First-in-human (FIH) phase I dose escalation study (part A) of the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3Kδ) roginolisib in patients with advanced cancer and dose confirmation in uveal melanoma (part B).
Authors: Di Giacomo Anna Maria , Santangelo Federica , Amato Giovanni , Simonetti Elena , Graham Jill , Lahn Michael M. F. , Di Conza Giusy , Hammett Tracey , Zorrilla Rebeca , Durini Marco , Tan Ziyang , Tadepally Lakshmikanth , Brodin Petter , Occhipinti Mariaelena , Simonelli Matteo , Carlo-Stella Carmelo , Santoro Armando , Spiliopoulou Pavlina , Evans T.R. Jeffry , Maio Michele 
Published: June 2023

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Background: The highly selective oral allosteric modulator of PI3Kδ, roginolisib (IOA-244), blocks the activity of PI3Kδ -dependent signalling, in both tumour cells and Tregs. Methods: Part A explored the continuous daily dosing of roginolisib at 10, 20, 40 and 80 mg in patients (pts) with solid tumours and Follicular Lymphoma (FL). Part B consists of dose confirmation cohorts, including uveal melanoma (UM) pts. Primary objective: safety of the anticipated biologically effective dose (BED), or the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1. or Lugano-based responses; PFS and OS. Exploratory studies: phenotypic changes in circulating immune cells by Cytometry by Time of Flight (CyTOF); response assessments by radiomics; analysis of circulating protein signatures via Olink proteomic. Results: Part A Solid Tumour (completed): Sixteen pts were treated in 4 cohorts, each with 4 pts. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). Only Grade 1 and 2 AEs by CTCAE v5 were observed, including 2 cases of transient (lasting < 24 hrs) diarrhoea and 2 of AST/ALT elevation. Part A FL Cohort (completed): 8 pts were treated at 20 mg (n=4) and 80 mg (n=4). Grade 3 toxicities were transient and observed in 2/8 (25%) pts. 2/4 pts (50%) at the 80 mg had PR as per Lugano criteria. Neither in the solid tumour nor in the haematology pts treatment-emergent adverse events (TEAE) led to study drug discontinuation, immune related toxicity, or a Dose Limiting Toxicity. Subgroup evaluation: UM pts (Part A and Part B): 24 pts (Part A: 9 pts; Part B ongoing: 15 pts), of which 18 pts treated at 80 mg QD (RP2D). Mean time on treatment: 8.6 mo (range: 1.0-27.9 mo). ORR (RECIST 1.1): PR: 1/20 (5%); SD: 16/20 (80%). Median OS for Part A: 20.8 mo (5/9 with 4 pts alive); Part B: not determined; 1-year OS rate: Part A 66.7%; Part B: ongoing. Exploratory Investigations: Radiomics-based evaluation of CT images in pts with solid tumors assessed each metastatic organ, detecting mixed responses; peripheral proteomic evaluation detected changes in several cytokines and chemokines; CyTOF detected reduction in circulating Tregs associated with increased activated effector CD8+ T cells. Conclusions: Roginolisib is well tolerated at the 80 mg dose, shows signs of efficacy and induces phenotypic changes in the circulating immune cells. As best response at the RP2D, the most robust anti-tumour activity was observed in FL (50% PR) and UM pts (5% PR; 80% SD). Clinical trial information: NCT04328844 .