Janet Elizabeth Pease

Abstract CT147: Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors

AZD1208 is a potent oral ATP-competitive, pan-PIM kinase inhibitor. Here we report the results of 2 Phase 1, open-label, multi-center dose escalation studies, recruiting patients with recurrent or refractory AML or advanced solid tumors including malignant lymphoma. The studies examined the safety, tolerability, pharmacokinetics and preliminary efficacy of AZD1208 in patients including evaluation of pharmacodynamic biomarkers in the AML study. The AML study was a first-in-patient study where 32 patients were treated and the range of treatment duration ranged from 15 to 27 days. In patients with heavily treated AML, AZD1208 was generally well tolerated up to doses of 700 mg QD, but was not tolerated at the 900 mg dose. The most common AEs reported likely to be associated with AZD1208 were nausea (37.5%), diarrhea (21.9%), vomiting (18.8%) and fatigue (18.8%). Three DLTs were reported including 1 case of Guillain-Barre syndrome at the 700mg dose and 2 cases of rash at the 900mg dose. Although there were no AML responses to AZD1208 treatment, reductions in peripheral blasts were seen in 5 patients. Modulation of PIM mediated biomarkers was observed with a greater than 50% reduction in pBAD in 14 out of 20 patients and a reduction in p4EBP1 in 6 out of 14 patients. There was no correlation of biomarker modulation and peripheral blast reduction. The solid tumor study recruited 35 patients with a median treatment duration of 41 days (range of 10-357 days). The best objective response was stable disease. Similar AEs to those seen in the AML study were observed in the solid tumor study. DLTs were reported in 4 patients including 2 patients with fatigue (800mg), increased GGT (240mg) and vomiting (540mg). In this study, AZD1208 was well tolerated as monotherapy at doses up to 700 mg QD, but was not tolerated at 800 mg QD. The MTD of AZD1208 was not determined in either study due to termination of development, however was below 900 mg in the AML study and below 800 mg in the solid tumor study. The PK of AZD1208 in both studies showed similar characteristics and was highly variable and generally dose proportional across the range of 120 mg to 900 mg. In the solid tumor study the absorption following multiple dosing was rapid, exposure showed time-dependent PK and interestingly, the accumulation ratios of exposure decreased with increasing doses. One possible mechanism for the decreased exposure is through increased CYP3A4 activity, demonstrated from a 4β-hydroxycholesterol assay showing that AZD1208 increased CYP3A4 activity after continuous dosing resulting in increased clearance of AZD1208 and perhaps resulting in decreased clinical activity. Overall, AZD1208 was generally well tolerated; however, there was no clear evidence of anti-tumor activity from AZD1208 monotherapy treatment. Citation Format: Jorge Cortes, Kenji Tamura, Daniel J. DeAngelo, Johann de Bono, David Lorente, Mark Minden, Geoffrey L. Uy, Hagop Kantarjian, Karen Keating, Kristen McEachern, Karthick Vishwanathan, Robert E. Godin, Janet Elizabeth Pease, Emma Dean. Phase I studies of AZD1208, a PIM kinase inhibitor, in patients with recurrent or refractory acute myelogenous leukemia or advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT147.

Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers

BackgroundProviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours.MethodsTwo dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208.ResultsSixty-seven patients received treatment: 32 in the AML study over a 120–900u2009mg dose range, and 25 in the solid tumour study over a 120–800u2009mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900u2009mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208.ConclusionsDespite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.