title: A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort.
abstract: JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22%, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA. theresa.werner@hci.utah.edu.|Department of Medicine, Oncology Division, University of Utah School of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT, 84112, USA. theresa.werner@hci.utah.edu.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Werner
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Wade
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Department of Oncologic Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Boucher
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Jesal
authors.initials: J
authors.lastname: Patel
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Luebke
authors.affiliation: Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D000068338:Everolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D010865:Pilot Projects; D011446:Prospective Studies; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors* / Q000097:blood; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: C561574:1-(1-(2-amino-pyridin-4-ylmethyl)-1H-indol-4-yl)-3-(5-bromo-2-methoxyphenyl)urea; D007211:Indoles; D010671:Phenylurea Compounds; D000068338:Everolimus; C000588866:KDR protein, human; D036224:Receptor, EphB4; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Everolimus; JI-101; Ovarian cancer; VEGF