A Phase1b Clinical Study of the Oral PI3Kδ Inhibitor, Linperlisib, in Patients with B-Cell Lymphomas
Authors: Qiu Lugui , Li Zhiming , Huang Yunhong , Liu Ligen , Liu Lihong , Guo Ye , Deng Lan , Yang Haiyan , CAI Zhen , Ye Xu , Wang Zhen , Bao Hanying , Xu Zusheng , Zheng Binghua 
Published: November 2021

Abstract
Introduction
The PI3Kδ inhibitor, linperlisib, is a structurally distinctive oral agent demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma (FL) and peripheral T-cell lymphoma (PTCL). Here we report initial results of a phase1b study (NCT04279405) evaluating the activity and safety of linperlisib across B-cell lymphoma types, namely DLBCL, MCL, MZL, FL and SLL/CLL.
Methods
Enrollment initiated in Jan 2020 at 11 clinical sites in China for patients (pts) of DLBCL, MCL, MZL, FL and SLL/CLL having received at least one standard anti-tumor systemic therapy and at least 2 cycles of each prior treatment. Linperlisib tablets were administered orally, 80mg once daily under fasted conditions for 28 days as a cycle, until disease progression, unacceptable toxicity or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was evaluated every 2 cycles using the IWG 2007 criteria.
Results
As of Jul 22, 2021, 43 r/r lymphoma patients were enrolled, including DLBCL (20 pts), MCL (9 pts), FL (8 pts), MZL (3 pts) and SLL/CLL (3 pts). With a median of 2 prior therapies, the majority (93%) of pts previously received first line immunochemotherapy including anti-CD20 targeted therapies. One pts withdrew consent before study treatment began. Three pts withdrew consent in first cycle without post baseline imaging assessment. Forty two pts and 39 patients were evaluable for safety and efficacy, respectively.
Linperlisib was well-tolerated in this study. The safety profile observed was consistent to that observed in the clinical studies with FL and PTCL patients, with no new toxicities reported. The most frequent TRAE (all Grade &gt;10%) were neutropenia (54.8%), lymphopenia (40.5%), thrombocytopenia (28.6%), anemia (23.8%), alanine aminotransferase increased (21.4%), aspartate aminotransferase increased (21.4%), blood triglycerides increased (16.7%), blood uric acid increased (14.3%), diarrhoea (11.9%), proteinuria (11.9%) and rash (11.9%). The most frequent Grade ≥3 TRAEs were neutropenia (26.2%) and lymphopenia (9.5%). Thirteen (31.0%) pts experienced SAE considered to be drug related, including pneumonia, thrombocytopenia, pancreatitis, and febrile neutropenia. SAE leading discontinuation from study occurred in 7 pts .Three pts experienced AE that lead to dose modification. No death happened due to any TRAE. No specific associations were observed between B-cell lymphoma types and adverse events on linperlisib treatment.
An overall response rate (ORR) and overall disease control rate (DCR) of 53.8% and 79.5% were observed in the evaluable patients. Table1 The 17 evaluable DLBCL pts contained 1 unconfirmed CR (GCB) and 3 PR (GCB, N-GCB, and DLBCL transformed from MZL). The DOR for the 4 DLBCL responders were 56 days, 56 days, 56 days and 196 days. The 8 evaluable FL pts were 3 unconfirmed CR plus 5 PR, and a median DOR of 112days. The 8 evaluable MCL pts contained 2 unconfirmed CR, 3 PR, and 2 SD. The median DOR of the 5 MCL responders were 56 days. The 3 evaluable MZL pts and 3 evaluable SLL/CLL pts were both consisted of 1 unconfirmed CR, 1 PR and 1 SD .The DOR for the 2 MZL responders were 196 days and 56 days, the DOR for the 2 SLL/CLL responders were both 196 days. At the data cutoff date, 16 pts were still treatment ongoing, 19 pts had received exceeding 6 months of treatment, and 1 pt had received exceeding 12 months of treatment, supporting a durable benefit of linperlisib monotherapy.
Conclusions
Linperlisib demonstrated broad anti-tumor activities in several r/r B -cell malignancies, including DLBC, MCL, MZL, FL and SLL/CLL. Furthermore, linperlisib showed a favorable safety profile with respect to the previously reported information from approved agents in the class of PI3K inhibitors. Further clinical studies of linperlisib in B-cell malignancies and in combination therapies are warranted.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.