First-in-human (FIH), pharmacokinetic (PK) and pharmacodynamic (PD) study of IOA-244, a phosphoinositide 3-kinase delta (PI3K) inhibitor, in patients with advanced metastatic mesothelioma, uveal and cutaneous melanoma

BackgroundIOA-244 is a non-ATP competitive, oral small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), designed to inactivate immune suppressive cells in the tumour microenvironment (TME).MethodsIOA-244 was given as a capsule once daily on a 28-day cycle at doses of 10, 20, 40 and 80 mg. Primary objective: safety, tolerability and confirmation of the anticipated biologically effective dose (BED). Using a 3 + 3 dose escalation design, human pharmacokinetic (PK) and pharmacodynamic (PD) data were continuously adapted into a PK/PD model to establish a BED. Because PI3Kδ signalling is linked to CD63 expression following basophil activation by IgE cross-linking, the inhibition of CD63 expression on basophils was used as the primary PD marker. Additional PD markers: immune cell subsets in peripheral blood and tumour tissue.ResultsNineteen patients (pts) entered the study between February 2020 and April 2021. Sixteen pts were treated in 4 cohorts with 4 pts in each cohort. Pt characteristics: 11 pts <70 years of age (11/16; 69%); 8 pts male and female, respectively. The primary cancer diagnosis: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and mesothelioma (2/16; 13%). IOA-224 exposure (Cmax and AUC0-24) increased approximately proportional to the increase in dose. CD63 expression on basophils was reduced in a dose-dependent manner and reached IC80 at 1000 ng/mL with no additional inhibition at 80 mg. Four pts had at least one serious Treatment Emergent Adverse Event (TEAE), none of them were related to IOA-244. No TEAE led to study drug discontinuation, immune-related toxicity or Dose Limiting Toxicity. CTCAE Grade 1 and 2 were observed, including 2 cases of diarrhoea and AST/ALT elevation each. Uveal Melanoma (UM): median time on treatment was 5.35 months; PD on prior treatment and before starting IOA-244 was present in 7/9 pts; longer treatment on IOA-244 compared to prior immunotherapy was reported in 6/9 UM pts.ConclusionsIOA-244 was well tolerated up to 80 mg, a dose selected for future studies in combination with immune- and chemotherapies.Clinical trial identificationNCT04328844.Editorial acknowledgementThe authors thank the patients and their families. Also, we thank all study personal at the clinical investigation centres and the LabCorp Drug Development team.Legal entity responsible for the studyiOnctura SA.FundingiOnctura SA.DisclosureA.M. Di Giacomo: Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Merck Sharp Dohme; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Glaxo Smith Kline; Financial Interests, Personal, Ownership Interest: Epigen Therapeutics. M. Lahn, L. van der Veen, Z. Johnson: Financial Interests, Personal, Officer: iOnctura. R. Zorilla, E. Maréchal, J. Blanco, M. Durini, B. Gufford: Financial Interests, Personal, Full or part-time Employment: iOnctura. C. Pickering: Financial Interests, Personal, Member of the Board of Directors: iOnctura. T. Lakshmikanth, P. Brodin: Financial Interests, Personal, Funding: iOnctura. T.R.J. Evans: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Speaker´s fee: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Speaker´s fee: Bayer; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Personal, Other, Travel International Conference: Bayer; Financial Interests, Institutional, Advisory Board: Bicycle Therapeutics; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board, GI cancers and Melanoma: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, GI Cancers and Melanoma: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel to Conference: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel to Conference: Celgene; Financial Interests, Institutional, Advisory Board: Clovis; Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Advisory Board: Medivir; Financial Interests, Institutional, Invited Speaker: Medivir; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Personal, Other, Travel to Conference: MSD; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Invited Speaker: Nucana; Financial Interests, Personal, Other, Travel to Conference: Nucana; Financial Interests, Personal, Other, Travel to Conference: Pierre Fabre; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel to Conference: Roche; Financial Interests, Institutional, Principal Investigator, Study Costs: Adaptimmune; Financial Interests, Institutional, Principal Investigator: Astella; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Basilea; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: Beigene; Financial Interests, Institutional, Principal Investigator: Bicycle Therapeutics; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator: Celgene; Financial Interests, Institutional, Principal Investigator: Codiak; Financial Interests, Institutional, Principal Investigator: CytomX; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: iOnctura; Financial Interests, Institutional, Principal Investigator: Johnson & Johnson; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: