Intermittent Dosing Schedule for Zandelisib Appears Safe With Low Incidence of High-Grade AEs in R/R B-Cell Malignancies

A low occurrence of grade 3 adverse effects and a promising safety profile were observed when 60 mg of zandelisib was given once daily on an intermittent schedule for patients with relapsed/refractory B-cell malignancies, according to results of a phase 1 trial (NCT02914938) published in The Lancet Oncology.

Objective response rates were similar across dose arms, including 92.0% (95% CI, 61.5%-99.8%) in the 60 mg arm and 120 mg groups and 83.0% (95% CI, 35.9%-99.6%) in the 180 mg group. The median duration of treatment exposure was 15.2 months for intermittent dosing and 10.4 months for continuous dosing. For those who remained on therapy, the median exposure duration was 18.6 months for intermittent dosing and 35.9 months for continuous.

A total of 97 patients enrolled and were eligible for assessment, 31 of whom were included in the dose-escalation cohorts and 66 in the expansion cohorts. The dose escalation cohorts were comprised of patients with follicular lymphoma, chronic lymphocytic leukemia, or small lymphocytic leukemia who received zandelisib at 60 mg (n = 13), 120 mg (n = 12), or 180 mg (n = 6). Notably, dose escalation stopped at the 180 mg dose due to a high rate of response and safety profile. The maximum tolerated dose was not able to be defined. The 60 mg dose was defined as minimally biologically effective dose and will be further evaluated in a phase 2 trial.

Of the patients enrolled on the study, zandelisib monotherapy was given to 56, of whom 41 were treated with zandelisib and rituximab (Rituxan). Zandelisib was given to 59 patients with an intermittent dosing schedule and 38 received continuous dosing. After a median of 7 cycles, 55% of patients in the continuous dosing schedule moved to the intermittent dosing schedule, with the 17 remaining patients discontinuing therapy. Overall, 60% of patients discontinued therapy, with 40% of patients remaining on treatment after the cutoff date of September 2020.

Grade 3/4 adverse effects (AEs) were observed in 44% of the intermittent dosing group and 76% of patients in the continuous dosing group. Frequent grade 3 or higher AEs included neutrophil count decrease (14%), diarrhea (11%), pneumonia (7%), alanine aminotransferase increase (5%), and colitis (3%).

Moreover, 39% of patients in the continuous dosing group and 44% in the intermittent group had treatment interruptions due to AEs. Serious AEs were observed in 34% vs 22%, and serious treatment-related AEs (TRAEs) occurred in 21% vs 8% in the continuous and intermittent dosing groups, respectively. Frequently reported serious TRAEs were pneumonia (n = 3) and diarrhea (n = 2) in the continuous group, and colitis (n = 3) and pneumonitis (n = 2) in the intermittent group. Grade 3 or higher AEs of special interest between both the continuous dosing group and the intermittent dosing group included diarrhea or colitis (24% vs 8%), and lung infection (16% vs 2%).

Reference

Pagel JM, Soumerai JD, Reddy N, et al. Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial. Lancet Oncol. 2022;23(8):1021-1030. doi:10.1016/S1470-2045(22)00333-3