roginolisib (IOA-244) / iOnctura - LARVOL DELTA

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). (ASCO 2025) - P2 | "A final analysis will be performed to assess efficacy after 72 patients become evaluable. Study Centres are currently being opened for enrolment."

Clinical • IO biomarker • Metastases • P2 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • PIK3CD

iOnctura starts randomised phase 1/2 trial in lung cancer treatment (PharmaTimes) - "iOnctura has begun a randomized phase 1/2 study investigating its lead asset, roginolisib, in combination with dostarlimab, with or without docetaxel, in advanced non-small cell lung cancer (NSCLC). The first patient has been dosed in the study, which aims to evaluate the safety of the drug combination and its potential in overcoming resistance to standard immunotherapy."

Trial status • Non Small Cell Lung Cancer

PULMO-01: A Study of Roginolisib (IOA-244) in Combination With Dostarlimab With or Without Docetaxel in Metastatic Non Small-cell Lung Cancer (NSCLC) Patients (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • IO biomarker • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL7R

HEMA-MED: A Study of Roginolisib in Combination With Ruxolitinib in Patients With Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors (clinicaltrials.gov) - P1/2 | N=26 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • Myelofibrosis

Molecular profiling of the PI3Kδ inhibitor roginolisib in metastatic uveal melanoma and its correlation with clinical outcomes (AACR 2025) - P1 | "These findings highlight the importance of immune modulation, PI3K/mTOR signaling, and GPCR gene expression in potentially driving treatment outcomes, and encourage further evaluation of Roginolisib in a Phase 2 randomized study."

Clinical • Clinical data • IO biomarker • Metastases • Tumor mutational burden • Cutaneous Melanoma • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CCL2 • CCL22 • CD8 • ENTPD1 • GPRC6A • IFNAR2 • IL15 • PD-1 • PIK3CD • TMB

HEMA-MED: A Study of Roginolisib in Combination with Ruxolitinib in Patients with Myelofibrosis (MF) Who Are Unresponsive to JAK Inhibitors (clinicaltrials.gov) - P1/2 | N=26 | Not yet recruiting | Sponsor: iOnctura

New P1/2 trial • Myelofibrosis

PULMO-01: A Study of Roginolisib (IOA-244) in Combination with Dostarlimab with or Without Docetaxel in Metastatic Non Small-cell Lung Cancer (NSCLC) Patients (clinicaltrials.gov) - P1/2 | N=45 | Not yet recruiting | Sponsor: iOnctura

New P1/2 trial • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • IL7R

iOnctura commences randomized Phase II study in metastatic uveal melanoma (PRNewswire) - "iOnctura...today announces it has dosed the first patient in the randomized Phase II OCULE-01 study investigating lead asset roginolisib in patients with metastatic uveal melanoma (UM), a rare cancer of the eye...The Phase II open label, randomized, parallel-arm OCULE-01 study (NCT06717126), has been designed to assess roginolisib as a monotherapy with the primary objective to evaluate overall survival in patients. The study will have multiple sites across Europe and the US, enrolling approximately 85 patients with metastatic UM, who have progressed following at least one prior therapy."

Trial status • Uveal Melanoma

OCULE-01: A Randomised Phase II Study of Roginolisib in Patients with Advanced/metastatic Uveal Melanoma (clinicaltrials.gov) - P2 | N=85 | Recruiting | Sponsor: iOnctura | Not yet recruiting ➔ Recruiting

Enrollment open • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

iOnctura reaches new clinical milestones in uveal melanoma (PRNewswire) - P1 | N=210 | NCT04328844 | Sponsor: iOnctura | "iOnctura...provides a clinical update on its lead asset, roginolisib. Results from the completed Phase I DIONE-01 study are due to be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) annual congress tomorrow, 12 December at 12:30 CET (presentation 164P)....Median overall survival (OS) was 16 months for the 29 patients with UM treated with roginolisib, who had previously received a median of two prior therapies. This exceeds the median OS of 7 months observed in historical controls in patients receiving immunotherapies as second line treatment. Median progression free survival (PFS) was 5 months for patients treated with roginolisib versus less than 3 months for historical controls."

