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|Ref Type||Journal Article|
|Authors||Cortes J, Tamura K, DeAngelo DJ, de Bono J, Lorente D, Minden M, Uy GL, Kantarjian H, Chen LS, Gandhi V, Godin R, Keating K, McEachern K, Vishwanathan K, Pease JE, Dean E|
|Title||Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers.|
|Journal||British journal of cancer|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||AZD1208||Phase I||Actionable||In a Phase I trial, AZD1208 treatment was tolerated and demonstrated activity in pharmacodynamic studies, resulted in stable disease for 6 weeks or longer as best objective response in 48% (13/27) of evaluable patients with advanced solid tumor (PMID: 29765150; NCT01588548).||29765150|
|Unknown unknown||acute myeloid leukemia||no benefit||AZD1208||Phase I||Actionable||In a Phase I trial, AZD1208 treatment was tolerated and demonstrated activity in pharmacodynamic studies, but resulted in no clinical response (0/32) in patients with acute myeloid leukemia (PMID: 29765150; NCT01489722).||29765150|
|Unknown unknown||prostate cancer||not applicable||AZD1208||Case Reports/Case Series||Actionable||In a Phase I trial, AZD1208 treatment resulted in considerable decrease of PSA levels in a patient with prostate cancer (PMID: 29765150; NCT01588548).||29765150|