Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not considered curable outside of allogeneic stem cell transplantation. Significant advances have been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. While response to ibrutinib has been high with therapy well-tolerated overall, some patients have relapsed while others have been taken off therapy for toxicity or other reasons. In addition, although remissions are durable in many patients, very few patients achieve a complete response (CR), and minimal residual disease (MRD) negativity on single agent ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as targeted therapies such as venetoclax that attainment of a CR is associated with longer progression free survival (PFS), it is likely that deepening responses associated with ibrutinib will result in more durable remissions. Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in BTK, the other is through a variety of mutations in the immediate downstream target of BTK, PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy. Subjects will receive SNX-5422 (56 mg/m2) in the morning once every other day for 21 days (11 doses), followed by a 7-day drug-free period. Subjects will continue to receive daily oral ibrutinib at their established dose level in the afternoon