[Translation] A Phase I, open-label, multicenter study to explore the safety, tolerability, pharmacokinetics, and preliminary efficacy of oral BB3008 tablets in patients with advanced solid tumors

主要目的：（1）评估不同剂量 BB3008 片单药治疗晚期实体瘤受试者的安全性和耐受性，确定 BB3008 片的 MTD，为 RP2D 的确定提供依据；次要目的：（1）评估 BB3008 片在晚期实体瘤受试者体内的 PK 特性；（2）初步评估 BB3008 片单药治疗晚期实体瘤受试者的疗效；（3）初步鉴定 BB3008 在晚期实体瘤患者中的代谢产物（如有）；探索性目的：（1）探索与 BB3008 药物疗效和安全性相关的生物标志物；（2）探索血药浓度和 Fridericia 法校正的 QT 间期（QTcF）的相关性（C-QTcF 分析）。

[Translation]

Primary objectives: (1) To evaluate the safety and tolerability of different doses of BB3008 tablets as a monotherapy in subjects with advanced solid tumors, determine the MTD of BB3008 tablets, and provide a basis for the determination of RP2D; Secondary objectives: (1) To evaluate the PK characteristics of BB3008 tablets in subjects with advanced solid tumors; (2) To preliminarily evaluate the efficacy of BB3008 tablets as a monotherapy in subjects with advanced solid tumors; (3) To preliminarily identify the metabolites of BB3008 in patients with advanced solid tumors (if any); Exploratory objectives: (1) To explore biomarkers related to the efficacy and safety of BB3008; (2) To explore the correlation between blood drug concentration and Fridericia-corrected QT interval (QTcF) (C-QTcF analysis).

Start Date27 Oct 2023

Sponsor / Collaborator

Beijing BroadenBio Co., Ltd.

NCT06143007 / RecruitingPhase 1

A Phase I, Open-label, Multicenter Study to Assess Safety, Tolerability, Pharmacokinetic, Efficacy and Preliminary Food Effect of BB3008 Tablet Administered Orally to Patients With Advanced Solid Tumors

This is a Phase 1 dose escalation study to evaluate the safety, tolerability, pharmacokinetics, efficacy and preliminary food effect of BB3008 as monotherapy in subjects with advanced solid tumors.

Start Date26 Oct 2023

Sponsor / Collaborator

Beijing BroadenBio Co., Ltd.

NCT06258408 / RecruitingPhase 1

A Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Profiles and Efficacy of Oral BB102 Tablets in Patients With Advanced Solid Tumors

This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, efficacy and preliminary food effect of BB102, a highly selective and potent FGFR4 inhibitor, as monotherapy in subjects with advanced solid tumors. This study has two phase: dose escalation phase and expansion phase.

Start Date29 Dec 2022

Sponsor / Collaborator

Beijing BroadenBio Co., Ltd.

100 Clinical Results associated with Beijing BroadenBio Co., Ltd.

0 Patents (Medical) associated with Beijing BroadenBio Co., Ltd.

Literatures (Medical) associated with Beijing BroadenBio Co., Ltd.

22 Mar 2024·Cancer Research

Abstract 603: BB5523, a multiple kinase inhibitor with HPK1, VEGFR2 and TNIK inhibition, enhanced antitumor immunity in tumor models

Author: Duan, Gongping ; Wang, Shipeng ; Zhang, Xingmin ; Zhang, Puyong ; Li, Min ; Ma, Xiaoyi ; Wang, Junheng ; Wei, Lijie ; Hao, Enlun ; Hua, Wei

