A Phase 1b Open-Label Study to Evaluate the Safety and Tolerability of Eganelisib As Monotherapy and in Combination with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Background

AML that recurs after an initial response (relapsed AML) or that fails to respond to therapy (resistant AML) has a poor prognosis and a low survival rate, especially in patients who are medically unfit and received a prior hypomethylating agent (HMA).

The PI3K pathway is often abnormally activated in AML, and genetic depletion of PIK3CG or PIK3R5 inhibited in vitro and in vivo growth of AML cells (Luo et al., 2024; Gu et al., 2024). CRISPR dependency screen showed that PI3K-γ but not other PI3Ks is essential for AML cell survival (Luo et al., 2024). Furthermore, the PI3K-γ dependency was selectively observed in blood cancers but not solid tumors (Luo et al., 2024), and PI3K-γ expression is almost exclusive in leukocytes (Castel et al., 2021), suggesting the selective essentiality of PI3K-γ in blood cancers including AML.

Eganelisib is an orally-available inhibitor for PI3K-γ, with >146-fold selectivity over other PI3K Class I isoforms including PI3Kα, PI3Kβ, and PI3Kδ (Evans et al., 2016). In vitro efficacy studies demonstrated that eganelisib significantly inhibits the viability of multiple leukemic cell lines as well as primary cells isolated from patients (Luo et al., 2024; Gu et al., 2024). Moreover, eganelisib inhibits the clonogenicity and serial replating capacity of cells from AML patients (Gu et al., 2024), suggesting the effect of eganelisib in suppressing leukemic stem cell activity. Mechanistically, eganelisib blocks multiple metabolic pathways in leukemic cells, including the pentose phosphate pathway and oxidative phosphorylation, which mediates the anti-leukemia effect of eganelisib (Luo et al., 2024; Gu et al., 2024). In addition, eganelisib dephosphorylates and suppresses the activity of p21 (RAC1) activated kinase 1 (PAK1) (Luo et al., 2024), which is critical for AML cell growth as well as leukemic stem cell maintenance (Pandolfi et al., 2015). Eganelisib also demonstrated significant in vivo tumor growth inhibition as monotherapy in murine AML model induced by oncogene MLL-AF9, as well as multiple human leukemic patient-derived xenograft (PDX) models by both prophylactic and therapeutic regimens (Gu et al., 2024). Moreover, eganelisib monotherapy demonstrated significant tumor growth inhibition in AML, acute lymphoblastic leukemia, and BPDCN blastic plasmacytoid dendritic cell neoplasm patient-derived xenograft (PDX) models expressing high levels of PIK3R5, while having less benefit in model with low PIK3R5 (Luo et al., 2024). Importantly, eganelisib synergizes with cytarabine in prolonging the survival of both PIK3R5-high as well as PIK3R5-low PDX models (Luo et al., 2024), suggesting the potentials for eganelisib monotherapy and combination with cytarabine as promising therapeutic strategies for improving outcome in leukemia patients.

Methods

This is a Phase 1b open-label, multicenter, dose-escalation and dose optimization study that will take place at 25 sites in the US and Europe (NCT06533761). Oral eganelisib will be administered as monotherapy and in combination with cytarabine. Approximately 125 patients will be enrolled. Patients will be aged ≥ 18 years with relapsed/refractory (r/r) AML or r/r higher-risk MDS (HR-MDS). Acute promyelocytic leukemia is excluded but secondary AML and treatment-related AML can be included.

The study consists of dose escalation (DE) and optimization (OPT) parts. The DE will be guided by a Backfill Bayesian Optimal Interval (BF-BOIN) design with a target MTD toxicity rate of 25%. The dose escalation will identifythe recommended dose for expansion (RDE), which will be either the optimal biological dose (OBD) or the maximum tolerated dose (MTD). Dose levels will be considered for escalation until the RDE is reached.

Once the RDE of eganelisib as monotherapy and in combination with cytarabine is established, an OPT part will be initiated. All patient data from the DE part will be combined with the data from the corresponding doses at the OPT part to select the Recommended Phase 2 Dose that will be studied further.

Primary endpoints are safety, tolerability, determining the RDE, and evaluating the preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine.

Ptaszynski:Stelexis Biosciences: Consultancy. Payton:Stelexis Biosciences: Consultancy, Current Employment. Farrow:Stelexis Biosciences: Consultancy, Current Employment. Feldman:Stelexis Biosciences: Consultancy.