53P - Characterization of the non-ATP competitive PI3Kdelta inhibitor IOA-244 in lymphoma models: From single agent to combination screen and clinical investigation

Background

IOA-244 is a highly selective PI3Kδ inhibitor with a differentiated chemical mechanism of action from other PI3K inhibitors. IOA-244 is currently being investigated in patients with solid tumors and lymphoma (NCT04328844). Here, we present preclinical and initial clinical data in lymphomas.

Methods

Anti-proliferative activity by MTT assay at 72h. Transcriptome analysis by total and targeted RNA-Seq on Illumina platform. Follicular lymphoma patients (pts) were treated at 20 mg and 80 mg QD continuous dosing and assessed for safety.

Results

IOA-244 showed moderate dose-dependent anti-proliferative activity, measured as area under the curve, across 66 human B and T cell lymphoma models, with IC50s < 10 mM in 18 cell lines. The activity correlated with PI3Kδ expression as measured by total RNA-Seq (R²=0.18, P=0.0009; 59 B and T cell lymphomas) or by HTG EdgeSeq Oncology Biomarker panel (R²=0.13, P=0.028; 36 B cell lymphomas). In MCL SP53 cells, IOA-244 (5μM; 24, 48, 72h) downregulated BCR, MYD88, NF-κB, MTOR and NOTCH signaling and upregulated cell cycle arrest genes (adj.P<10^-10). Changes overlapped with signatures obtained with other PI3K and BTK inhibitors (adj.P <10^-10). IOA-244 was then combined with 474 compounds (each given at 5μM) in two cell lines (MCL, SP-53; cutaneous T cell lymphoma, HH) and increased anti-proliferative activity was observed for combinations with inhibitors of other kinases, chemotherapy as well as metabolic and nuclear targets. NHL-FL pts treated with 20mg QD (4/4; 2 female and 2 males) and 80mg QD daily (4/4; 3 female and 1 male) had no DLT. Transient platelet reduction (G3) (N=1), AST/ALT elevation (G2) and Neutropenia (G3) (N=1) were observed in 3/8 pts, which returned to baseline without dose modifications.

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.

Clinical trial identification

NCT04328844.

Editorial acknowledgement

Legal entity responsible for the study

IOnctura SA.

Funding

IOnctura SA.

Disclosure

F. Bertoni: Financial Interests, Institutional, Other, consultancy: Helsinn, Menarini; Financial Interests, Institutional, Other, member of the Advisory Board: Phi Pharma; Financial Interests, Personal, Other, co-inventor of patent WO2019185117A1: Fondazione per l'Istituto Oncologico di Ricerca (IOR); Financial Interests, Institutional, Funding: ADC Therapeutics, Bayer AG, Cellestia, Helsinn, ImmunoGen, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, PIQUR Therapeutics AG, Oncology Therapeutic Development; Financial Interests, Institutional, Research Grant: Spexis; Non-Financial Interests, Institutional, Product Samples: HTG; Other, Personal, Other, travel grant: Amgen, AstraZeneca, Jazz Pharmaceuticals; Other, Personal, Other, Travel grant: IOnctura SA, Geneva, Switzerland. C. Tarantelli: Other, Institutional, Other: IOnctura. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer; Financial Interests, Institutional, Advisory Board: Janssen, Roche, Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer, Merck, Roche, Novartis, ADC Therapeutics, AbbVie, Bayer, Philogen, Cellestia, AstraZeneca. K. Niewola, G. Di Conza: Financial Interests, Personal, Full or part-time Employment: IOnctura SA. M. Lahn: Financial Interests, Personal, Officer: iOnctura; Financial Interests, Personal, Stocks/Shares: iOnctura. A. Santoro, C. Carlo-Stella: Financial Interests, Institutional, Sponsor/Funding: IOnctura SA. All other authors have declared no conflicts of interest.