AbstractIntroduction: Immuno-suppressive micro-environment and abnormal signaling pathways are crucial for the proliferation of tumor cells. Hematopoietic progenitor kinase 1 (HPK1) inhibitor plays important roles in activation of exhausted T cells and enhancement of anti-tumor immune responses. VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. Traf2- and Nck-interacting kinase (TNIK) is a member of the germinal center kinase family, and is reported to be essential for Wnt signaling and colorectal cancer (CRC) proliferation and progression. Blockade of critical kinases in multiple signaling pathways inhibits the proliferation, invasion and metastasis of cancer cells. Therefore, intergradation of these functions in a small molecule serves as the next generation of immune-oncology small molecules for cancer therapy. Methods: BB5523 was developed through structure-based drug design, and optimized by SAR analysis and medicinal chemistry iteration. Biochemical assays and cell-base functional assays were applied in compound evaluation. Pharmacokinetic (PK) and preliminary toxicity studies were performed with mice. CDX and syngeneic tumor models in mice were conducted to evaluate the in vivo efficacy of BB5523 as a single agent. Results: BB5523 shows high inhibition potency on HPK1 with good selectivity against other TCR signaling-related kinases, such as FYN and ZAP70. Inhibition of HPK1 kinase activity (IC50 = 3.3 nM) by BB5523 strongly suppresses the phosphorylation of the downstream biomarker protein SLP-76 (IC50 = 30 nM); and boosts the IL-2 secretion in purified human T cells and human peripheral blood mononuclear cells. BB5523 also shows good activities on VEGFR2 (IC50 = 1.6 nM) and TNIK (IC50 = 0.7 nM) which are crucial for the proliferation of cancer cells. In in vitro experiments, BB5523 significantly inhibits the proliferation of various tumor cell lines at sub-micromolar concentrations. PK profile of BB5523 shows good oral bioavailability (F > 80%). In preliminary safety evaluation, no abnormal symptoms were observed in mice dosed up to 100 mpk for 14 days. BB5523 showed significant tumor-growth inhibition efficacy in TE-8, JIMT-1, B16-F10 and MC38 tumor models. Conclusion: As a potent and oral available small molecule kinase inhibitor, BB5523 boosts anti-tumor immunity through HPK1 inhibition, while also blocking crucial signaling pathways in tumor micro-environment. BB5523 shows promising in vitro and in vivo efficacy with a well-tolerated safety profile. The preclinical study of BB5523 is in progress.Citation Format: Gongping Duan, Min Li, Puyong Zhang, Wei Hua, Enlun Hao, Shipeng Wang, Xiaoyi Ma, Junheng Wang, Lijie Wei, Xingmin Zhang. BB5523, a multiple kinase inhibitor with HPK1, VEGFR2 and TNIK inhibition, enhanced antitumor immunity in tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 603.

22 Mar 2024·Cancer Research

Abstract 1963: BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models

Author: Wei, Xianglong ; Zhang, Xingmin ; Duan, Gongping ; Wang, Qi ; Wang, Junheng ; Li, Min ; Hua, Wei

AbstractIntroduction: Fibroblast growth factor receptor 4 (FGFR4) belongs to the FGFR family which interact with fibroblast growth factors (FGFs) to regulate cell proliferation, differentiation and apoptosis. Due to unique structural domain, FGFR4 is specifically bound by FGF19 with high affinity in the presence of co-receptor β-Klotho. Hyperactivated FGF19/FGFR4 signaling, induced by FGF19/FGFR4 overexpression and FGFR4 mutation, was reported to be associated with the growth, metastasis and invasion of various cancer. Thus, FGFR4 is considered as a novel target to treat cancer with hyperactivated FGF19/FGFR4 signaling. Here we report BB102 as a highly selective and potent reversible-covalent FGFR4 inhibitor.Methods: BB102 was developed through structure-based drug design, and optimized by SAR analysis and medicinal chemistry iteration. Biochemical and cell assays were applied in evaluation of BB102 inhibitory activity. Preclinical studies including pharmacokinetic (PK) and toxicity were performed in rats and dogs. Xenograft tumor models in mice were conducted to demonstrate the in vivo efficacy of BB102.Results: As a reversible-covalent FGFR4 inhibitor, about half compound of BB102 dissociated from FGFR4 kinase within 24 h, which was conducive to overcome the fast re-synthesis rate of FGFR4 (< 2 h) in hepatocellular carcinoma cells. BB102 only inhibited kinase activity of FGFR4WT, FGFR4N535K and FGFR4V550L at nanomolar levels in 207 kinase panel screening. BB102 completely blocked the phosphorylation of the downstream protein ERK at 16.7 nM. BB102 exhibited strong inhibitory effects on the cell proliferation in vitro and tumor growth in mouse models inoculated with the high expression of both FGF19 and FGFR4, or FGFR4 mutated tumor cells. PK profile of BB102 showed good oral bioavailability (F>70%) with a nearly linear dose-dependent exposure. The compound had no effects on the respiratory and central nervous systems in rats, cardiovascular system in Beagle dogs or hERG liability in vitro. In comprehensive safety evaluation, the Severely Toxic Dose in 10% (STD10) in rats was 300 mg/kg/day and the Highest Non-Severely Toxic Dose (HNSTD) in dogs were 100 mg/kg/day.Conclusion: BB102 is a highly selective and potent reversible-covalent FGFR4 inhibitor with promising efficacy in high expression of both FGF19 and FGFR4, and/or FGFR4 mutated tumor models and good safety in preclinical studies. The phase I study of BB102 is in progress.Citation Format: Qi Wang, Gongping Duan, Wei Hua, Xianglong Wei, Min Li, Junheng Wang, Xingmin Zhang. BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1963.

