A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors
| Autor: | T.R.J. Evans, Malcolm R Ranson, Ruth Plummer, Alastair Greystoke, Martijn P. Lolkema, L Ottesen, Sarah Slater, Jan H.M. Schellens, Emma Dean, Petronella O. Witteveen, M Megui-Roelvink, M Flynn, Larisa Reyderman, B. Milojkovic Kerklaan, F. Y.F.L. de Vos, Rebecca Kristeleit |
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| Přispěvatelé: | Sub Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Medical Oncology |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Indoles Integrin alpha2 Administration Oral Angiogenesis Inhibitors Pharmacology Gastroenterology Food-Drug Interactions 0302 clinical medicine Neoplasms Pharmacology (medical) Sulfonamides Cross-Over Studies Middle Aged Food effect Gene Expression Regulation Neoplastic Treatment Outcome Oncology 030220 oncology & carcinogenesis Female medicine.symptom Adult medicine.medical_specialty Nausea Anemia Neutropenia Maximum tolerated dose 03 medical and health sciences Pharmacokinetics Internal medicine medicine Journal Article Humans RNA Messenger Dosing Adverse effect Aged Dose-Response Relationship Drug business.industry Integrin-α2 medicine.disease Crossover study Aromatic sulfonamide E7820 030104 developmental biology Pharmacodynamics business |
| Zdroj: | Investigational New Drugs, 34(3), 329–337. Kluwer Academic Publishers Investigational New Drugs, 34(3), 329. Kluwer Academic Publishers Investigational New Drugs, 34(3), 329-337. Kluwer Academic |
| ISSN: | 0167-6997 |
| Popis: | UNLABELLED: Introduction E7820 is an orally administered sulfonamide that inhibits alfa-2-integrin mRNA expression. Pre-clinically E7820 showed tumor anti-angiogenic effects in various tumor cell lines and xenograft mouse models. Human daily dosing of 100 mg QD had previously been shown to be safe and tolerable. Methods The study consisted of two parts: Part A (food effect) and Part B (determination of maximum tolerated dose (MTD) for bi-daily (BID) dosing). E7820 dosing started at 50 mg BID with planned escalation to 60, 80 and 100 mg BID every 28 days. Results Fifteen patients were enrolled in Part A and 26 in Part B. The most frequent adverse events of all grades were constipation, diarrhea, nausea, and fatigue while anemia, neutropenia, and fatigue were most frequent grade ≥3 toxicities. At dose-level 60 mg BID, two patients experienced dose-limiting toxicities (grade 3 neutropenic sepsis and grade 4 neutropenia). Therefore the recommended dose (RD) was 50 mg BID. Food had no effect on E7820 exposure. E7820 exposure following twice daily administration was dose-proportional. Expression of platelet integrin-α2 measured as a response biomarker in Part B, generally decreased by a median 7.7 % from baseline following treatment with 50 mg BID E7820. Reduction was most pronounced within 1-week post treatment. The median duration of treatment was median 54, range 20-111 days. The best overall response in any treatment group was stable disease (SD): 23.1 % in Part A (100 mg QD); at the RD 66.7 % (12 of 18 patients) and 40 % in the 60 mg BID group in Part B. CONCLUSIONS: Food had no effect on E7820 exposure. A dose of 50 mg BID was considered the MTD. Treatment with E7820 is safe and tolerable with 2/3 of patients (66.7 %) at MTD having SD as their best response. |
| Databáze: | OpenAIRE |
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