First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014.
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Date
2015-08-01Author
Basu, B
Dean, E
Puglisi, M
Greystoke, A
Ong, M
Burke, W
Cavallin, M
Bigley, G
Womack, C
Harrington, EA
Green, S
Oelmann, E
de Bono, JS
Ranson, M
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry. RESULTS: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively. CONCLUSIONS: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses.
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Subject
Humans
Neoplasms
Benzamides
Morpholines
Pyrimidines
Multiprotein Complexes
Administration, Oral
Dose-Response Relationship, Drug
Adult
Aged
Middle Aged
Female
Male
TOR Serine-Threonine Kinases
Drug-Related Side Effects and Adverse Reactions
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2015-03-11
License start date
2015-08
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, 21 (15), pp. 3412 - 3419
Publisher
AMER ASSOC CANCER RESEARCH