In a first-in-patients phase Ib study reported in The Lancet Oncology, John M. Pagel, MD, PhD, and colleagues identified the safety profiles of the PI3Kδ inhibitor zandelisib given in intermittent vs continuous dosing schedules with or without rituximab in patients with relapsed of refractory B-cell malignancies.
John M. Pagel, MD, PhD
Study Details
The U.S./Swiss multicenter study enrolled 97 patients between November 2016 and June 2020. A dose-escalation phase examined zandelisib at continuous daily dosing with 60, 120, and 180 mg per day, with no dose-limiting toxicities observed and 60 mg being selected as the dose for further evaluation. Subsequently, patients received 60 mg as monotherapy or with rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3 through 6 on a continuous daily schedule (n = 38, 5 with rituximab) or on an intermittent schedule of days 1 to 28 of cycles 1 and 2 and days 1 to 7 of subsequent cycles in 28-day cycles (n = 59, 36 with rituximab).
Key Findings
During the dose-escalation phase, objective response was observed in 11 (92%) of 12 patients receiving 60 mg/day, 11 (92%) of 12 receiving 120 mg/day, and 5 (83%) of 6 receiving 180 mg/day.
With a median duration of exposure of 15.2 months (interquartile range = 3.7–21.7 months), grade 3 or 4 adverse events occurred in 29 (76%) of 38 patients in the continuous-dosing group vs 26 (44%) of 59 in the intermittent-dosing group. The most common were decreased neutrophils (11% of continuous group vs 17% of intermittent group), diarrhea (21% vs 5%), pneumonia (16% vs 2%), increased alanine aminotransferase (5% vs 5%), and colitis (3% vs 3%).
Serious adverse events occurred in 34% of patients in the continuous-dosing group vs 22% of the intermittent-dosing group. Treatment was interrupted due to adverse events in 39% of the continuous-dosing group vs 44% of the intermittent-dosing group. No treatment-related deaths occurred.
Among 62 patients with follicular lymphoma, objective response was observed in 19 (76%) of 25 in the continuous-dosing group (all zandelisib monotherapy); in 14 (79%) of 18 receiving intermittent-dosing monotherapy; and in 18 (95%) of 19 receiving intermittent dosing with rituximab. Among 20 patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, objective response was observed in 10 (100%) of 10 with continuous dosing (all monotherapy) and in 10 (100%) of 10 with intermittent dosing (6 with rituximab). Objective response was observed in four (100%) of four patients with marginal zone lymphoma and in one (11%) of nine with diffuse large B-cell lymphoma, all receiving intermittent dosing combined with rituximab.
The investigators concluded, “Zandelisib at 60 mg once daily on an intermittent dosing schedule was safe, with low frequency of grade 3 or worse adverse events, warranting the ongoing global phase II and phase III trials.”
Andrew D. Zelenetz, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by MEI Pharma. For full disclosures of the study authors, visit thelancet.com.
