Phase 1b/2 roginolisib PI3K-delta inhibitor with sequential obinutuzumab and venetoclax after BTK inhibitors in CLL

Dana-Farber Cancer Institute is running a Phase 1b/2, open-label, single-arm study testing roginolisib (IOA-244), a selective, allosteric PI3K-delta inhibitor developed by iOnctura, in relapsed or refractory chronic lymphocytic leukemia following prior covalent BTK-inhibitor therapy. Patients initially receive oral roginolisib with obinutuzumab, a CD20-directed antibody, for six 28-day cycles. Beginning in cycle 7, obinutuzumab is replaced by venetoclax, a BCL-2 inhibitor, with standard dose escalation. The Phase 1b portion establishes a tolerable roginolisib dose, while Phase 2 evaluates treatment response and the ability to achieve undetectable measurable residual disease (uMRD), meaning no residual leukemia is detected using a test with a defined sensitivity threshold. The scientific rationale is to combine selective PI3K-delta blockade with antibody-based B-cell depletion, followed by BCL-2 inhibition to deepen remissions. Preclinical research has shown synergy between roginolisib and venetoclax, but whether this translates into more durable responses remains unproven. Safety is particularly important given the immune-related toxicities historically associated with PI3K-delta inhibitors and the tumor lysis risk of venetoclax. Current options after covalent BTK-inhibitor progression include venetoclax-based regimens and the noncovalent BTK inhibitor pirtobrutinib. This study asks whether a structured, sequential approach can provide deeper disease control without unacceptable toxicity.