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PHASE 1 STUDY OF LP-108, A SELECTIVE BCL-2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA
Author(s): ,
Wei Xu
Affiliations:
Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Chine;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,China;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Cina;Department of Hematolog
,
Ru Feng
Affiliations:
Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Chine;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Cina;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of
,
Li Wang
Affiliations:
Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Chine;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,China;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Cina;Department of Hematolog
,
Yuqin Song
Affiliations:
Department of Lymphoma,Beijing Cancer Hospital,Beijing,Chine;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,Cina;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Canc
,
Huayuan Zhu
Affiliations:
Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Chine;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,China;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Cina;Department of Hematolog
,
Lei Fan
Affiliations:
Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Chine;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,China;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Cina;Department of Hematolog
,
Xutao Guo
Affiliations:
Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Chine;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Cina;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of
,
Xiaolei Wei
Affiliations:
Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Chine;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,Cina;Department of Hematology,Nanfang Hospital of Southern Medical University,Guangzhou,China;Department of Hematology,Nanfang Hospital of
,
Ningjing Lin
Affiliations:
Department of Lymphoma,Beijing Cancer Hospital,Beijing,Chine;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,Cina;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Cancer Hospital,Beijing,China;Department of Lymphoma,Beijing Canc
,
Chongyuan Xu
Affiliations:
Phase I Unit,Nanfang Hospital of Southern Medical University,Guangzhou,Chine;Phase I Unit,Nanfang Hospital of Southern Medical University,Guangzhou,China;Phase I Unit,Nanfang Hospital of Southern Medical University,Guangzhou,Cina;Phase I Unit,Nanfang Hospital of Southern Medical University,Guangzhou,China;Phase I Unit,Nanfang Hospital of Southern Medical University,Guangzhou,China;Phase I Unit,Nan
,
Zheng Wang
Affiliations:
Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Chine;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Cina;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Develo
,
Xiang Xiao
Affiliations:
Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Chine;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Cina;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Develo
,
Yue Shen
Affiliations:
Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Chine;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Cina;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Develo
,
Yi Chen
Affiliations:
Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,États-unis;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Vereinigte Staaten;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Stati Uniti;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,United States;Department of Clinical Development,Newave Pharmaceut
,
Yu Chen
Affiliations:
Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,États-unis;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Vereinigte Staaten;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Stati Uniti;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,United States;Department of Clinical Development,Newave Pharmaceut
,
Fenlai Tan
Affiliations:
Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Chine;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,Cina;Department of Clinical Development,Guangzhou Lupeng Pharmaceutical Co., Ltd.,Guangzhou,China;Department of Clinical Develo
,
Stephen P. Anthony
Affiliations:
Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,États-unis;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Vereinigte Staaten;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,Stati Uniti;Department of Clinical Development,Newave Pharmaceutical Inc.,Pleasanton,United States;Department of Clinical Development,Newave Pharmaceut
Jianyong Li
Affiliations:
Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Chine;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,China;Department of Hematology,The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital,Nanjing,Cina;Department of Hematolog
(Abstract release date: 05/12/22) EHA Library. Xu W. 06/10/22; 357546; P684
Wei Xu
Wei Xu
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P684

Type: Poster presentation

Session title: Chronic lymphocytic leukemia and related disorders - Clinical

Background
Targeting BCL-2 family proteins is a well-recognized therapeutic approach. Globally approved BCL-2 inhibitor venetoclax has shown efficacies in certain hematologic malignancies (HMs) but requires weekly ramp-up to the target dose to mitigate the risk of tumor lysis syndrome (TLS). LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown promising preclinical antitumor activity in various HMs.

Aims
To present preliminary results from an ongoing phase 1 study of LP-108 under daily dose ramp-up in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) (NCT04356846).

Methods
This is an open-label, multicenter, phase I study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of LP-108 in Chinese patients with r/r B-cell NHL, consisting of a dose-escalation phase and a dose-expansion phase. Adult r/r B-cell NHL patients requiring therapy are eligible if they had received at least one prior line of treatment (except BCL-2i). LP-108 is orally administered once daily in 28-day cycles until disease progression, unacceptable toxicity, or per investigator discretion. All patients provided and signed informed consent.

