A Phase 1b Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd) in Combination With Other Anti-cancer Agents in Patients With Metastatic HER2-low Breast Cancer (DESTINY-Breast08)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 138
- 试验地点
- 38
- 主要终点
- Occurrence of adverse events (AEs)- Part 1
研究概览
简要总结
DESTINY-Breast 08 will investigate the safety, tolerability, PK and preliminary anti-tumour activity of T-DXd in combination with other therapies in patients with Metastatic HER2-low Advanced or Metastatic Breast Cancer
详细描述
This study is modular in design allowing assessment of the safety, tolerability, PK and preliminary anti-tumour activity of T-DXd in combination with other therapies. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the Part 2 dose-expansion phase will use the RP2D determined in Part 1.
The target population of interest in this study is patients with HER2-low (IHC 1+ or IHC 2+/ISH -) (as per ASCO/CAP 2018 guidelines) advanced/MBC. Part 1 of each module will enroll patients with locally confirmed HER2-low advanced/MBC in second-line or later (≥ 2L) settings
Part 2 of each module will enroll patients with HER2-low MBC who have either not received prior treatment, or received only 1 prior treatment (depending on the module-specific exclusion criteria) for advanced/metastatic disease
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Patients must be at least 18 years of age
- •Male or female patients who have pathologically documented breast cancer that:
- •Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay
- •Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines in the metastatic setting
- •Patient must have adequate tumor sample for biomarker assessment
- •ECOG Performance Status of 0 or 1
- •For patients with HR+ disease:
- •Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.
- •Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and
- •For patients with HR- disease:
- •Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and
- •Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and
排除标准
- •Uncontrolled intercurrent illness
- •Uncontrolled or siginificant cardiovascular disease
- •History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- •Lung-specific intercurrent clinically significant illnesses
- •Has spinal cord compression or clinically active central nervous system metastases
- •Active primary immunodeficiency
- •Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- •Prior treatment with ADC that comprises of an exatecan derivative that is a topoisomerase I inhibitor.
结局指标
主要结局
Occurrence of adverse events (AEs)- Part 1
时间窗: Up to follow-up period, approximately 24 months
Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of serious adverse events (SAEs)- Part 1
时间窗: Up to follow-up period, approximately 24 months
Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of adverse events (AEs)- Part 2
时间窗: Up to follow-up period, approximately 24 months
Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0
Occurrence of serious adverse events (SAEs)- Part 2
时间窗: Up to follow-up period, approximately 24 months
Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0
Part 2: AEs, SAEs, laboratory findings
Part 2: AEs, SAEs, laboratory findings
Part 1: AEs, SAEs, DLTs, laboratory findings
Part 1: AEs, SAEs, DLTs, laboratory findings
次要结局
- Objective Response Rate (ORR)- Part 2(Until progression, assessed up to approximately 24 months)
- Progression Free Survival (PFS)- Part 2(Until progression or death, assessed up to approximately 24 months)
- Duration of Response (DoR)- Part 2(Until progression or death, assessed up to approximately 24 months)
- Overall Survival (OS)- Part 2(Until death, assessed up to approximately 24 months)
- Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a(While on study drug up to study completion, approximately 24 months)
- Immunogenicity of trastuzumab deruxtecan(Up to follow-up period, approximately 24 months)
- Serum Concentration of durvalumab(While on study drug up to study completion, approximately 24 months)
- Immunogenicity of durvalumab(Up to follow-up period, approximately 24 months)
- Part 2: ORR defined as the proportion of patients who have a confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1
- Part 2: PFS defined as time from the date of first dose until the date of progression as determined by the investigator at local site per RECIST 1.1, or death due to any cause
- Part 2: DoR defined as time from the date of first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression
- Part 2: OS defined as time from the date of first dose until the date of death by any cause
- Serum concentration of T-DXd, total anti-HER2 antibody and MAAA- 1181a
- Serum concentration of durvalumab
- Immunogenicity of T-DXd and durvalumab