A Phase 1-2 Multicenter, Open Label Trial of H3B-6545, a Covalent Antagonist of Estrogen Receptor Alpha, in Women With Locally Advanced or Metastatic Estrogen Receptor-positive, HER2 Negative Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Eisai Inc.
- 入组人数
- 151
- 试验地点
- 38
- 主要终点
- Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
研究概览
简要总结
The primary purpose of phase 1 portion of this study is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of H3B-6545 in women with locally advanced or metastatic estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-negative breast cancer.
The primary purpose of phase 2 portion of this study is to estimate the efficacy of H3B-6545 in terms of best overall response rate, duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in all participants with ER-positive, HER2-negative breast cancer and in those with and without ER alpha mutation (including a clonal estrogen receptor 1 gene [ESR1] Y537S mutation).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Pre- or post-menopausal women.
- •ER-positive, HER2-negative breast cancer that is advanced or metastatic.
- •Progressed on prior therapy. Multiple prior lines of therapy allowed in Phase 1 and
- •Participants under amendment 6 (or subsequent amendments) must have received prior cyclin-dependent kinase (CDK4/6) inhibitor therapy. Up to one prior chemotherapy in the metastatic setting is allowed.
- •A recent archival tumor tissue obtained within 6 months prior to enrollment or a fresh tumor biopsy must be provided. A second biopsy after initiating trial therapy is not required.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or
- •Adequate bone marrow and organ function.
- •Participants under amendment 6 (or subsequent amendments) must have measurable disease at baseline as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
- •Participants under amendment 6 (or subsequent amendments) must have ESR1 Y537S mutation in absence of ESR1 D538G mutation as per the results of a central laboratory from a Nucleic Acids Whole Blood sample.
排除标准
- •Participants must have at least one measurable lesion.
- •Participant with inflammatory breast cancer.
- •Participant has received more than one prior chemotherapy regimen for metastatic disease (Phase 2 only).
- •Females of childbearing potential who are unable or unwilling to follow adequate contraceptive measures.
研究组 & 干预措施
H3B-6545 Arm 1: Dose escalation
干预措施: H3B-6545 (Drug)
H3B-6545 Arm 2: Phase 2
干预措施: H3B-6545 (Drug)
结局指标
主要结局
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
时间窗: Cycle 1 (Cycle length=28 days)
DLT was graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. DLTs were defined as the following events that occurred in Cycle 1, for which a causal relationship with the study drug could not be ruled out: febrile neutropenia; Grade 4 neutropenia that was not resolved within 7 days; Grade 4 thrombocytopenia; Grade 3 thrombocytopenia lasting greater than (\>) 7 days or associated with clinically significant bleeding; Grade 4 vomiting and diarrhea; Grade 3 vomiting and diarrhea lasting \>72 hours despite treatment; Grade 4 electrolyte abnormality or Grade 3 abnormality lasting \>24 hours; Grade 3 or 4 serum creatinine or bilirubin increase; Grade 4 biochemistry or Grade 3 lasting \>7 days; Grade 4 or Grade 3 or intolerable Grade 2 toxicities of any non-hematologic adverse event.
Phase 1 and Phase 2: Objective Response Rate (ORR)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of progressive disease (PD) or death, whichever occurred first (up to 33 months)
ORR was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as defined by the Investigator based on radiologic criteria. ORR was defined as the percentage of participants who achieved a best overall response of confirmed partial response (PR) or complete response (CR). CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to less than (\<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg dose was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
Phase 1 and Phase 2: Duration of Response (DoR)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)
The DoR was assessed according to RECIST version 1.1. DoR was defined as the time from the date of the first documented CR/PR until the first documentation of disease progression or death, whichever comes first. CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
Phase 1 and Phase 2: Disease Control Rate (DCR)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)
The DCR was assessed according to RECIST version 1.1. DCR was defined as the percentage of participants who achieved best response of CR, PR, or stable disease (SD). CR was defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters while on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
Phase 1 and Phase 2: Clinical Benefit Rate (CBR)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)
The CBR was assessed according to RECIST version 1.1. CBR defined as the percentage of participants with best overall response (BOR) of PR, CR, or durable SD (duration \>=23 weeks). It was calculated for participants whose BOR was SD. CR defined as disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) with reduction in short axis to \<10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (at least a 20% increase in the sum of diameters of target lesions) taking as reference the smallest sum diameters on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
Phase 1 and Phase 2: Progression-free Survival (PFS)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 33 months)
PFS was defined as the time from the first dose date to the date of the first documentation of PD or death whichever occurred first. PD defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum diameters while on study. As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
Phase 1 and Phase 2: Overall Survival (OS)
时间窗: Phase 1 and Phase 2: From the first dose of study drug to date of death or last known alive (up to 63 months)
OS was defined as the time from first dose date to the date of death (event) or date last known alive (censored). As per planned analysis, pooled data for phase 1 and phase 2 for 450 mg arm was presented as enrolled participants in both the phases had similar demographics and disease characteristics.
次要结局
- Phase 1 and 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From start of the study up to 74 months)
- Phase 1: (AUC0-t): Area Under the Plasma Concentration-time Curve From Time 0 Through the Last Measurable Point of H3B-6545(Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 1: Cmax: Maximum Observed Plasma Concentration for H3B-6545(Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 1: Tmax: Time of Maximum Observed Plasma Concentration of H3B-6545(Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 1: Rac (Cmax): Accumulation Ratio of Cmax for H3B-6545(Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 1: Rac (AUC0-24h): Accumulation Ratio of Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24h) for H3B-6545(Cycle 1 Days 1 and 15: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using AUC(0-24h)(Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 2: Relative Bioavailability (Food Effect) of H3B-6545 Assessed Using Cmax(Cycle 1 Days 15 and 22: predose and up to 24 hours postdose (Cycle length = 28 days))
- Phase 2: Mean Change From Baseline in Endometrial Thickness Due to H3B-6545(Baseline, Week 12, Week 36 and Week 60)
- Phase 2: Mean Change From Baseline in Uterine Volume Due to H3B-6545(Baseline, Week 12 and Week 36)
- Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Bone-specific Alkaline Phosphatase(Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days))
- Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - Amino-Terminal Propeptide of Type 1 Collagen (PINP)(Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days))
- Phase 1 and 2: Change From Baseline in Bone Turn-over Marker - C-terminal Cross-linking Telopeptide of Type 1 Collagen (CTX)(Baseline (predose), Cycle 2 Day 15, Cycle 4 Day 1, and off-Treatment (up to 33 months) (Cycle length = 28 days))