P1 data • Uveal Melanoma

Roginolisib (IOA-244), the first highly selective oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ), has immuno-modulatory effects associated with clinical benefits in patients with metastatic uveal melanoma (ESMO-IO 2024) - P1 | "GNAQ/GNA11 mutations were observed in 11/12 pts and 3/18 pts were HLA-A02:01 positive. ctDNA was reduced in 10/17 pts of which 6 had a clearance at Week 8.Conclusions Long-term continuous dosing of roginolisib rebalances the immune response at Week 16 by modulating PI3K-δ-targets, of which some have the potential to predict OS."

Clinical • Immunomodulating • Metastases • Eye Cancer • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • AKT1S1 • CD5 • CD8 • CXCL13 • ENTPD1 • GNA11 • GNAQ • HLA-A • IFNAR2 • IL15

Total tumor burden and radiomics to evaluate response in dose escalation studies: Roginolisib (IOA-244), a highly selective PI3Kδ inhibitor in metastatic uveal melanoma patients (ESMO-IO 2024) - P1 | "Baseline and delta radiomic features, particularly shape, intensity and texture, show promise in predicting long-term lesion response. These findings support using volumetric and radiomic analysis for more accurate monitoring of treatment response in metastatic patients."

Clinical • Metastases • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • PIK3CD

OCULE-01: Study of Roginolisib in UM Patients (clinicaltrials.gov) - P2 | N=85 | Not yet recruiting | Sponsor: iOnctura

Metastases • New P2 trial • Eye Cancer • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Baseline and early follow-up radiomics biomarkers for tumor growth in uveal melanoma patients treated with roginolisib (IOA-244) (SITC 2024) - "Generally, the Random Forest models performed better for predicting LRS in both lungs (AUC = 0.76, F1 Score = 0.8 ) and liver (AUC = 0.9, F1 score = 0.83) lesions. For TLVP outcomes, mixed effects models (with 'patient' as a random effect) performed better in the liver (R2 = 0.5) Conclusions Baseline and change at early follow up radiomics hold potential as early response biomarkers in patients with UM treated with Roginolisib."

Biomarker • Clinical • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma

Loss-of-function and gain-of-function genetic screens identify potential biomarkers and combination partners for the highly selective allosteric PI3Kδ inhibitor roginolisib (IOA-244) (EORTC-NCI-AACR 2024) - "Since the latter group contains possible therapeutic targets, we combined roginolisib with the KDM5A inhibitor GSK467 and with PRMT5 inhibitor onametostat in three MCL cell lines (Z138, SP53, SP49), observing synergism/additivity in 3/3 and 2/3 models, respectively. Conclusions. A genome-wide genetic screening identified genes modulating the lymphoma cells' response to the roginolisib, identifying potential biomarkers of response and providing combination partners to be further explored."

Biomarker • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • ARID1A • ARID1B • CCNE1 • CDKN1A • CDKN1C • CHD8 • CREBBP • EP300 • FLI1 • KDM5A • LYN • NFKBIA • NFKBIE • PIK3CD • PLK1 • PTEN • SMARCA4 • SMARCA5 • TNFRSF10A • TOX4 • TP73

A Phase 1/2, Open Label, Study of Roginolisib (IOA-244), an Orally Bioavailable, Selective PI3Kδ Inhibitor in Patients With Refractory/Relapsed Chronic Lymphocytic Leukemia (CLL) in Combination With Venetoclax and Rituximab (clinicaltrials.gov) - P1/2 | N=64 | Not yet recruiting | Sponsor: Jennifer R. Brown, MD, PhD

Combination therapy • New P1/2 trial • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Roginolisib (IOA-244), a first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with metastatic uveal melanoma (ESMO 2024) - P1 | "Uninterrupted administration of roginolisib in mUM pts with advanced malignancies is well tolerated, exhibits immuno-modulatory effects, and in a subset of pts with mUM, shows immune cell activation with associated survival benefit."

