Reference Detail

Ref Type Journal Article
PMID (25805799)
Authors 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
Title First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 21
Issue 15
Date 2015 Aug 01
URL
Abstract Text 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.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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 act mut estrogen-receptor positive breast cancer predicted - sensitive Vistusertib Phase I Actionable In a Phase I trial, Vistusertib (AZD2014) demonstrated safety and preliminary efficacy in patients with advanced solid tumors, including a patient with ER-positive breast cancer harboring an ERBB2 activating mutation (PMID: 25805799). 25805799
PDGFRA act mut pancreatic cancer predicted - sensitive Vistusertib Phase I Actionable In a Phase I trial, Vistusertib (AZD2014) demonstrated safety and preliminary efficacy in patients with advanced solid tumors, including a patient with pancreatic cancer harboring a PDGFRA activating mutation (PMID: 25805799). 25805799