A Phase 1/2, Open-Label, Dose-Escalation and -Expansion Study of the Bruton Tyrosine Kinase Targeted Protein Degrader BGB-16673 in Patients With B-Cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 645
- 试验地点
- 202
- 主要终点
- Phase 1: Number of Participants with Adverse Events (AEs)
研究概览
简要总结
Study consists of two main parts to explore tacabrutideg recommended dosing, a Phase 1 monotherapy dose finding comprised of monotherapy dose escalation and monotherapy safety expansion of selected doses, and a Phase 2 (expansion cohorts)
详细描述
Our company, previously known as BeiGene, is now officially BeOne Medicines. Because some of our older studies were sponsored under the name BeiGene, you may see both names used for this study on this website.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis (per World Health Organization (WHO) guidelines, unless otherwise noted) of one of the following: Marginal Zone Lymphoma (MZL), R/R follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL), Waldenström macroglobulinemia (WM), R/R diffuse large B-cell lymphoma (DLBCL), or Richter's transformation to DLBCL.
- •Participants who have previously received a covalently-binding Bruton´s tyrosine kinase (BTK) inhibitor (BTKi) in any line of therapy must have received treatment with the BTK inhibitor for ≥ 8 weeks (unless reason for discontinuation is intolerance).
- •For dose-finding and dose-expansion, participants who had previously received a covalently-binding BTK inhibitor as monotherapy or in combination with other anticancer agents are eligible for the study if they meet any of the following criteria: discontinued the previous BTK inhibitor due to disease progression, experienced disease progression after completing treatment with a BTK inhibitor or discontinued the BTK inhibitor due to toxicity or intolerance.
- •Phase 2 Cohorts in R/R CLL/SLL, R/R MCL, and R/R WM only: Participants who previously received a BTKi are eligible if they had disease progression on only one regimen containing a covalent BTKi. Note: Participants may have received treatment with ≥ 2 different covalent BTKis if additional BTKis were discontinued secondary to an event other than disease progression.
- •Measurable disease by radiographic assessment or serum IgM level (WM only)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
- •Participants enrolling in the dose finding phase of the study may be previously treated with a BTKi or may be naïve to BTKi therapy depending on the diagnosis and country of enrollment; participants with MCL enrolling in the expansion cohorts (Phase 2) must have been treated with a BTKi in a prior line of therapy; CLL/SLL participants, in addition to being treated with a BTKi in a prior line of therapy, must also have received a Bcl-2 inhibitor in a prior line of therapy as well (Phase 2).
排除标准
- •Prior malignancy (other than the disease under study) within the past 2 years, except in situ malignancies that have been curatively resected, localized breast cancer treated with curative intent with no evidence of breast active disease for more than 3 years and receiving adjuvant hormonal therapy, localized Gleason score ≤ 6 prostate cancer undergoing observation or treatment with androgen depravation, or any other cancer treated with curative intent, not on adjuvant treatment, and in the opinion of the investigator is unlikely to recur.
- •Requires ongoing systemic treatment for any other malignancy
- •Requires ongoing systemic (defined as ≥ 10 mg/day of prednisone or equivalent) corticosteroid treatment.
- •Current or history of central nervous system involvement including the brain, spinal cord, leptomeninges, and cerebrospinal fluid (as documented by imaging, cytology, or biopsy) by B-cell malignancy, regardless of whether participants had received treatment for central nervous system disease
- •Known active plasma cell neoplasm, prolymphocytic leukemia, T-cell lymphoma, Burkitt lymphoma, acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, Castleman disease, post-transplant lymphoproliferative disorders, hairy cell leukemia, germinal center B-cell (GCB), DLBCL, EBV+ DLBCL NOS, primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL - leg type, DLBCL associated with chronic inflammation, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, primary effusion lymphoma, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, high-grade B-cell lymphoma - NOS, B-cell lymphoma unclassifiable with features intermediate between DLBCL and classical Hodgkin lymphoma, or history of or currently suspected transformation of an indolent lymphoma to an aggressive histology (except for participants with Richter Transformation to DLBCL are eligible for Part 1a, 1c, or Phase 2 and participants with history of follicular lymphoma transforming to non-GCB DLBCL who are eligible for Part 1a, 1c, or Phase 2).
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
Part 1a (Monotherapy Dose Escalation)
Dose escalation in specific subtypes of non-Hodgkin lymphoma (NHL), including relapsed or refractory (R/R) marginal zone lymphoma (MZL), R/R follicular lymphoma (FL) Grades 1, 2, and 3a, R/R mantle cell lymphoma (MCL), R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), R/R diffuse large B-cell lymphoma (DLBCL), R/R Richter's transformation (RT), and R/R Waldenström macroglobulinemia (WM), to evaluate the safety and tolerability of tacabrutideg.
干预措施: Tacabrutideg (Drug)
Part 1b (Monotherapy Safety Expansion)
Participants with R/R MZL, MCL, CLL/SLL, and WM will be enrolled at selected doses to help determine the recommended dose(s) for expansion (RDFE(s)) for tacabrutideg.
