TY - JOUR
T1 - Phase i studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers
AU - Cortes, Jorge
AU - Tamura, Kenji
AU - Deangelo, Daniel J.
AU - De Bono, Johann
AU - Lorente, David
AU - Minden, Mark
AU - Uy, Geoffrey L.
AU - Kantarjian, Hagop
AU - Chen, Lisa S.
AU - Gandhi, Varsha
AU - Godin, Robert
AU - Keating, Karen
AU - McEachern, Kristen
AU - Vishwanathan, Karthick
AU - Pease, Janet Elizabeth
AU - Dean, Emma
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Background: 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. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. 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. 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. 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.
AB - Background: 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. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. 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. 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. 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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U2 - 10.1038/s41416-018-0082-1
DO - 10.1038/s41416-018-0082-1
M3 - Article
C2 - 29765150
AN - SCOPUS:85046889218
SN - 0007-0920
VL - 118
SP - 1425
EP - 1433
JO - British journal of cancer
JF - British journal of cancer
IS - 11
ER -