Cabozantinib exposure –response analyses of efficacy and safety in patients with advanced hepatocellular carcinoma

AbstractCabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx®) dose is 60  mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure–response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lowe r for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); H...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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ConclusionsThe efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.Trial registration IDClinicalTrials.gov. No. NCT01761266.
Source: Journal of Gastroenterology - Category: Gastroenterology Source Type: research
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Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
In conclusion, HF-CDAA feeding in C57Bl/6J mice was identified as an optimal model of steatohepatitis with robust fibrosis and ductular proliferations that progress to cirrhosis and HCC within 24 weeks. This model will aid the testing of interventions and drugs for severe NASH. PMID: 31630534 [PubMed - as supplied by publisher]
Source: American Journal of Physiology. Gastrointestinal and Liver Physiology - Category: Physiology Authors: Tags: Am J Physiol Gastrointest Liver Physiol Source Type: research
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Source: Oncology Research - Category: Cancer & Oncology Tags: Oncol Res Source Type: research
Authors: Personeni N, Rimassa L, Pressiani T, Smiroldo V, Santoro A Abstract Introduction: The randomized, placebo-controlled, phase III CELESTIAL trial demonstrated statistically and clinically significant improvement in overall survival with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. Most frequently reported adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea. Areas covered: In this review we analyze and discuss preclinical and clinical data of cabozantinib. We summarize e...
Source: Expert Review of Anticancer Therapy - Category: Cancer & Oncology Tags: Expert Rev Anticancer Ther Source Type: research
Authors: Carrier P, Debette-Gratien M, Jacques J, Loustaud-Ratti V Abstract The global population is aging, and so the number of older cirrhotic patients is increasing. Older patients are characterised by a risk of frailty and comorbidities, and age is a risk factor for mortality in cirrhotic patients. The incidence of non-alcoholic fatty liver disease as an aetiology of cirrhosis is increasing, while that of chronic viral hepatitis is decreasing. Also, cirrhosis is frequently idiopathic. The management of portal hypertension in older cirrhotic patients is similar to that in younger patients, despite the greater ri...
Source: World Journal of Hepatology - Category: Gastroenterology Tags: World J Hepatol Source Type: research
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Source: Annals of Hepatology - Category: Gastroenterology Tags: Ann Hepatol Source Type: research
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Source: International Journal of Hyperthermia - Category: Internal Medicine Tags: Int J Hyperthermia Source Type: research
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Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Rattus norvegicus Source Type: research
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Source: Digestive and Liver Disease - Category: Gastroenterology Authors: Tags: Liver, Pancreas and Biliary Tract Source Type: research
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