Phase I trial of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed/refractory lymphoma
Mené sur 10 patients atteints d'une leucémie lymphocytaire chronique et 15 patients atteints d'un lymphome récidivant ou réfractaire, cet essai de phase I évalue la toxicité et l'activité antitumorale du pilaralisib, un inhibiteur de PI3K
Purpose:This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. Experimental Design:Patients and Methods Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AEs) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. Results:Twenty-five patients were included in the study; 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%) and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%) and anemia (16.0%). Pilaralisib exposure on cycle 1 Day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and three patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥ 50%. Overall, 14 patients (56.0%; seven patients with CLL and seven patients with lymphoma) had progression-free survival ≥ 6 months. Conclusions:Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development.