roginolisib (IOA-244)

P2, N=85, Not yet recruiting, iOnctura

P1; Trial completion date: Apr 2024 --> Mar 2025 | Trial primary completion date: Sep 2023 --> Mar 2025

ConclusionsThe safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kd and functions as a non-ATP competitive inhibitor.

Furthermore, the PK profile subsequently proved to be a decisive factor for achieving selective PI3Kδ inhibition without the toxicities observed in dogs. As the result of the unique PK profile of roginolisib, patients were able to take daily roginolisib without dose modification and showed pharmacodynamic PI3Kδ inhibition over several months without gastrointestinal or dermatologic toxicities.

To further validate this finding, the combination of roginolisib with venetoclax or with another bcl-2 inhibitor S55746 was tested in a broad range of lymphoma cell lines including GRANTA519, JVM2, SP49 (MCL); FARAGE, TMD8 (diffuse large B cell lymphoma); MEC1 (chronic lymphocytic leukemia); MJ (cutaneous T cell lymphoma); and YT (NK lymphoma)...Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls...In addition, roginolisib synergized with venetoclax in lymphoma cell lines and CLL patient samples. Our data support extending this combination strategy to clinical trials in hematological malignancies.

P1; Recruiting --> Active, not recruiting

Material and MethodsWe have used patient derived tumor cells to evaluate roginolisib in combination with immune-targeted or molecularly-targeted therapies to identify synergies that could be translated to future clinical studies.Results and DiscussionsHere, we show that in two ex vivo co-culture models of patient-derived mesothelioma cells with matched PBMC, the addition of roginolisib to cisplatin plus nivolumab specifically increased activated Ki67+/IFNg+ CD8 T cells and M1-like macrophages, and concomitantly decreased Tregs, exhausted TIM3+ CD8 T cells and MDSCs with an overall effect to increase the antitumoral immune response. Our data supports combining roginolisib with checkpoint inhibitors, for example in lung cancers, and targeted molecular therapies such as BCL2 inhibitors in CLL. The mechanistic synergy of these combinations has potential to provide greater patient benefit compared to the use of these medicines as single agents.

In Part A for pts with FL, there were two cohorts: (a) Cohort 1: 20 mg QD daily (4/4; 2 female, 2 male); (b) Cohort 2: 80 mg QD (4/4; 3 female, 1 male). There were no DLT and no dose modifications. The mean time on treatment was 1.9 mo (20 mg QD) and 3.4 mo (80 mg QD), with one patient at the 80 mg still on treatment after 5 mo).

The safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kδ and functions as a non-ATP competitive inhibitor. The observed early signs of clinical activity are promising, alongside the reported non-clinical data on selectivity and combination possibilities.

IOA-244 is a first-in-class non-ATP-competitive, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

Conclusions Single-agent IOA-244 has moderate activity in vitro in lymphoma, correlated with PI3Kδ expression. Given its favorable monotherapy safety profile, IOA-244 may be used in combination with drugs identified in the present pharmacological screen.

P1; N=60 --> 210 | Trial completion date: Apr 2023 --> Apr 2024 | Trial primary completion date: Sep 2022 --> Sep 2023

Legal entity responsible for the study iOnctura SA. Funding iOnctura SA.

P1, N=60, Recruiting, iOnctura