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), and pharmacodynamic (PD) results.
Authors: Di Giacomo Anna Maria , Santangelo Federica , Amato Giovanni , Simonetti Elena , Graham Jill , Lahn Michael M. F. , van der Veen Lars Anders , Johnson Zoe , Pickering Catherine Anne , 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 2022

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Background: T regulatory (Tregs) cells contribute to immune suppression in cancer. The highly selective inhibitor of PI3Kδ, IOA-244, blocks the activity of Tregs among other things, thus reprograms the anti-tumor immune response. Methods: IOA-244 was investigated in a two-part FIH study. Part A explored the continuous daily dosing of IOA-244 at 10, 20, 40 and 80 mg. Part B consists of expansion cohorts of specific tumor indications, including pre-treated uveal melanoma patients (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.-based responses; PFS and OS. Exploratory studies: changes in circulating immune cells by Cytometry by Time of Flight (CyTOF); response assessments by radiomics Results: Part A Solid Tumor (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%). Four pts had at least one serious TEAE, none considered related to IOA-244. There was no treatment-emergent adverse events (TEAE) leading to study drug discontinuation, immune related toxicity or Dose Limiting Toxicity. CTCAE v5 Grade 1 and 2 were observed, including 2 cases of transient diarrhoea and 2 of AST/ALT elevation. Part A (Completed) – Subgroup Uveal Melanoma Pts (progressed ≥1 line prior therapy): 9 pts treated (3/9 pts ongoing). Mean time on treatment: 7.7 mo (range: 1.8-16.0 mo with 3 pts ongoing). ORR (RECIST 1.1): CR+PR: 0/9 (0%); SD: 6/9 (67%). Median OS: 5.4 mo - not determined (% alive at 1 year: 44% with 3 pts ongoing). CT images from 7/9 patients were assessed for changes in their metastatic lesions by radiomics (baseline and Week 8). Based on 147 matched lesions, 19% had complete responses and 16% had new lesions. In the liver, non-progressive disease was observed in 61% of all lesions, including 42% with either complete response or volume reduction of more than 30%. Using CyTOF, circulating Tregs were reduced while CD8 and NK cells were increased. Part B Uveal Melanoma Expansion Cohort (ongoing): 7 patients (7/7 pts ongoing); mean time on treatment 3.7 mo. ORR (RECIST 1.1): SD in 4/7 pts (57%). Part A Follicular Lymphoma Cohort (ongoing): At 20 mg: 4/4 pts. No DLT. At 80 mg: recruiting. Conclusions: In addition to being well tolerated, IOA-244 at the 80 mg dose shows reduction in peripheral blood Tregs and anti-tumor responses based on radiomics. Therefore, RECIST 1.1.-derived SD may underestimate anti-tumor activity of IOA-244 in treatment-resistant uveal melanoma. Additional patients will be treated to further refine this radiomics-based observation. Clinical trial information: NCT04328844.