14 Apr 2023·Cancer Research

Abstract LB324: BB3008, a potent and selective small molecular HPK1 inhibitor effective in multiple syngeneic tumor models

Author: Li, Min ; Zhang, Xingmin ; Duan, Gongping

AbstractIntroduction: Hematopoietic progenitor kinase 1 (HPK1) is a serine/threonine kinase in the MAP4K family predominantly expressed in immune cells, and has been identified as a negative regulator of T cell and B cell receptor signaling and dendritic cell function. Inhibition of the kinase activity of HPK1 results in the activation of exhausted T cell in tumor microenvironment and enhanced anti-tumor immune response. Observation of HPK1 overexpression in various tumor tissues further indicates the kinase as a novel target for immuno-oncology therapy. Here we report BB3008 as a small molecular HPK1 inhibitor.Methods: BB3008 was developed through structure-based drug design, and optimized by SAR analysis and medicinal chemistry iteration. Biochemical assays and cell-base functional assays were applied in compound evaluation. Pharmacokinetic (PK) and preliminary toxicity studies were performed with mice and dogs. Syngeneic tumor models in mice were conducted to demonstrate the in vivo efficacy of BB3008 as a single agent and in combination with mouse PD-1 antibody.Results: BB3008 shows sub-nanomolar HPK1 potency, with good selectivity against kinases in the MAP4K family and other TCR signaling-related kinases, such as FYN and ZAP70. Inhibition of HPK1 by BB3008 strongly suppresses the phosphorylation at Ser376 of the downstream biomarker protein SLP-76, with IC50 at 30 nM. With the stimulation of CD3/CD28, boost of IL-2 production was observed in Jurkat cells, purified human T cells, and human peripheral blood mononuclear cells upon treatment of BB3008 at sub-micromolar concentration. BB3008 also enhanced the killing activity of T cell against EL4 lymphoma cell in vitro in a concentration-dependent manner. PK profile of BB3008 showed good bioavailability (>80%) with a nearly linear dose-dependent exposure. The compound had no significant suppression on various normal cell lines proliferation, and had no hERG liability. In preliminary safety evaluation, no abnormal clinical symptoms and serum/blood tests were observed in mice and dogs dosed up to 1000mpk and 150mpk for 14 days, respectively. BB3008 showed significant tumor-growth inhibition rates in CT26, Hepa 1-6 and 4T1 mouse models as single agent, and in MC-38 mouse model in combination with mouse PD-1 antibody.Conclusion: As a potent, selective and oral available small molecule HPK1 inhibitor, BB3008 shows good safety tolerance in preclinical animals, and promising efficacy in multiple solid tumor models, both as single agent or in combination with immune checkpoint blockade. The IND-enabling study of BB3008 is in progress.Citation Format: Gongping Duan, Min Li, Xingmin Zhang. BB3008, a potent and selective small molecular HPK1 inhibitor effective in multiple syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB324.

100 Deals associated with Beijing BroadenBio Co., Ltd.

100 Translational Medicine associated with Beijing BroadenBio Co., Ltd.

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Pipeline

Pipeline Snapshot as of 23 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

BB-102 (BroadenBio) ( FGFR4 )	Advanced Malignant Solid Neoplasm More	Phase 1
BB3008 ( HPK1 )	Advanced Malignant Solid Neoplasm More	Phase 1
BB-5523 ( HPK1 x TNIK x VEGFR2 )	Neoplasms More	Preclinical
BB-4506	Solid tumor More	Preclinical
BB-TME	Neoplasms More	Preclinical

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