Results
As of February 18, 2022, 19 patients have been enrolled and were evaluable for safety, with disease types of MCL (n = 7), CLL/SLL (n = 7), DLBCL (n = 2), FL, WM, and MALT (n = 1 each), and median age of 61 years (range, 39 to 83). Patients had received a median of 3 prior lines of therapy (range, 1~6), of which 13 (68%) patients were previously BTKi exposed. No dose-limiting toxicity (DLT) has been observed in patients who were treated with LP-108 up to 600 mg, thus the maximum tolerated dose (MTD) was not identified. With median duration of treatment of 55 days (range, 4~472), treatment-related adverse events (TRAEs) were reported in 17 patients (89.4%), most of which were grade 1 to 2 in severity. TRAEs of any grade occurred ≥20% of patients were neutropenia (36.8%), leukopenia (31.5%), ALT elevation (31.5%), AST elevation (26.3%), hyperphosphatemia (21%), hyperuricemia (21%), and diarrhea (21%). Grade 3 or 4 TRAEs were reported in 7 patients (36.8%), including neutropenia, thrombocytopenia, lymphopenia, laboratory TLS, and rash. Serious TRAEs included rash, thrombocytopenia, and laboratory TLS, each occurring in 1 patient. No patient discontinued treatment due to toxicity, and no clinical TLS was observed. No deaths occurred during treatment or within 28 days of the end of treatment. At doses ≥200 mg, 3 of 10 efficacy evaluable patients achieved an objective response (1 CR and 2 PR), 4 patients had stable disease (2 with substantially reduced lymphomegaly), and 3 patients had progressive disease. Rapid reduction in ALC was observed in CLL patients (pending imaging assessment) during ramp-up and the first cycle of treatment at doses as low as 20mg. At data cutoff, 11 patients remain on treatment and 8 patients discontinued treatment due to disease progression or patient decision. The PK profile showed that plasma exposure proportionally increased with doses ranging from 20 to 600 mg (mean AUC24h range, 1.26~46.5 h*μg/ml, mean Cmax range, 0.087~2.67 μg/ml). Plasma concentrations peaked approximately 4 to 10 hours after dosing, and the average terminal half-life of LP-108 was approximately 11.8 hours (range, 6.9~16.6).

Conclusion
LP-108 showed favorable safety profile up to 600 mg with daily dose ramp-up schedule, and antitumor activity in patients with r/r B-cell NHL. Dose escalation beyond 600 mg and further dose expansion are ongoing.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Non-Hodgkin's lymphoma, Phase I

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P684

Type: Poster presentation

Session title: Chronic lymphocytic leukemia and related disorders - Clinical

Background
Targeting BCL-2 family proteins is a well-recognized therapeutic approach. Globally approved BCL-2 inhibitor venetoclax has shown efficacies in certain hematologic malignancies (HMs) but requires weekly ramp-up to the target dose to mitigate the risk of tumor lysis syndrome (TLS). LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown promising preclinical antitumor activity in various HMs.

Aims
To present preliminary results from an ongoing phase 1 study of LP-108 under daily dose ramp-up in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) (NCT04356846).

Methods
This is an open-label, multicenter, phase I study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of LP-108 in Chinese patients with r/r B-cell NHL, consisting of a dose-escalation phase and a dose-expansion phase. Adult r/r B-cell NHL patients requiring therapy are eligible if they had received at least one prior line of treatment (except BCL-2i). LP-108 is orally administered once daily in 28-day cycles until disease progression, unacceptable toxicity, or per investigator discretion. All patients provided and signed informed consent.

Results
As of February 18, 2022, 19 patients have been enrolled and were evaluable for safety, with disease types of MCL (n = 7), CLL/SLL (n = 7), DLBCL (n = 2), FL, WM, and MALT (n = 1 each), and median age of 61 years (range, 39 to 83). Patients had received a median of 3 prior lines of therapy (range, 1~6), of which 13 (68%) patients were previously BTKi exposed. No dose-limiting toxicity (DLT) has been observed in patients who were treated with LP-108 up to 600 mg, thus the maximum tolerated dose (MTD) was not identified. With median duration of treatment of 55 days (range, 4~472), treatment-related adverse events (TRAEs) were reported in 17 patients (89.4%), most of which were grade 1 to 2 in severity. TRAEs of any grade occurred ≥20% of patients were neutropenia (36.8%), leukopenia (31.5%), ALT elevation (31.5%), AST elevation (26.3%), hyperphosphatemia (21%), hyperuricemia (21%), and diarrhea (21%). Grade 3 or 4 TRAEs were reported in 7 patients (36.8%), including neutropenia, thrombocytopenia, lymphopenia, laboratory TLS, and rash. Serious TRAEs included rash, thrombocytopenia, and laboratory TLS, each occurring in 1 patient. No patient discontinued treatment due to toxicity, and no clinical TLS was observed. No deaths occurred during treatment or within 28 days of the end of treatment. At doses ≥200 mg, 3 of 10 efficacy evaluable patients achieved an objective response (1 CR and 2 PR), 4 patients had stable disease (2 with substantially reduced lymphomegaly), and 3 patients had progressive disease. Rapid reduction in ALC was observed in CLL patients (pending imaging assessment) during ramp-up and the first cycle of treatment at doses as low as 20mg. At data cutoff, 11 patients remain on treatment and 8 patients discontinued treatment due to disease progression or patient decision. The PK profile showed that plasma exposure proportionally increased with doses ranging from 20 to 600 mg (mean AUC24h range, 1.26~46.5 h*μg/ml, mean Cmax range, 0.087~2.67 μg/ml). Plasma concentrations peaked approximately 4 to 10 hours after dosing, and the average terminal half-life of LP-108 was approximately 11.8 hours (range, 6.9~16.6).

Conclusion
LP-108 showed favorable safety profile up to 600 mg with daily dose ramp-up schedule, and antitumor activity in patients with r/r B-cell NHL. Dose escalation beyond 600 mg and further dose expansion are ongoing.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Non-Hodgkin's lymphoma, Phase I

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