Clinical • IO biomarker • Metastases • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • CD63 • CTLA4 • IFNG • IL15 • PIK3CD

DIONE-01: A Study to Assess a PI3Kδ Inhibitor (IOA-244) in Patients With Metastatic Cancers (clinicaltrials.gov) - P1 | N=210 | Active, not recruiting | Sponsor: iOnctura | Trial completion date: Apr 2024 ➔ Mar 2025 | Trial primary completion date: Sep 2023 ➔ Mar 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Eye Cancer • Follicular Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Lymphoma • Melanoma • Mesothelioma • Mucosal Melanoma • Myelofibrosis • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Uveal Melanoma • ALK • BRAF • PD-L1 • ROS1

iOnctura announces expansion of roginolisib clinical trial program to NSCLC (PRNewswire) - "iOnctura...announces expansion of the clinical trial program for lead pipeline asset, roginolisib. Via clinical collaboration agreements with the ETOP IBCSG Partners Foundation and GSK, roginolisib will be evaluated in combination with dostarlimab in NSCLC....Under the terms of the agreement with iOnctura, GSK will supply dostarlimab for use in a randomized Phase II clinical trial in NSCLC patients resistant to first-line checkpoint inhibitor therapy, with or without docetaxel. iOnctura will retain worldwide rights to roginolisib....Phase II study in non-small-cell-lung-cancer (NSCLC) to be run in collaboration with the ETOP IBCSG Partners Foundation across sites in Europe. Study will investigate dostarlimab + roginolisib +/- docetaxel in patients with NSCLC resistant to first-line checkpoint inhibitor therapy."

Licensing / partnership • New P2 trial • Non Small Cell Lung Cancer

iOnctura announces EUR80 million Series B financing to progress pipeline through Phase II trials (PRNewswire) - "iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, today announces that it has closed an EUR80 million Series B financing....iOnctura is developing a portfolio of precision oral small molecules that target cancers in novel ways....The financing will be used to accelerate development of roginolisib for the treatment of uveal melanoma (UM), a rare cancer of the eye with few available treatments....iOnctura plans to commence trials in other cancer indications, including non-small cell lung cancer and primary myelofibrosis, later in 2024."

Financing • New trial • Myelofibrosis • Non Small Cell Lung Cancer • Uveal Melanoma

Roginolisib, an oral, highly selective and allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) in patients with uveal melanoma and advanced cancers. (ASCO 2024) - P1 | "Roginolisib is well tolerated at 80 mg, demonstrates efficacy, and induces phenotypic changes in circulating immune cells. At the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (3% PR; 72% SD)."

Clinical • Metastases • Cutaneous Melanoma • Eye Cancer • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Malignant Pleural Mesothelioma • Melanoma • Mesothelioma • Oncology • Solid Tumor • Uveal Melanoma • CD63 • PIK3CD

The highly selective and oral phosphoinositide 3-kinase delta (PI3K-δ) inhibitor roginolisib induces apoptosis in mesothelioma cells and increases immune effector cell composition. (PubMed, Transl Oncol) - "To this aim, we analyzed the expression of PI3K-δ by immunohistochemistry in specimens from primary MPM, cell viability and death in three different MPM cell lines treated with roginolisib alone and in combination with ipatasertib (AKT inhibitor) and sapanisertib (mTOR inhibitor). Overall, roginolisib induces apoptosis in MPM cells and increases the antitumor immune cell effector function when combined with nivolumab and cisplatin. These results provide first insights on the potential of roginolisib as a therapeutic agent in patients with MPM and its potential in combination with established immunotherapy regimen."

IO biomarker • Journal • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor

Novel Pi3kδ Inhibitor Roginolisib Synergizes with the Bcl-2 Inhibitor Venetoclax in Hematological Malignancies (ASH 2023) - "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."

IO biomarker • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • BCL2L1 • MCL1 • PIK3CD

Updated clinical safety and efficacy data for iOnctura's roginolisib presented at ESMO Immuno-Oncology Congress 2023 (PRNewswire) - P1 | N=210 | NCT04328844 | Sponsor: iOnctura | "iOnctura...today announces clinical results for roginolisib, a first-in-class oral allosteric modulator of PI3Kδ, presented at the ESMO Immuno-Oncology Congress 2023 in Geneva....The poster presentation titled 'Safety and clinical efficacy of Roginolisib (IOA-244), the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ)' demonstrated that roginolisib continues to be well tolerated over long periods of treatment and continues to show a favourable trend in overall survival exceeding the overall survival previously reported with immune checkpoint inhibitors....'We eagerly anticipate a final clinical readout in 2024.'"

P1 data • Uveal Melanoma

Roginolisib a Highly Selective Allosteric Modulator of the Phosphoinositide 3-Kinase Delta (PI3Kδ) in Patients with Refractory/Relapsed Follicular Lymphoma (ASH 2023) - P1 | "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."

Clinical • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Respiratory Diseases • Solid Tumor • Transplantation • PIK3CD