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

• Published in: British journal of cancer Vol. 118; no. 11; pp. 1425 - 1433
• Main Authors: Cortes, Jorge, Tamura, Kenji, DeAngelo, Daniel J, de Bono, Johann, Lorente, David, Minden, Mark, Uy, Geoffrey L, Kantarjian, Hagop, Chen, Lisa S, Gandhi, Varsha, Godin, Robert, Keating, Karen, McEachern, Kristen, Vishwanathan, Karthick, Pease, Janet Elizabeth, Dean, Emma
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2018; Nature Publishing Group UK
• Subjects: Acute myeloid leukemia; Adult; Aged; Aged, 80 and over; Biological activity; Biphenyl Compounds - administration & dosage; Biphenyl Compounds - adverse effects; Biphenyl Compounds - pharmacology; Blood cancer; Cytochrome P-450 CYP3A - metabolism; Enzyme inhibitors; Fatigue; Female; Gene Expression Regulation, Neoplastic - drug effects; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - metabolism; Hematology; Humans; Integration; Leukemia; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Patients; Pharmacodynamics; Pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacology; Solid tumors; Thiazolidines - administration & dosage; Thiazolidines - adverse effects; Thiazolidines - pharmacology; Toxicity; Tumorigenesis; Tumors; Up-Regulation; Viruses; Vomiting; Young Adult
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-018-0082-1

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. 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. 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. 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.