干预措施: Tacabrutideg (Drug)
Phase 2 (Monotherapy Expansion)
Cohorts of participants with R/R CLL/SLL, R/R MCL, R/R WM, R/R MZL, R/R FL, R/R RT, and R/R DLBCL will be enrolled to receive the RDFE(s) identified in Phase 1 to further evaluate the safety and efficacy of tacabrutideg.
干预措施: Tacabrutideg (Drug)
Part 1c (Additional Monotherapy Safety Expansion)
Additional safety data will be collected from participants with R/R MZL, WM, RT, DLBCL, or FL to confirm the RDFE(s) of tacabrutideg for those with non-CLL/SLL/MCL histologies.
干预措施: Tacabrutideg (Drug)
Part 1f (Additional Monotherapy Safety Expansion in BTKi Naive B-Cell Malignancies)
Participants with CLL/SLL, MCL, WM, MZL, or Richter's transformation to DLBCL who have not received a prior BTKi (either covalent or noncovalent) will be enrolled at selected dose levels.
干预措施: Tacabrutideg (Drug)
Part 1d (Additional Monotherapy Safety Expansion in R/R CLL/SLL)
Participants with R/R CLL/SLL will be enrolled at selected RDFE(s) to generate additional safety and efficacy data for tacabrutideg.
干预措施: Tacabrutideg (Drug)
Part 1e (Japan-only Cohort)
Japanese participants with R/R MZL, FL, MCL, CLL/SLL, and WM will be enrolled at selected RDFE(s) to assess the safety and tolerability of tacabrutideg.
干预措施: Tacabrutideg (Drug)
结局指标
主要结局
Phase 1: Number of Participants with Adverse Events (AEs)
时间窗: From the first dose of BGB-16673 until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (Up to 47 weeks)
Number of participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) including results from laboratory assessments, electrocardiograms (ECGs), and physical examinations, and that meet protocol-defined dose-limiting toxicities (DLTs); as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.
Phase 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-16673
时间窗: Approximately 28 days
MTD is defined as the highest evaluated dose with an estimated toxicity rate closest to the target, while MAD is the highest dose given if MTD is not reached.
Phase 2: Overall response rate (ORR)
时间窗: approximately 3 years
Defined as the percentage of participants achieving a best overall response of partial response (PR) or better, assessed by the Independent Review Committee for participants with R/R CLL/SLL and R/R WM (in participants with WM, this is also referred to as major response rate) and by the investigator for other cohorts (R/R MCL, R/R MZL, R/R FL, R/R non-GCB DLBCL, R/R Richter's transformation to DLBCL), evaluated using the Lugano criteria for NHL and SLL, International Workshop of Chronic Lymphocytic Leukemia (iwCLL) criteria for CLL, and the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) criteria for WM.
Phase 1: Number of Participants with Adverse Events (AEs)
时间窗: From the first dose of tacabrutideg until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (Up to 47 weeks)
Number of participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) including results from laboratory assessments, electrocardiograms (ECGs), and physical examinations, and that meet protocol-defined dose-limiting toxicities (DLTs); as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.
Phase 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Tacabrutideg
时间窗: Approximately 28 days
MTD is defined as the highest evaluated dose with an estimated toxicity rate closest to the target, while MAD is the highest dose given if MTD is not reached.
Phase 1: Recommended dose(s) for Expansion (RDFE) of tacabrutideg
时间窗: Approximately 3 years
RDFE of tacabrutideg alone will be determined based upon the MTD or MAD.
Phase 1: Number of Participants with Adverse Events (AEs)
时间窗: From the first dose of BGB-16673 until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (Up to 47 weeks)
Number of participants with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) including results from laboratory assessments, electrocardiograms (ECGs), and physical examinations, and that meet protocol-defined dose-limiting toxicities (DLTs); as graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.
Phase 1: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-16673
时间窗: Approximately 28 days
MTD is defined as the highest evaluated dose with an estimated toxicity rate closest to the target, while MAD is the highest dose given if MTD is not reached.
Phase 1: Recommended dose(s) for Expansion (RDFE) of BGB-16673
时间窗: Approximately 3 years
RDFE of BGB-16673 alone will be determined based upon the MTD or MAD.
Phase 2: Overall response rate (ORR)
时间窗: approximately 3 years
Defined as the percentage of participants achieving a best overall response of partial response (PR) or better, assessed by the Independent Review Committee for participants with R/R CLL/SLL and R/R WM (in participants with WM, this is also referred to as major response rate) and by the investigator for other cohorts (R/R MCL, R/R MZL, R/R FL, R/R non-GCB DLBCL, R/R Richter's transformation to DLBCL), evaluated using the Lugano criteria for NHL and SLL, International Workshop of Chronic Lymphocytic Leukemia (iwCLL) criteria for CLL, and the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) criteria for WM.
