Paul Nathan, MBBS, PhD, MRCP
The randomized phase 2 OCULE-01 trial (NCT06717126) is evaluating the efficacy of roginolisib, a novel non-ATP competitive allosteric modulator of PI3Kδ, in patients with metastatic uveal melanoma.1
The trial builds on results from the two-part phase 1 DIONE-01 study (NCT04328844), which first assessed continuous daily dosing of roginolisib in 24 patients with pretreated solid tumors and follicular lymphoma, followed by a dose-confirmation cohort in 20 patients with uveal melanoma.2
Roginolisib was well tolerated at the recommended phase 2 dose of 80 mg, with less than 7% of grade 3/4 treatment-emergent adverse effects deemed related to the agent. No immune-mediated or dose-limiting toxicities were reported, and, unlike prior PI3Kδ inhibitors, no dose modifications were required. The agent demonstrated long-term tolerability, with treatment durations extending up to 4.5 years.
Among 29 patients with uveal melanoma enrolled across both DIONE-01 cohorts, the median overall survival (OS) was 16 months. This exceeded the 7-month median OS historically observed with second-line immunotherapy, according to the drug’s developer, iOnctura. Moreover, the median progression-free survival (PFS) was 5 months compared with less than 3 months in historical controls. Translational analyses demonstrated reductions in immune-suppressive cell populations and chemokines, decreases in circulating tumor DNA from uveal melanoma–associated clones, and suppression of PI3K-related signaling, which is consistent with a shift toward a more activated tumor immune microenvironment.
In OCULE-01, approximately 85 adults with disease progression following at least 1 prior therapy will be randomly assigned to receive either roginolisib at a dose of 80 mg or 40 mg daily, or investigator’s choice of standard therapy. The primary end point is overall survival, with secondary end points including PFS, objective response, duration of response, disease control, safety, pharmacokinetics, healthcare utilization, and quality-of-life measures.
In an interview with OncLive®, Paul Nathan MBBS PhD BA FRCP, a consultant medical oncologist at Mount Vernon Cancer Centre in England, emphasized early-phase findings validating the mechanistic rationale for targeting PI3Kδ in metastatic uveal melanoma; the need for randomized data to determine whether roginolisib can deliver clinically meaningful survival gains in this rare malignancy; and how OCULE-01 aims to address this question by directly comparing the agent with established agents in a patient population with limited treatment options.
OncLive: What was the rationale for conducting this analysis?
Nathan: This pathway is of real interest in tumors that appear to have an immunosuppressed phenotype. What we know about this pathway is that there is a rare, inherited condition that leads to an overactivation of the PI3K pathway, which results in patients being immunosuppressed. It turns out that this pathway appears activated in several tumors and may be involved in suppressing immune responses to the tumor.
We see changes in the balance of T regulatory [Treg] cells compared with cytotoxic T cells, as well as other changes in the immune microenvironment, that lead to suppressed immune responses.
What is the mechanism of action of roginolisib?
Roginolisib is a small-molecule inhibitor of PI3K-δ, which is an isoform of the PI3K enzyme. Early data show that it appears to change the immune microenvironment in cancers to be more activated and less suppressed. We see reductions in Treg infiltrate and changes in myeloid-derived suppressor cells as well.
Uveal melanoma is an area of high unmet need, high in terms of the extent of the need rather than the number of patients, because it is a relatively rare disease. For these patients, we struggle to [maintain long-term disease control], and we know that uveal melanoma tumors have an immunosuppressed microenvironment.
Early data with roginolisib in uveal melanoma [suggest an] association with reversal of Treg-to-CD8 ratios but also show early signs of clinical benefit in early-phase clinical studies, with some patients doing better than expected.
This ongoing randomized phase 2 trial is comparing roginolisib with the standard of care [SOC] in patients who have progressed after prior immunotherapy. The primary end point is overall survival, [which is] a robust end point, and we’ve just opened a number of sites in Europe,
What is the design of this phase 2 trial?
Patients are randomized to receive either roginolisib at the full 80-mg dose, a lower 40-mg dose that could be escalated to 80 mg, or the SOC. Secondary end points include clinical outcomes and translational measures, with mandated tumor biopsies at baseline and after a defined period of drug exposure to evaluate effects on the tumor microenvironment, and [hopefully] that will tell us a lot about whether this drug is doing what we want it to do in the tumor microenvironment.
References
- Nathan PD, Maria A, Piulats JM, et al. A phase II randomised study to evaluate the antitumour activity of roginolisib, a novel non-ATP competitive and allosteric modulator inhibiting PI3Kδ, in patients with metastatic uveal melanoma (OCULE-01). J Clin Oncol. 2025;43(16_suppl).doi:10.1200/jco.2025.43.16_suppl.tps9613
- iOnctura reaches new clinical milestones in uveal melanoma. News Release. iOnctura. November 12, 2024. Accessed August 15, 2025. https://www.synconaltd.com/news-insights/news/ionctura-reaches-new-clinical-milestones-in-uveal-melanoma/