Safety and efficacy of TQ-B3525, a novel and selective oral PI3K α/δ inhibitor, in Chinese patients with advanced malignancies: A phase I dose-escalation and expansion trial.

Abstract

8058 Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor with activity 41 and 138 folds higher than Buparlisib against PI3K α and PI3K δ in pre-clinical research. This Phase I study (NCT03510767) assessed the safety, tolerability, pharmacokinetics and antitumor activity of TQ-B3525 in Chinese patients with advanced malignancies. Methods: Patients with relapsed or refractory (R/R) lymphoma who have experienced at least two prior systemic anti-cancer treatments, and advanced solid tumor who have failed standard anti-cancer treatment, were enrolled. TQ-B3525 was administered orally from 2mg, 5mg, 10mg, 20mg once daily (qd) to 10mg, 20mg twice daily (bid). DLT was observed in the first cycle (28 days) of dose-escalation phase. Dose-expansion phase started at the dose level which objective response occurs. Results: Between June 2018 and December 2019, a total of 40 patients were enrolled, Including 27 patients with R/R lymphoma and 13 patients with advanced solid tumor. Three DLTs (both grade 3 hyperglycemia) were observed: two in the 20mg bid dose cohort and one in the 10mg bid. The common AEs of all grades were hyperglycemia (65.0%), glycosylated hemoglobin increased (35.0%) and diarrhea (32.5%). Grade 3 or 4 treatment-related AEs occurred in 11 patients (27.5%), with the most common one also being hyperglycemia (10.0%). TQ-B3525 was rapidly absorbed (Tmax: 1-2 h) and moderately eliminated (T1/2: 10-12 h). At steady state, the geometric mean AUC0-24 and Ctrough of TQ-B3525 at 20mg qd were 1060.7 ± 198.6 h*ng/mL and 23.4 ± 9.5 ng/mL, which was above IC50 (4.2 ng/ml). 23 lymphoma patients were evaluable for clinical response per 2014 Lugano Classification. The overall response rate (ORR) was 60.9% (95% CI, 38.5-80.2). The ORR at ≥10mg qd was 70.0% (14/20, [95% CI, 49.9-90.1]). For R/R FL, the ORR was 72.7% (8/11, [95% CI, 46.4-99.1]). At data cut-off (2nd February, 2020), the median PFS for lymphoma was not reached (events rate: 33.3%). The longest duration of response at data cutoff was 11.8 months in a patient with FL. Conclusions: TQ-B3525 is well-tolerated in Chinese patients with advanced malignancies, and demonstrated high promising antitumor activity in R/R lymphoma patients. Recommended phase II dose was established at 20mg qd. A single-arm phase 2 trial of TQ-B3525 in patients with R/R FL is currently underway. Clinical trial information: NCT03510767 .