title: A phase I, dose escalation, pharmacodynamic, pharmacokinetic, and food-effect study of α2 integrin inhibitor E7820 in patients with advanced solid tumors.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Clinical Pharmacology, Division of Internal Medicine, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Milojkovic Kerklaan
authors.affiliation: The Beatson West of Scotland Cancer Centre, University Glasgow, Glasgow, UK.
authors.forename: S
authors.initials: S
authors.lastname: Slater
authors.affiliation: University College London Hospital, London, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Flynn
authors.affiliation: The Christie NHS Foundation Trust / University of Manchester, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Greystoke
authors.affiliation: Department of Medical Oncology, Cancer Center, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: P O
authors.initials: PO
authors.lastname: Witteveen
authors.affiliation: Department of Clinical Pharmacology, Division of Internal Medicine, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Megui-Roelvink
authors.affiliation: Department of Medical Oncology, Cancer Center, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: de Vos
authors.affiliation: The Christie NHS Foundation Trust / University of Manchester, Manchester, UK.
authors.forename: E
authors.initials: E
authors.lastname: Dean
authors.affiliation: Eisai Inc, Woodcliff Lake, NJ, USA.
authors.forename: L
authors.initials: L
authors.lastname: Reyderman
authors.affiliation: Eisai Ltd, Hatfield, UK.
authors.forename: L
authors.initials: L
authors.lastname: Ottesen
authors.affiliation: The Christie NHS Foundation Trust / University of Manchester, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Department of Medical Oncology, Cancer Center, University Medical Centre Utrecht, Utrecht, The Netherlands.|Erasmus Medical Center Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M P J
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Sir Bobby Robson Cancer Trials Research Centre Newcastle, Newcastle, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: University College London Hospital, London, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Kristeleit
authors.affiliation: The Beatson West of Scotland Cancer Centre, University Glasgow, Glasgow, UK.
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
authors.affiliation: Department of Clinical Pharmacology, Division of Internal Medicine, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. j.schellens@nki.nl.|Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. j.schellens@nki.nl.
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D018565:Food-Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D039421:Integrin alpha2 / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D039421:Integrin alpha2; D012333:RNA, Messenger; D013449:Sulfonamides; C468872:N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzene-sulfonamide
keywords: Aromatic sulfonamide; E7820; Food effect; Integrin-α2; Maximum tolerated dose; Pharmacokinetics