131P - Safety and clinical efficacy of Roginolisib (IOA-244), the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3K_)

Background

The highly selective oral allosteric modulator of PI3Kδ, roginolisib, has a unique safety and pharmacodynamic profile showing immune modulation in patients with solid tumours.

Methods

IOA-244 was investigated in a two-part FIH study: Part A explored daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with solid tumours and Follicular Lymphoma (FL). Part B confirmed the 80 mg QD as the recommended Phase 2 dose in uveal melanoma (UM) pts. Primary objective: Safety. Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); radiographic responses (RECIST 1.1. or Lugano); PFS and OS. Exploratory studies: changes in circulating immune cells by mass cytometry (Cytometry by Time of Flight; CyTOF); response assessments by radiomics and blood-based proteins.

Results

Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts with uveal (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Part A NHL-FL pts (completed): 8 pts at 20 mg (n=4) and 80 mg (n=4). At 80 mg, 2/4 pts (50%) had PR as per Lugano criteria. Safety: No treatment-emergent adverse events (TEAE) led to study drug discontinuation, immune related toxicity, or a Dose Limiting Toxicity. UM evaluation (recruitment completed): 29 pts (Part A: 9 pts; Part B1/2: 20 pts; total 29 pts), of which 23 pts were treated at 80 mg QD. Mean time on treatment: 9.6 mo (range: 1.5-35.3 mo). ORR (RECIST 1.1): PR: 1/29 (3%); SD: 20/29 (69%). Median OS for Part A: 20.8 mo (7/9 with 2 pts alive); Part B: not determined; 1-year OS rate: Part A: 66.7%; Part B1: 71.4%, B2: ongoing. Exploratory Investigations: Radiomics-based studies showed mixed responses in CT images. Pts with reduction of plasma soluble CTLA-4 exhibited a reduction in blood T_reg cells, while increased plasma IL-15 levels accompanied an increase in CD8⁺ T and NK cells. Patients with RECIST 1.1 defined SD at Cycle 5 (∼4.5 mo of treatment): stable LDH levels, increased plasma levels of IFNg and IFNg-induced proteins.

Conclusions

Roginolisib is well tolerated at the 80 mg dose. Long term administration (>6 months) translates to encouraging OS in UM and lymphoma pts.

Clinical trial identification

NCT04328844.

Legal entity responsible for the study

iOnctura SA.

Funding

iOnctura SA.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi. M. Simonelli: Financial Interests, Personal, Advisory Board: Incyte, Cytovia; Financial Interests, Personal, Invited Speaker: GSK, Bristol Myers Squibb; Financial Interests, Personal, Other, Data Monitoring Committee: Sanofi. M. Lahn: Financial Interests, Personal, Officer: iOnctura; Financial Interests, Personal, Stocks/Shares: iOnctura. G. Di Conza, T. Hammett, R. Zorrilla, P. Kaur: Financial Interests, Personal, Full or part-time Employment: iOnctura. T. Lakshmikanth: Financial Interests, Personal, Stocks/Shares, Cofounder and shareholder in Cytodelics AB, Sweden with no remuneration: Cytodelics AB. M. Occhipinti: Financial Interests, Personal, Full or part-time Employment: Radiomics. P. Spiliopoulou: Financial Interests, Personal, Invited Speaker: Pfizer. T.R.J. Evans: Financial Interests, Institutional, Advisory Board, Advisory Board for GI cancers and melanoma (immune checkpoint inhibitors): Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, Invited speaker - GI cancers, melanoma, immunotherapy: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board, Advisory Boards - GI cancers, melanoma: Roche / Genentech; Financial Interests, Institutional, Invited Speaker, Invited speaker GI cancer, melanoma: Roche / Genentech; Financial Interests, Institutional, Advisory Board, Advisory Board (Lenvatinib): Eisai; Financial Interests, Institutional, Invited Speaker, Speaker's fees (lenvatinib): Eisai; Financial Interests, Institutional, Advisory Board, advisory board: MSD, AstraZeneca, Bayer, Bicycle Therapeutics, Clovis; Financial Interests, Institutional, Invited Speaker, Speaker's fees: MSD, AstraZeneca, Bayer; Financial Interests, Institutional, Advisory Board, Advisory board: Nucana; Financial Interests, Institutional, Invited Speaker, speaker's fees: Nucana; Financial Interests, Institutional, Advisory Board, advisory board; Chair of Scientific Advisory Council (HCC & MIV-818): Medivir; Financial Interests, Institutional, Invited Speaker, speaker's fees (and presentation to potential investors): Medivir; Financial Interests, Personal, Other, Support to attend international conferences: Bristol Myers Squibb, Roche / Genentech, MSD, Nucana, Bayer, Celgene, Pierre Fabre; Financial Interests, Institutional, Advisory Board, Advisory Board for Upper GI Cancer: Ascelia; Financial Interests, Institutional, Advisory Board, Advisory Board for Oesophageal Cancer: Seagen; Financial Interests, Institutional, Coordinating PI, Educational grant (supply of study agents) for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Local PI, reimbursement of study costs for commercial studies: Astellas, Bayer, Basilea, Celgene, GSK, Roche, Medivir, Starpharma, Immunocore, Novartis, Sapience Therapeutics, MiNa Therapeutics, CytomX, Lilly, Bicycle Therapeutics, Sierra, BeiGene, Pfizer, Johnson & Johnson, UCB, Avacta, Codiak, Nurix, T3P; Financial Interests, Institutional, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, MSD, Nucana, Sanofi, iOnctura; Financial Interests, Institutional, Local PI, support for non-commercial investigator-led study: Verastem; Financial Interests, Institutional, Local PI, reimbursement for costs of commercial studies: Boehringer Ingelheim; Financial Interests, Institutional, Local PI, reimbursement of costs of commercial study: Seagen; Non-Financial Interests, Personal, Member, Cancer Society Member: American Society of Clinical Oncology, America Association for Cancer Research, British Association for Cancer Research, Association of Cancer Physicians (UK), European Association for Cancer Research, International Liver Cancer Association; Non-Financial Interests, Personal, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Personal, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Institutional, Product Samples, Supply of investigational and licensed compounds for a non-commercial study for which I'm Chief Investigator: AstraZeneca; Other, Personal, Other, Editor-in-Chief: British Journal of Cancer; Other, Personal, Other, Chair of Independent Data Monitoring Committee for a phase 1 trial - honorarium payable to the employing institution: Genmab; Other, Personal, Other, Chair and panel member, Scientific Evaluation Committee: early phase trials (Amgen, Merck, AstraZeneca): Institut National du Cancer (France). M. Maio: Financial Interests, Personal, Advisory Board: BMS, Roche, GSK, Sanofi, Alfasigma, Amgen, Sciclone, Eli Lilly, MSD, Incyte, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Stocks/Shares: Epigen, Theravance. All other authors have declared no conflicts of interest.