Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies

Bo Jiang, Junyuan Qi, Yuqin Song, Zengjun Li, Meifeng Tu, Lingyan Ping, Zongliang Liu, Hanying Bao, Zusheng Xu, Lugui Qiu, Bo Jiang, Junyuan Qi, Yuqin Song, Zengjun Li, Meifeng Tu, Lingyan Ping, Zongliang Liu, Hanying Bao, Zusheng Xu, Lugui Qiu

Abstract

YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20-200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://ichgcp.net/clinical-trials-registry/NCT03757000?term=NCT03757000&draw=2&rank=1 .

Keywords: Dose-limiting toxicity; Linperlisib; Non-Hodgkin’s lymphoma; PI3Kδ inhibitor; Pharmacokinetics.

Conflict of interest statement

Prof. Lugui Qiu and Prof. Junyuan Qi received research grants from Shanghai Yingli Pharmaceutical Co., Ltd.; Prof. Bo Jiang, Prof. Lugui Qiu, Prof. Junyuan Qi, Prof. Yuqin Song, Prof. Meifeng Tu, Prof. Lingyan Ping, Prof. Zengjun Li received consulting fees from Shanghai Yingli Pharmaceutical Co., Ltd; Dr. Zusheng Xu is a shareholder of Shanghai Yingli Pharmaceutical Co., Ltd; Dr. Hanying Bao and Mr. Zongliang Liu are employees of Shanghai Yingli Pharmaceutical Co., Ltd.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Efficacy evaluation of YY-20394 treatments in the dose escalation study of B-cell malignancies. a Overall efficacy chart of YY-20394. b Waterfall plot of overall tumor changes from baseline #indicates transient staging with ongoing treatment at the end of the study period. c PFS curve (days) in the 5 patient dosing groups. Note: CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CR, complete remission; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; LPL, Lymphatic plasma cell lymphoma; MCL, mantle cell lymphoma; MZL marginal zone lymphoma; PD, progressive disease; PR, partial remission; SD, stable disease

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