Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial
| Autor: | Gerald Steven Falchook, Peter Ansell, Wijith Munasinghe, Mark J. Ratain, Razelle Kurzrock, Michael L. Maitland, Sanja Karovic, David S. Hong, Ly M. Nguyen, Elizabeth Hoening, Guinan K. Lian, Joann P. Palma, Linda Janisch, Mark D. McKee, Cherrie K. Donawho, Sarina Anne Piha-Paul, Shekman Wong |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research Maximum Tolerated Dose Oncology and Carcinogenesis Aurora B kinase Aminopyridines Pharmacology Article Dose-Response Relationship 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Neoplasms 80 and over medicine Humans Oncology & Carcinogenesis Adverse effect Protein Kinase Inhibitors Aged Aged 80 and over Dose-Response Relationship Drug business.industry Phenylurea Compounds Middle Aged medicine.disease Clinical trial Dose–response relationship 030104 developmental biology Treatment Outcome Oncology Tolerability 030220 oncology & carcinogenesis Pharmacodynamics Adenocarcinoma Female Drug business |
| Zdroj: | Maitland, ML; Piha-Paul, S; Falchook, G; Kurzrock, R; Nguyen, L; Janisch, L; et al.(2018). Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial. BRITISH JOURNAL OF CANCER, 118(8), 1042-1050. doi: 10.1038/s41416-018-0020-2. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/6cc4x3jv British Journal of Cancer British journal of cancer, vol 118, iss 8 |
| DOI: | 10.1038/s41416-018-0020-2. |
| Popis: | BACKGROUND:Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. METHODS:Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle. RESULTS:Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. CONCLUSIONS:In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue. CLINICAL TRIAL REGISTRATION:NCT01110486. |
| Databáze: | OpenAIRE |
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