Roginolisib in Combination with JAK Inhibitors in Patients with Myelofibrosis Who are Unresponsive to Approved JAK Inhibitors (Study HEMA-MED) – A Trial in Progress

Jasson Villarreal Hernandez,1 Javier Octavio Díaz Carbonero,1 Chiara Paoli,2 Paola Guglielmelli,2 Mario Tiribelli,3 Francesca Palandri,4 Jesus Maria Hernandez-Rivas,5 María Laura Fox,6 Damián Cubillas García de la Torre,7 Graeme Greenfield,8 Ciro Rinaldi,9 Priya Sriskandarajah,10 Claire Harrison,10 Fabrizio Pane,11 Giuseppe Lanzarone,12 Daniela Cilloni,13 Matteo Pacilli,14 Massimo Breccia,15 Michael Lahn,16 Giusy Di Conza,16 Tracey C Hammett,16 Paramjit Kaur,16 Michael Emig,16 Karen M Tonge,16 Mireille Cantarini,16 Johanne Polasek,16 Alessandro Lucchesi,17 Armando Santoro,18 Alessandro Maria Vannucchi21Hematología Clínica, Institut Català d’Oncologia-Hospital Duran i Reynals, L’Hospitalet del Llobregat, Barcelona, Spain; 2Centro di Ricerca e Innovazione per le Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera Universitaria (AOU) Careggi of the University of Florence, Florence, Italy; 3Division of Hematology and Bone Marrow Transplantation (BMT), Department of Medicine of the University of Udine and Azienda Sanitaria Universitaria (ASU) Friuli Centrale, Udine, Italy; 4Dipartimento di Ematologia "Seràgnoli”, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) of the Azienda Ospedaliero-Universitaria (AOU) Bologna, Bologna, Italy; 5Department of Hematology, Hospital Universitario de Salamanca, Salamanca, Spain; 6Hematology and Hemotherapy Department, Vall d’Hebron University Hospital, Barcelona, Spain; 7START Madrid Phase I Unit, Hospital Sanchinarro, Madrid, Spain; 8Johnston Cancer Research Centre, Queen’s University Belfast, Belfast, UK; 9Department of Hematology, United Lincolnshire Teach Hospitals National Health Services (NHS) Trust, Lincolnshire, UK; 10Guy´s and St. Thomas National Health Services (NHS) Foundation Trust, London, UK; 11Unità Operativa Complessa (UOC) Ematologia e Trapianti di Midollo, Azienda Ospedaliera Universitaria (AOU) Federico II, Naples, Italy; 12Dipartimento di Oncologia e Ematologia U, Azienda Ospedaliera Universitaria (AOU) Citta’ della Salute e della Scienza di Torino, Turin, Italy; 13Struttura Complessa a Direzione Universitaria (SCDU) Ematologia, Azienda Osperaliera (AO) Ordine Mauriziano di Torino, Turin, Italy; 14Unità Operativa Complessa (UOC) Ematologia, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio, Calabria, Italy; 15Department of Translational and Precision Medicine, Azienda Ospedaliera Universitaria (AOU) Sapienza University Policlinico Umberto I, Rome, Italy; 16iOnctura Research and Development, iOnctura SA, Geneva, Switzerland; 17Hematology Department, Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) E Istituto Romagnolo per Lo Studio Dei Tumori (IRST) "dino Amadori”, Meldola, Italy; 18Hematology and Phase I Department, Cancer Center and Istituto Di Ricovero E Cura a Carattere Scientifico (IRCCS) Humanitas, Rozzano-Milan, ItalyCorrespondence: Michael Lahn, iOnctura Research and Development, iOnctura SA, Geneva, 1202, Switzerland, Tel +41 795066366, Email m.lahn@ionctura.comBackground and Significance: Inhibition of both the phosphoinositide 3-kinase delta (PI3Kδ) pathway and Janus kinase (JAK) signaling decreases proliferation of cells from patients with myelofibrosis (MF). Roginolisib is a novel oral conformation-selective PI3Kδ inhibitor and when combined with JAK inhibitors it shows efficacy in primary progenitor cells isolated from MF patients. The biologically effective dose (BED) previously established at the daily 80 mg dose and corresponding to ≥ 90% target inhibition was well tolerated during the first-in-human (FiH) dose study. This dose of roginolisib was combined with approved JAK inhibitors in MF patients who no longer responded to JAK inhibition.Study Design and Methods: The HEMA-MED trial (NCT06887803) is a prospective, multi-center Phase 1/2 study. The primary objective of this study is to evaluate the tolerability of roginolisib when combined with an approved JAK inhibitor in MF patients. Secondary objectives include: (a) changes in peripheral blood Tregs; (b) splenic response rate (SRR); (c) proportion of patients with a reduction in Total Symptom Score (TSS) as measured by Myelofibrosis Symptom Assessment Form (modified MFSAF version 4). Key Inclusion criteria: (1) diagnosis of primary MF; (2) prior treatment with approved JAK inhibitors for ≥ 3 months and on a stable dose for ≥ 1 month prior to starting the add-on treatment. Furthermore, patients must show an unsatisfactory spleen reduction; (3) active symptoms of MF as demonstrated by the presence of a TSS of ≥ 10; (4) platelet count ≥ 50 × 109/L and haemoglobin ≥ 8 g/dL. The study is actively enrolling at 17 sites in Italy, Spain and United Kingdom.Conclusion: Given the safety profile of roginolisib as monotherapy in patients of the FiH study, the combination of a JAK inhibitor (eg, ruxolitinib) and roginolisib is expected to provide a well-tolerated treatment in patients with MF who are no longer responding to JAK inhibition.Keywords: myelofibrosis, roginolisib, IOA-244, PI3Kdelta, JAK1/2 inhibition, ruxolitinib, momelotinib, resistance mechanism