A dose-escalation and pharmacodynamic study of AT9283 in patients with refractory solid tumours

Abstract

2519 Background: AT9283, a multitargeted kinase inhibitor, inhibits tyrosine and serine/threonine kinases with an IC50 of <10 nM including Aurora A and B, JAK 2 and 3 Tyk2, RSK2, Ret, Mer, Yes and GSK3 beta. Exposure of solid tumor cell lines to AT9283 induces an “aurora inhibitory” phenotype creating large aneuploidal cells with limited replication potential. Cell survival decreases with increased duration of exposure. Methods: A phase I dose escalation study was performed using a 72 hour iv infusion every 3 weeks using a standard “3+3” design. Epidermal skin biopsies were performed for immunohistochemistry at screening and 48 hours into first infusion. Serum samples were taken during and post infusion for quantification of the apoptosis marker cleaved cytokeratin. Results: Twenty-two patients (pts) have been treated with a median age of 63 (range 33–77 years) (6 F). Biological evidence of activity was seen across all dose levels with a dose dependent reduction in histone H3 phosphorylation, incomplete inhibition in 2/3 pts at dose level 1, complete inhibition in 2/3 pts at dose level 2 and inhibition in 3/3 pts (2 complete) at dose level 3. Reduction in phosphohistone H3 was accompanied by stabilisation of p53 which was more marked in pt samples exhibiting complete inhibition. Reduction in Ki67 staining and increases in the levels of cleaved cytokeratin in serum was seen in pts receiving a dose of 6 mg/m2/day. A plateaux steady state plasma concentration was achieved at all dose levels, exposure increased linearly with dose. The maximum tolerated dose is 27 mg/m2/72 hours and dose limiting toxicity observed to date has been febrile neutropenia. The best response to date is stable disease with three pts receiving at least six cycles of therapy (squamous cell carcinoma of the lung, colorectal adenocarcinoma [2]). Conclusions: The MTD of AT9283 administered as a 72 hour infusion is 9 mg/m2/day. Febrile neutropenia is the dose limiting toxicity and treatment results in significant disease stabilisation in a proportion of patients. Dosing Summary Dose level (mg.m2.day) Number of patients treated Number of cycle (median) Dose limiting toxicities 1 (1.5) 3 2–7 (2) None 2 (3) 3 1–4 (4) None 3 (6) 3 1–2 (2) None 4 (12) 6 1–6 (ongoing) (1) Febrile neutropaenia (3) 5 (9) 7 1–2 (ongoing) (tbc) None Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Astex Therapeutics Limited