次要结局
- Single dose and steady-state maximum observed plasma concentration (Cmax) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent volume of distribution (Vz/F) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state accumulation ratios of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Bruton's tyrosine kinase (BTK) protein degradation in peripheral blood after BGB-16673 monotherapy(Week 1 Day 1 pre-dose; 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose and 8 hours post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state time to reach half of Cmax (T1/2) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state minimum observed plasma concentration (Cmin) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state time to reach Cmax (tmax) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state area under the plasma concentration-time curve (AUC) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Phase 1: Overall response rate (ORR)(approximately 3 years)
- Phase 1: Number of Participants with AEs in part 1e (Japan-only cohort )(From the first dose of BGB-16673 in Part 1e until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Phase 2: Recommended Phase 2 Dose (RP2D)(approximately 3 years)
- Phase 2: Number of Participants with AEs(From the first dose of BGB-16673 in Phase 2 until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Phase 2: Duration of Response (DOR)(approximately 3 years)
- Phase 2: Progression- Free Survival (PFS)(approximately 3 years)
- Phase 2: Overall Survival (OS)(approximately 3 years)
- Phase 2: Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionaire(Baseline and day 1 of Weeks 5, 13, 25, and 37)
- Phase 2: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Cancer Symptom Index - 18 (NFLymSI-18)(Baseline and day 1 of Weeks 5, 13, 25, and 37)
- Single dose and steady-state time to reach Cmax (tmax) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state maximum observed plasma concentration (Cmax) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state minimum observed plasma concentration (Cmin) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state elimination half-life (T1/2) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state area under the plasma concentration-time curve (AUC) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent total clearance of drug from plasma after oral administration (CL/F) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent volume of distribution (Vz/F) of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state accumulation ratios of tacabrutideg(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Bruton's tyrosine kinase (BTK) protein degradation in peripheral blood after tacabrutideg monotherapy(Week 1 Day 1 pre-dose; 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose and 8 hours post-dose; Week 9 Day 1 pre-dose.)
- Phase 1: Number of Participants with AEs in part 1e (Japan-only cohort)(From the first dose of tacabrutideg in Part 1e until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Phase 2: Number of Participants with AEs(From the first dose of tacabrutideg in Phase 2 until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Single dose and steady-state maximum observed plasma concentration (Cmax) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state minimum observed plasma concentration (Cmin) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state time to reach Cmax (tmax) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state time to reach half of Cmax (T1/2) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state area under the plasma concentration-time curve (AUC) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent total clearance of drug from plasma after oral administration (CL/F) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state apparent volume of distribution (Vz/F) of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Single dose and steady-state accumulation ratios of BGB-16673(Week 1 Day 1 pre-dose; 2, 4, 6, 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose; and 2, 4, 6, 8 post-dose; Week 9 Day 1 pre-dose.)
- Bruton's tyrosine kinase (BTK) protein degradation in peripheral blood after BGB-16673 monotherapy(Week 1 Day 1 pre-dose; 8, 24, 48, and 72 hours post-dose; Week 5 Day 1 pre-dose and 8 hours post-dose; Week 9 Day 1 pre-dose.)
- Phase 1: Overall response rate (ORR)(approximately 3 years)
- Phase 1: Response Rate in Participants with R/R CLL/SLL(approximately 3 years)
- Phase 1: Overall Response Rate in Participants with R/R WM(approximately 3 years)
- Phase 1: Number of Participants with AEs in part 1e (Japan-only cohort )(From the first dose of BGB-16673 in Part 1e until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Phase 2: Recommended Phase 2 Dose (RP2D)(approximately 3 years)
- Phase 2: Number of Participants with AEs(From the first dose of BGB-16673 in Phase 2 until 30 days after the last dose of the study drug or before the initiation of a new anticancer therapy, whichever occurs first (approximately 3 years))
- Phase 2: ORR in Participants with CLL/SLL assessed by investigators(approximately 3 years)
- Phase 2: Major Response Rate for Participants with WM assessed by investigator(approximately 3 years)
- Phase 2: Overall Response Rate for Participants with WM assessed by investigator and IRC(approximately 3 years)
- Phase 2: Rate of Very Good Partial Response (VGPR) or Better in Participants with WM Assessed by Investigator and IRC(approximately 3 years)
- Phase 2: Response Rate in Participants with R/R CLL/SLL Assessed by Investigator and IRC(approximately 3 years)
- Phase 2: Duration of Response (DOR)(approximately 3 years)
- Phase 2: Time to Overall Response (TTOR)(approximately 3 years)
- Phase 2: Time to Major Response (TTMR) in Participants with WM(approximately 3 years)
- Phase 2: Time to Response in Participants with R/R CLL/SLL Assessed by Investigator and IRC(approximately 3 years)
- Phase 2: Time to Response in Participants with WM Assessed by Investigator and IRC(approximately 3 years)
- Phase 2: Time to Next Treatment (TTNT)(approximately 3 years)
- Phase 2: Progression- Free Survival (PFS)(approximately 3 years)
- Phase 2: Overall Survival (OS)(approximately 3 years)
- Phase 2: Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionaire(Baseline and day 1 of Weeks 5, 13, 25, and 37)
- Phase 2: National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy Lymphoma Cancer Symptom Index - 18 (NFLymSI-18)(Baseline and day 1 of Weeks 5, 13, 25, and 37)