Roginolisib (IOA-244), an orally bioavailable, selective PI3Kδ inhibitor, in combination with venetoclax and rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) Free

Preclinical work established the synergy of BCL-2 inhibitors with phosphoinositide 3-kinase (PI3K) inhibitors in B cell malignancies. Chronic lymphocytic leukemia (CLL) remains an incurable chronic disease with reduced benefit of BCL-2 inhibition following disease progression on Bruton Tyrosine Kinase (BTK) inhibitors. Our group has previously shown promising clinical activity with the combination of the first-generation PI3K inhibitor duvelisib and venetoclax, albeit hampered by PI3Ki-related adverse events.

In contrast to the first generation PI3K inhibitors, roginolisib is a novel, oral, non-ATP competitive, allosteric small molecule inhibitor of PI3Kδ with a unique safety profile. Roginolisib together with venetoclax suppressed downstream PI3K/AKT pathways in preclinical models and we have recently demonstrated ex vivo synergy between roginolisib and venetoclax in CLL patient samples resistant to BTK inhibitors. In its first-in-human study (NCT04328844), 44 patients (36 with solid tumors and 8 with follicular lymphoma) received roginolisib with no drug-associated PI3K inhibitor related toxicities or dose modifications, including in 30% of patients treated longer than 12 months.

This Phase 1/2 study (NCT06644183) is an investigator-sponsored, prospective, single-center, open-label randomized-controlled trial funded by a grant from the United States Department of Defense. In the initial 3+3 safety lead-in (Phase 1), patients will receive roginolisib first at 40 mg QD and then at 80 mg QD, in combination with venetoclax and rituximab (R+Ven+R) as per standard of care. In the Phase 2 part, patients will be randomized 1:1 to receive either venetoclax plus rituximab (Ven+R) or R+Ven+R.

The primary objective is to compare the proportion of patients with undetectable minimal residual disease (uMRD) after treatment with either R+Ven+R, or Ven+R, as measured after 12 months of combined therapy, in bone marrow at a level of 10^-4 by the clonoSEQ® assay. Secondary objectives include continuous evaluation of safety (focused on adverse events of special interest with 1^st generation PI3K inhibitors) and tolerability of R+Ven+R during the Phase 1 lead-in and the randomized Phase 2. Assessment will be based on NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) grading for non-hematologic toxicity, and International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicity. uMRD rate will also be evaluated serially in peripheral blood and bone marrow by flow cytometry for comparison to clonoSEQ. Additional efficacy assessments will be performed using iwCLL criteria (investigator-assessed PFS, ORR, complete response (CR and CRi), and DoR). Exploratory correlative studies will be conducted to assess pharmacodynamic effects of roginolisib including impact on immune cell subsets particularly T cells.

Key inclusion criteria include relapsed/refractory CLL patients who have measurable disease and meet iwCLL criteria for requiring treatment and have received at least two prior therapies for CLL including a covalent BTK inhibitor. Key exclusion criteria include having received prior treatment with venetoclax or PI3K inhibitors in the last 6 months.

The Phase 1 lead-in will consist of dose level -1 (40 mg QD) followed by dose level 1 (80 mg QD). Patients will start with venetoclax dose escalation per standard of care. In cycle 2, roginolisib will be added. DLTs will be evaluated during cycle 2, the first month of therapy with combination Ven, which will continue for 12 months. Monthly rituximab will initiate in cycle 3 for 6 cycles. In Phase 2, patients will be randomized equally (1:1) either to R+Ven+R (Arm A) or to Ven+R (Arm B). In Arm A, roginolisib will be administered at the selected dose from Phase 1 starting at cycle 2 day 1 upon completion of the venetoclax escalation.

The study is currently actively enrolling at one site in the USA at Dana Farber Cancer Institute. At the time of submission of the abstract, the first dose level cohort of patients in Phase 1 was enrolled.

First generation PI3K inhibitors have had limitations in patients with hematologic malignancies. Novel non-ATP competitive, highly selective inhibitors may provide a tailored safe therapy targeting a key biologic pathway in CLL and enable combinations with standard of care treatments in relapsed/refractory CLL.