Abstract
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 120–900 mg dose range, and 25 in the solid tumour study over a 120–800 mg 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 900 mg, 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.
Highlights
Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are a family of nuclear and cytoplasmic serine (S)/threonine (T) kinases that regulate apoptosis and control cell cycle progression by phosphorylating substrates such as Bcl-2 antagonist of cell death (BAD),[1,2] p21Cip1/WAF13 and cMyb.[4]PIM kinases appear overexpressed in several tumour types, contributing to oncogenesis.[5,6] For example, PIM1 is overexpressed in ~30% of haematopoietic malignancies, in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia.[7]
PIM1 in T cells induces the formation of lymphoma and increases the rate of lymphoma development in response to Murine Leukaemia Virus.[6]
AZD1208 is a potent, ATP-competitive, pan-PIM kinase inhibitor designed to target PIM1, 2 and 3.11 It has been investigated in preclinical models of AML and prostate cancer.[12,13]
Summary
Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are a family of nuclear and cytoplasmic serine (S)/threonine (T) kinases that regulate apoptosis and control cell cycle progression by phosphorylating substrates such as Bcl-2 antagonist of cell death (BAD),[1,2] p21Cip1/WAF13 and cMyb.[4]PIM kinases appear overexpressed in several tumour types, contributing to oncogenesis.[5,6] For example, PIM1 is overexpressed in ~30% of haematopoietic malignancies, in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia.[7]. Proviral 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. METHODS: Two 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. RESULTS: Sixty-seven patients received treatment: 32 in the AML study over a 120–900 mg dose range, and 25 in the solid tumour study over a 120–800 mg dose range. CONCLUSIONS: Despite 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
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