A Phase I/II, Multi-site, Open-label, Two-part Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of BNT323 in Combination With BNT327 in Participants With Advanced Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- BioNTech SE
- 入组人数
- 380
- 试验地点
- 90
- 主要终点
- Part 1 - Occurrence of dose limiting toxicities (DLTs)
研究概览
简要总结
This is a Phase I/II, multi-site, open-label, two-part study designed to evaluate the efficacy, safety, optimized dose and contribution of components of BNT323 (also known as trastuzumab pamirtecan and DB-1303) in combination with BNT327 (also known as pumitamig and PM8002) in participants with hormone receptor-positive (HR+) or hormone receptor-negative (HR-), Human epidermal growth factor receptor (HER)2-positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization -), HER2-ultralow (IHC 0, with membrane staining) or HER2-null breast cancer (BC), or triple-negative breast cancer (TNBC).
详细描述
The study consists of two parts:
- Part 1 - Dose escalation: In this part of the study, participants with histologically confirmed, chemotherapy-pretreated advanced HR+, HER2-low or HER2-ultralow BC will receive BNT323 in combination with BNT327 (BNT323 + BNT327) in a dose escalation design. This will define the recommended Phase 2 dose (RP2D) for the BNT323 + BNT327 combination therapy.
- Part 2 - Dose optimization and exploratory cohorts: This part of the study will be an expansion phase, aiming to evaluate the efficacy and safety of the optimal dose combination and providing a more robust comparison against the other treatments. It will start once the enrollment in Part 1 is completed and the sponsor in conjunction with the Safety Review Committee has assessed available Part 1 efficacy and safety data. Part 2 of the study will have four cohorts, i.e., Cohorts 1 (dose optimization cohort), and Cohorts 2, 3, and 4 (exploratory cohorts). Recruitment to Cohorts 2, 3, and 4 will begin with RP2D from Part 1 and in parallel to randomization in Cohort 1.
Randomization is planned for Cohort 1 in Part 2, i.e., participants will be randomized in 2:2:1:1 ratio into one of the four arms (Arms 1-4). No randomization is planned for any other cohort in Part 2.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- All
- 接受健康志愿者
- 否
入选标准
- •(applicable to all participants and all parts unless otherwise specified):
- •Have pathologically documented BC that:
- •Is locally advanced, unresectable or metastatic.
- •Has a confirmed HER2 status as determined by the local laboratory as standard of care testing prior to study screening (Part 1, Part 2 Cohorts 2 and 4) or the central laboratory (Part 2, Cohorts 1 and 3) from the most recently collected pre-randomization tumor sample.
- •Has a documented history of HER2 expression consistent with the subgroup definitions (i.e., HER2-low, HER2-ultralow, HER2-null, HER2-positive, or TNBC) as per current American Society of Clinical Oncology/College of American Pathologists guidelines.
- •Have measurable disease defined by RECIST v1.
- •Has left ventricular ejection fraction ≥55% by either echocardiography or multi-gated acquisition (scanning) within 28 days before randomization/enrollment.
排除标准
- •Have history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.
- •Have an uncontrolled intercurrent illness that would limit compliance with study requirement or substantially increase risk of incurring adverse events.
- •Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.
- •Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- •Had prior treatment with topoisomerase I inhibitors, including antibody-drug conjugates with topoisomerase I inhibitor payloads such as trastuzumab deruxtecan.
- •Have received any of the following therapies or drugs prior to the initiation of the study:
- •Participants who have received prior treatment with BNT
- •Participants who received prior treatment with a programmed death-ligand 1 (PD-L1) / vascular endothelial growth factor (VEGF) bispecific antibody. Note: Prior treatment with programmed death 1 (PD-1)/VEGF bispecific antibodies, PD-1/PD-L1 inhibitors or anti-VEGF therapies are permitted.
- •Have received other systemic immunostimulatory agents or immunosuppressive therapies (such as interferon-α, interleukin-2, or methotrexate) within 4 weeks prior to the initiation of study treatment or are within five half-lives of the treatment drug (whichever is longer). Exception: excluding local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens).
- •Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior to the initiation of study treatment.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria apply.
