On May 27, 2022 iOnctura SA, a clinical-stage oncology company targeting key resistance mechanisms in solid tumours, reported that it will present at the 2022 ASCO (Free ASCO Whitepaper) (American Society of Clinical Oncology) Annual Meeting, taking place June 3-7 in Chicago, new interim Phase I data from completed study Part A and ongoing study Part B showing stable disease and improved overall survival compared to historical controls, with IOA-244 treatment (Press release, iOnctura, MAY 27, 2022, View Source [SID1234615207]).

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"We observed, in patients who progressed on prior therapies, that IOA-244 stabilized their disease and halted the progression after we had exhausted all prior therapies," said Dr Jeff Evans, Professor of Translational Cancer Research and Clinical Lead of the Institute of Cancer Sciences, University of Glasgow (UK). "We are pleased to be offering patients such a well-tolerated therapeutic candidate with potentially meaningful clinical benefit."

"Life expectancy in metastatic UM patients refractory to immunotherapy is severely limited: These patients have a median survival of just 7.2 months. Patients receiving the Recommended Phase 2 Dose of IOA-244 in the DIONE-01 study have already demonstrated a median treatment time exceeding this and encouragingly, the majority of patients are continuing on treatment," said Catherine Pickering, PhD, CEO of iOnctura. "The data in this study also show that daily oral IOA-244 has potentially best-in-class tolerability, which has allowed us to continue treating patients without the need for dose alterations. Based on these highly encouraging data in this Orphan indication, and with the full support of our current investors, we are now focusing on raising our Series B venture financing to fuel future development of IOA-244 and the other anti-cancer resistance products in our pipeline"

DIONE-01 is a two-part, first-in-human dose-escalation study evaluating oral IOA-244 in advanced metastatic cancers and as a combination partner for conventional and immune-therapies (ClinicalTrials.gov: NCT04328844). The objective of Part A, now complete, was to determine the safety, tolerability, the biologically effective dose range and consequently the dosage of IOA-244 in solid tumor cancer patients. The subsequent and continuing Part B of the study consists of expansion cohorts of patients with different solid tumor types, including patients with metastatic UM.

The poster presented at ASCO (Free ASCO Whitepaper) by lead author, Prof. Anna Maria Di Giacomo, Department of Medical Oncology, University Hospital of Siena, Italy, shows interim Phase I data in refractory UM patients, confirming safety and tolerability observed in Part A as well as longer than expected overall survival (OS). This OS trend is also being observed in subsequent Part B. Together and across both parts 16 UM patients have been treated to date. The one-year OS rate was 66.7% for patients in Part A (n=9). It is still too early to estimate the 1-year OS rate in Part B (n=7); at 6-months the OS rate is 100%. Significant reduction of Tregs in peripheral blood and tumor tissue was observed confirming the expected mechanism of action of a precision targeted PI3Kδ inhibitor.

"IOA-244 is a therapy which appeals to our patients, who come from various parts of the country. It allows patients to stay at home while receiving a well-tolerated and potentially effective treatment." added Professor Maio, Department of Medical Oncology, University Hospital of Siena, Italy. "We are eager to explore in greater detail the mechanism of action of IOA-244, its contribution in modulating T regulatory cells in cancer patients and applying new imaging approaches to document the effects of this novel immunotherapy."

Details of the presentation:

Title: First-in-human (FIH) phase I study of the highly selective phosphoinositide 3-kinase inhibitor delta (PI3Kδ) inhibitor IOA-244 in patients with advanced cancer: Safety, activity, pharmacokinetic (PK), pharmacodynamic (PD) results.
Type: Poster
Session: Developmental Therapeutics-Molecularly Targeted Agents and Tumor Biology
Time: Sunday, June 5, 2022, 8:00 AM-11:00 AM CDT
PI3Kδ and IOA-244

High expression of PI3Kδ in both cancer cells and in the tumor immune landscape is a contributing factor to many solid tumor types escaping the host’s immune response. This is achieved by tumors, in part, through PI3kδ-mediated upregulation of T regulatory (Treg) cells, making the tumors "cold", or difficult to detect by the body’s immune system. IOA-244 selective inhibition of PI3kδ blocks proliferation of Treg cells, thus making "cold" tumors "hot", unveiling them to immune system detection and facilitating an anti-tumour immune response.

Exquisite selectivity for PI3Kδ over other PI3 Kinase subtypes, including the closely related PI3Kγ, taken together with IOA-244’s unique semi-allosteric mechanism, which is achieved through differentiated binding to the PI3kδ protein’s kinase domain, represents a unique first-in-class mechanism in solid tumors. This mechanism may allow IOA-244 to lock the kinase in its resting state, preventing initiation of downstream cell signalling pathways normally triggered when it is activated at the cell membrane. The Company is investigating whether IOA-244’s semi-allosteric non-ATP competitive mechanism may block Treg upregulation and simultaneously avoid affecting other signalling cascades that may lead to toxicities. Other PI3kδ inhibitors are thought to act on PI3kδ by blocking the ATP pocket without preventing the kinase from being activated at the cell membrane.

Uveal melanoma (UM) is a rare malignancy arising within the uveal tract of the eye. There are approximately 7,000 newly diagnosed cases of uveal melanoma each year (around 2,000 in the United States). Over 50% of patients will progress to metastatic disease. Median overall survival for metastatic patients refractory to immunotherapy, the population included in the DIONE-01 trial, is approximately 7 months.