Medivir; Financial Interests, Institutional, Principal Investigator: MiNa Therapeutics; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: Nucana; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: Sanofi; Financial Interests, Institutional, Principal Investigator: Sapience Therapeutics; Financial Interests, Institutional, Principal Investigator: Seagen; Financial Interests, Institutional, Principal Investigator: Sierra; Financial Interests, Institutional, Principal Investigator: Starpharma; Financial Interests, Institutional, Principal Investigator: UCB; Financial Interests, Institutional, Principal Investigator: Verastem. M. Maio: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Merck Sharp Dohme; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: Glaxo Smith Kline; Financial Interests, Personal, Advisory Role: Sciclone; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Alfasigma; Financial Interests, Personal, Advisory Role: Merck KGaA; Financial Interests, Personal, Ownership Interest: EpiGen Therapeutics. All other authors have declared no conflicts of interest. BackgroundIOA-244 is a non-ATP competitive, oral small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), designed to inactivate immune suppressive cells in the tumour microenvironment (TME). IOA-244 is a non-ATP competitive, oral small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), designed to inactivate immune suppressive cells in the tumour microenvironment (TME). MethodsIOA-244 was given as a capsule once daily on a 28-day cycle at doses of 10, 20, 40 and 80 mg. Primary objective: safety, tolerability and confirmation of the anticipated biologically effective dose (BED). Using a 3 + 3 dose escalation design, human pharmacokinetic (PK) and pharmacodynamic (PD) data were continuously adapted into a PK/PD model to establish a BED. Because PI3Kδ signalling is linked to CD63 expression following basophil activation by IgE cross-linking, the inhibition of CD63 expression on basophils was used as the primary PD marker. Additional PD markers: immune cell subsets in peripheral blood and tumour tissue. IOA-244 was given as a capsule once daily on a 28-day cycle at doses of 10, 20, 40 and 80 mg. Primary objective: safety, tolerability and confirmation of the anticipated biologically effective dose (BED). Using a 3 + 3 dose escalation design, human pharmacokinetic (PK) and pharmacodynamic (PD) data were continuously adapted into a PK/PD model to establish a BED. Because PI3Kδ signalling is linked to CD63 expression following basophil activation by IgE cross-linking, the inhibition of CD63 expression on basophils was used as the primary PD marker. Additional PD markers: immune cell subsets in peripheral blood and tumour tissue. ResultsNineteen patients (pts) entered the study between February 2020 and April 2021. Sixteen pts were treated in 4 cohorts with 4 pts in each cohort. Pt characteristics: 11 pts <70 years of age (11/16; 69%); 8 pts male and female, respectively. The primary cancer diagnosis: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and mesothelioma (2/16; 13%). IOA-224 exposure (Cmax and AUC0-24) increased approximately proportional to the increase in dose. CD63 expression on basophils was reduced in a dose-dependent manner and reached IC80 at 1000 ng/mL with no additional inhibition at 80 mg. Four pts had at least one serious Treatment Emergent Adverse Event (TEAE), none of them were related to IOA-244. No TEAE led to study drug discontinuation, immune-related toxicity or Dose Limiting Toxicity. CTCAE Grade 1 and 2 were observed, including 2 cases of diarrhoea and AST/ALT elevation each. Uveal Melanoma (UM): median time on treatment was 5.35 months; PD on prior treatment and before starting IOA-244 was present in 7/9 pts; longer treatment on IOA-244 compared to prior immunotherapy was reported in 6/9 UM pts. Nineteen patients (pts) entered the study between February 2020 and April 2021. Sixteen pts were treated in 4 cohorts with 4 pts in each cohort. Pt characteristics: 11 pts <70 years of age (11/16; 69%); 8 pts male and female, respectively. The primary cancer diagnosis: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and mesothelioma (2/16; 13%). IOA-224 exposure (Cmax and AUC0-24) increased approximately proportional to the increase in dose. CD63 expression on basophils was reduced in a dose-dependent manner and reached IC80 at 1000 ng/mL with no additional inhibition at 80 mg. Four pts had at least one serious Treatment Emergent Adverse Event (TEAE), none of them were related to IOA-244. No TEAE led to study drug discontinuation, immune-related toxicity or Dose Limiting Toxicity. CTCAE Grade 1 and 2 were observed, including 2 cases of diarrhoea and AST/ALT elevation each. Uveal Melanoma (UM): median time on treatment was 5.35 months; PD on prior treatment and before starting IOA-244 was present in 7/9 pts; longer treatment on IOA-244 compared to prior immunotherapy was reported in 6/9 UM pts. ConclusionsIOA-244 was well tolerated up to 80 mg, a dose selected for future studies in combination with immune- and chemotherapies. IOA-244 was well tolerated up to 80 mg, a dose selected for future studies in combination with immune- and chemotherapies.