First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014

Abstract

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 ngÁh/mL, C max 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.

Pharmacodynamic Biomarker Development for PI3K Pathway Therapeutics

“…Importantly, at the maximum tolerated dose (MTD), the authors also demonstrated reduced levels of phosphorylated S6 (∼20%-100%) in all evaluable posttreatment biopsies and reduction of phosphorylated AKT levels (20%-50%) in 3/4 assessable posttreatment biopsies. 82 In addition to these proof-of-mechanism PD biomarkers, proof-of-concept biomarkers such as reduction of proliferation (Ki67) and reduction in metabolism ( 18 F-FDG PET) also supported evidence of target inhibition in tumor. 82 At the MTD, five of nine patients showed reduction in Ki67 expression of 50%-100%.…”

“…82 In addition to these proof-of-mechanism PD biomarkers, proof-of-concept biomarkers such as reduction of proliferation (Ki67) and reduction in metabolism ( 18 F-FDG PET) also supported evidence of target inhibition in tumor. 82 At the MTD, five of nine patients showed reduction in Ki67 expression of 50%-100%. In addition, 8 of 11 patients showed a reduction of change in maximum standardized uptake value (SUV max ), with three patients attaining a partial response (30% reduction in SUV max ).…”

“…[82][83][84][85][86] In the phase I study of AZD2014, the PD profile demonstrated target engagement in both surrogate and tumor tissues. 82 Proof-of-mechanism biomarkers of mTORC1 and mTORC2 inhibition, such as A 40%-45% reduction in levels of phosphorylated 4E-BP1 in peripheral blood mononuclear cells (PBMCs) and A 37%-62% reduction in phosphorylated AKT in PRP, respectively, were seen at 2 and 8 hours but recovered at 24 hours following a single dose of AZD2014. Therefore, this, together with the PK profile demonstrating an elimination half-life of approximately three hours supported a twice-a-day schedule.…”

Molecular Docking and Pharmacokinetic of Highly Specific Novel Pan-Mtor Inhibitors against Solid Tumors

“…The 3S-3-methylmorpholin is associated with perfect aqueous solubility of AZD2014 [40]. Besides interacting with active side residues few amino acids were present in close proximity Ser-2342, Ser-2165, Lys-2187 and non-conventional residues Gly-2238, Val-2240 that attacked the adenine ring in ATP for hydrogen bonding.AZD2014 is rationally designed having IC50 2.8nM and adverse effects similar to other pan-mTOR inhibitors [19].…”

“…Besides being highly potent against several tumors none of ATP-competitive inhibitors entered clinical phase 3 or available commercially [2,18]. AZD2014, rationally designed pan-mTOR inhibitor currently in phase 1 of clinical trials, display higher specificity over PIKK family and exhibit better therapeutic effects against solid tumors [19][20][21]. AZD8055 the parent molecule is no longer in clinical trials and results are expected [22].…”