研究组 & 干预措施
Part1 - BNT323 + BNT327 combination therapy
Escalating dose levels (DLs) of BNT323 and BNT327 to define RP2D. Six DLs are planned, i.e., DL0-1, DL1-1, DL2-1, DL0-0, DL1-0, DL2-0, a combination of three different DLs for BNT323 (DL0, DL1, and DL2) and two DLs for BNT327 (DL0 and DL1).
干预措施: BNT323 (Drug)
Part 2 Cohort 1 - Arm 1 - RP2D of BNT323 + BNT327
干预措施: BNT323 (Drug)
Part1 - BNT323 + BNT327 combination therapy
Escalating dose levels (DLs) of BNT323 and BNT327 to define RP2D. Six DLs are planned, i.e., DL0-1, DL1-1, DL2-1, DL0-0, DL1-0, DL2-0, a combination of three different DLs for BNT323 (DL0, DL1, and DL2) and two DLs for BNT327 (DL0 and DL1).
干预措施: BNT327 (Drug)
Part 2 Cohort 1 - Arm 2 - BNT323 + BNT327
干预措施: BNT327 (Drug)
Part 2 Cohort 1 - Arm 3 - BNT323 monotherapy
BNT323 monotherapy at a fixed dose
干预措施: BNT323 (Drug)
Part 2 Cohort 4 - RP2D of BNT323 + BNT327
干预措施: BNT323 (Drug)
Part 2 Cohort 4 - RP2D of BNT323 + BNT327
干预措施: BNT327 (Drug)
Part 2 Cohort 2 - RP2D of BNT323 + BNT327
干预措施: BNT323 (Drug)
Part 2 Cohort 1 - Arm 1 - RP2D of BNT323 + BNT327
干预措施: BNT327 (Drug)
Part 2 Cohort 1 - Arm 4 - BNT327 monotherapy
BNT327 monotherapy at a fixed dose
干预措施: BNT327 (Drug)
Part 2 Cohort 3 - RP2D of BNT323 + BNT327
干预措施: BNT323 (Drug)
Part 2 Cohort 2 - RP2D of BNT323 + BNT327
干预措施: BNT327 (Drug)
Part 2 Cohort 1 - Arm 2 - BNT323 + BNT327
干预措施: BNT323 (Drug)
Part 2 Cohort 3 - RP2D of BNT323 + BNT327
干预措施: BNT327 (Drug)
结局指标
主要结局
Part 1 - Occurrence of dose limiting toxicities (DLTs)
时间窗: During the DLT evaluation period (Cycle 1), i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days
By dose level.
Occurrence of Treatment-emergent adverse events (TEAEs), Grade ≥3 TEAEs, serious adverse events (SAEs), treatment-related TEAEs, treatment-related Grade ≥3 TEAEs, and treatment-related SAEs
时间窗: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
In Part 1 by dose level. In Part 2 by cohort and arm.
Occurrence of dose interruption, reduction, and discontinuation due to TEAEs
时间窗: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
In Part 1 by dose level. In Part 2 by cohort and arm.
Part 1 - Occurrence of dose limiting toxicities (DLTs)
时间窗: During the DLT evaluation period (Cycle 1), i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days
By dose level.
Part 2 - Objective response rate (ORR)
时间窗: From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.
ORR defined as the proportion of participants in whom a confirmed complete response (CR) or partial response (PR) (per Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST v1.1\] based on the investigator's assessment) is observed as best overall response. By cohort and arm.
Occurrence of Treatment-emergent adverse events (TEAEs), Grade ≥3 TEAEs, serious adverse events (SAEs), treatment-related TEAEs, treatment-related Grade ≥3 TEAEs, and treatment-related SAEs
时间窗: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
In Part 1 by dose level. In Part 2 by cohort and arm.
Occurrence of dose interruption, reduction, and discontinuation due to TEAEs
时间窗: From the time of initiation of the first dose of IMP to 90 days after the last IMP dose
In Part 1 by dose level. In Part 2 by cohort and arm.
次要结局
- Part 1 - ORR(From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.)
- Part 2 - Disease control rate (DCR)(From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.)
- Part 2 - Time to response (TTR)(From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.)
- Part 2 - Duration of response (DoR)(From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.)
- Part 2 Cohort 1 only - Progression free survival (PFS)(From the time of initiation of the first dose of IMP to last tumor assessment scan, i.e., up to 36 months.)