, and AKT/mTOR signaling pathways). However, in a study, ceritinib had limited efficacy in ATC patients with the ALKL1198F mutation in full-length ALK or the EML4-ALK fusion protein. An additional trial is currently evaluating this drug in patients harboring ALK mutations or fusions (NCT02289144).
Statistical Considerations in Phase I Oncology Trials
Published in Satrajit Roychoudhury, Soumi Lahiri, Statistical Approaches in Oncology Clinical Development, 2018
Simon Wandel, Satrajit Roychoudhury
To illustrate the concepts and model introduced before, we now discuss the two phase I studies of ceritinib (LDK378, Novartis Pharmaceuticals). Ceritinib was developed as a targeted anticancer therapy against the anaplastic lymphoma kinase (ALK) gene (Shaw et al., 2014). When ceritinib was available for clinical development, another potent ALK inhibitor, crizotinib, was already in late clinical development (Shaw et al., 2013) with promising phase I data (Kwak et al., 2010). However, in preclinical experiments, ceritinib showed much higher potency against ALK than crizotinib (Li et al., 2011) and activity in both crizotinib-sensitive and crizotinib-resistant tumors (Li et al., 2011; Marsilje et al., 2013). These encouraging results provided solid evidence to initiate a phase I study in the Western population, followed by an evaluation in Japanese patients.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ceritinib (ZykadiaTM) (Figure 6.61), a selective and potent inhibitor of the ALK kinase, was developed by Novartis for the treatment of non-small-cell lung cancer (NSCLC), receiving FDA approval in 2014. Initially, it was only approved for patients who had developed resistance to (or could not tolerate) crizotinib but has since been approved as a first-line option for metastatic NSCLC. An FDA-approved test developed by Roche, the VENTANA ALK (D5F3) CDx Assay, is required to identify ALK-positive NSCLC patients who should benefit from ceritinib treatment. Structure of ceritinib (ZykadiaTM).Structure of alectinib (AlecensaTM).Structure of brigatinib (AlunbrigTM).Structure of lorlatinib (LorviquaTM).
Pharmacological and clinical properties of lorlatinib in the treatment of ALK-rearranged advanced non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Haidar El Darsa, Omar Abdel-Rahman, Randeep Sangha
Ceritinib, a second-generation oral ALKi, is 20 times more potent than crizotinib for ALK fusions and was approved as a second- and first-line treatment for ALK rearranged NSCLC based on the ASCEND-2 and ASCEND-4 clinical trials, respectively [20,21]. In ASCEND-4, a phase III study against platinum-doublet chemotherapy, first-line ceritinib dosed at 750 mg oral daily showed a significant ORR of 72.5% and a median PFS (mPFS) of 16.6 months (versus 8.1 months; HR 0.55) [21]. Despite its efficacy, ceritinib use is often curtailed because of its gastrointestinal (GI) toxicities of diarrhea, nausea, and vomiting. Data from the ASCEND-8 trial showed that a lower dose of ceritinib (450 mg oral daily) taken with a low-fat meat had similar exposure and a more favorable GI safety profile than the 750 mg dose in fasted patients with ALK-positive NSCLC [22].
Cost-effectiveness of ceritinib in previously untreated anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer in the United States
Published in Journal of Medical Economics, 2018
Zheng-Yi Zhou, Alex Mutebi, Simeng Han, Arielle G. Bensimon, Marie Louise Ricculli, Jipan Xie, Anand Dalal, Ken Culver
Ceritinib is a next-generation ALK inhibitor that was first approved in the US in 2014 for the treatment of ALK-positive metastatic NSCLC patients who had been previously treated with chemotherapy. In May 2017, ceritinib was also approved in the US for the treatment of previously untreated ALK-positive metastatic NSCLC patients. The approval of ceritinib in first line was based on the results of the Phase 3 trial ASCEND-49, which directly compared ceritinib and platinum doublet chemotherapy (pemetrexed combined with cisplatin or carboplatin, followed by pemetrexed maintenance therapy). In the ASCEND-4 trial, ceritinib provided a statistically significant and clinically meaningful difference in progression-free survival (PFS) compared to platinum doublet (median = 16.6 vs 8.1 months), with a PFS of over 2 years in patients with no baseline brain metastases. Furthermore, the adverse events (AEs) associated with ceritinib are typically manageable, with the most common being diarrhea, nausea, and vomiting10. Results from the recently concluded ASCEND-8 trial indicate that such gastrointestinal toxicities can be considerably reduced by modifying the dose of ceritinib and by administering ceritinib with food10.
Treating brain metastases in non-small cell lung cancer patients: what have we learnt from pharmaceutical recent clinical trials?
Published in Expert Opinion on Pharmacotherapy, 2018
Bin-Chi Liao, Chia-Chi Lin, James Chih-Hsin Yang
The ASCEND-8 study is a phase I randomized, parallel-design study, which demonstrated that ceritinib, administered at 450 mg/day with food, achieved a similar exposure and had a more favorable gastrointestinal toxicity profile compared to ceritinib at 750 mg/day in fasting patients [64]. This study further enrolled treatment-naïve patients with advanced ALK-rearranged NSCLC, and of 121 patients, 32.2% harbored neurologically stable BM, and the ORRs were 78.0%, 75%, and 70% in 450 mg fed, 600 mg fed, and 750 mg fasted groups, respectively [65]. The intracranial efficacy data were not reported. While administering ceritinib at a dose that is associated with a lower gastrointestinal toxicity profile and a similar blood drug concentration, patients can tolerate the treatment well and experience similar or even better efficacies than observed at higher doses.