A phase I study of duvelisib in combination with oral azacitidine (CC-486) in relapsed lymphoid malignancies.

Abstract

TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.