On 11 thApril 2017, the U.S. Food and Drug Administration ( FDA) has cleared an Investigational New Drug ( IND) application by ArQule Inc. to conduct a phase Ia/b trial of ARQ 531 in patients with refractory B-cell malignancies.
ARQ 531 is a potent, orally bioavailable, and reversible inhibitor of wild type and C481S-mutant Bruton’s Tyrosine Kinase (BTK).
CLL, DLBCL, MCL, and WM are driven by BTK. Currently, ibrutinibis the only approved BTK inhibitor; it is irreversible and makes a covalent bond with the C481 residue of the BTK protein. Clinical resistance to ibrutinib has been reported, and it seems that the predominant mechanism of resistance is the BTK C481S mutation. ARQ 531, being a reversible inhibitor, does not interact with the C481 residue and so is an attractive treatment option for patients with C481S-mutant BTK and resistant to irreversible BTK inhibitors.
The phase Ia/b trial is planned to start in Q3 of 2017. The Ia portion of the trial will be a dose escalation study aiming to define a recommended dose in patients with B-cell malignancies. Following this, the phase Ib trial will contain numerous expansion cohorts, including refractory patients harboring the C481S mutation.