A Phase Ib/II, Multi-site, Open-label, Two-part Trial to Evaluate the Efficacy, Safety, Pharmacokinetics, and Recommended Combination Dose of BNT324 With BNT327 in Participants With Advanced Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- BioNTech SE
- 入组人数
- 594
- 试验地点
- 104
- 主要终点
- Part 1 - Occurrence of dose limiting toxicities (DLTs) by dose level
研究概览
简要总结
This study aims to investigate the combination of BNT324, a B7-H3 antibody-drug conjugate (ADC) with BNT327, a programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) bispecific antibody, in participants with advanced/metastatic or relapsed/progressive small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC).
详细描述
This is a two-part study designed to evaluate and establish two safe combination dose levels (recommended Phase 2 dose [RP2D] and a lower/another combination dose level [RP2D-1]) of BNT324 with BNT327 (Part 1), to determine the optimal combination dose (dose optimization [DO]) in NSCLC and SCLC lead indication cohorts at the RP2D and RP2D-1, to evaluate the preliminary efficacy in selected lung cancer cohorts at the highest combination dose level (in a signal seeking Part 2), and to confirm the clinical efficacy of BNT324 in combination with BNT327 at the optimal dose level in participants with advanced lung cancer in expansion cohorts (proof-of-concept [POC] cohorts).
The study consists of a screening period, a treatment period, a safety follow-up period, and a long-term survival follow-up period.
In Part 1 participants with histologically or cytologically confirmed relapsed or progressive lung cancer (both SCLC and NSCLC are eligible) will receive BNT324 in combination with BNT327 using a dose escalation design.
In Part 2 of the study, BNT324 will be studied in combination with BNT327 at the RP2D compared to RP2D-1 in participants with advanced metastatic treatment-naïve NSCLC (DO Cohort 1) and relapsed/progressive SCLC after failure of cytotoxic chemotherapy with or without immuno-oncology (IO) (DO Cohort 2). The totality of the available data (e.g., safety, efficacy, pharmacokinetics etc.) will be reviewed to select the optimal dose. After the optimal dose is selected, additional participants in each cohort may be enrolled in the selected optimal dose.
In the signal seeking cohorts (Cohort 3-7), participants will receive BNT324 in combination with BNT327 at the RP2D from Part 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Aged ≥18 years at the time of giving informed consent.
- •Histological or cytological confirmed unresectable advanced/metastatic lung cancer. Histological classification may be based on tumor samples prior to metastatic disease. Participants with mixed histology must be classified based on the main component. Participants with NSCLC are eligible with any or no PD-L1 expression. Participants with AGA-positive disease must have received targeted therapy prior to enrollment in this study.
- •Part 1: Participants with NSCLC and SCLC
- •Part 2 Cohort 1: Participants with NSCLC (subpopulation 1) AGA negative, 1L
- •Part 2 Cohort 2: Participants with SCLC, 2L+
- •Part 2 Cohort 3: Participants with NSCLC (subpopulation 1) AGA negative, 2L+
- •Part 2 Cohort 4: Participants with NSCLC (subpopulation 2) AGA negative, 1L
- •Part 2 Cohort 5: Participants with NSCLC (subpopulation 2) AGA negative, 2L+
- •Part 2 Cohort 6: Participants with NSCLC AGA positive
- •Part 2 Cohort 7: Participants with SCLC, 1L
- •Have measurable disease defined by RECIST version 1.
- •Have an Eastern Cooperative Oncology Group performance status of 0 or
- •Have a life expectancy of ≥12 weeks.
排除标准
- •Prior treatment with B7-H3 targeted therapy.
- •Prior treatment with ADC with topoisomerase inhibitor (e.g., datopotamab deruxtecan, trastuzumab deruxtecan). Note: This exclusion applies to participants in the first-line/treatment-naïve cohorts in the advanced/metastatic setting. Prior treatment with ADC with topoisomerase inhibitor payload is only allowed for participants in the second-line plus cohorts in the advanced/metastatic setting.
- •Is a candidate to locoregional treatment (including surgical resection, stereotactic radiotherapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as "radical" intent), per investigator's assessment.
- •Has a history of significant hematologic toxicity to prior lines of therapy, as assessed by investigator, e.g., Grade 4 febrile neutropenia or recurrent/persistent Grade 3 to 4 neutropenia.
- •NOTE: Other protocol defined Inclusion/Exclusion criteria may apply to all or some participants depending on the cohort.
研究组 & 干预措施
Part 2 - Cohort 3: RP2D of BNT324 + BNT327
In subpopulation 1 of NSCLC AGA negative, 2L+
干预措施: BNT324 (Biological)
Part 1 - BNT324 + BNT327 combination therapy
Escalating combination dose levels of BNT324 and BNT327 to define RP2D and RP2D-1 for NSCLC and SCLC.
干预措施: BNT327 (Biological)
Part 2 - Cohort 1: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327
In subpopulation 1 of NSCLC actionable oncogenic alteration (AGA) negative, first-line (1L)
干预措施: BNT324 (Biological)
Part 2 - Cohort 3: RP2D of BNT324 + BNT327
In subpopulation 1 of NSCLC AGA negative, 2L+
干预措施: BNT327 (Biological)
Part 2 - Cohort 1: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327
In subpopulation 1 of NSCLC actionable oncogenic alteration (AGA) negative, first-line (1L)
干预措施: BNT327 (Biological)
Part 2 - Cohort 2: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327
In SCLC, second-line plus (2L+)
干预措施: BNT324 (Biological)
Part 2 - Cohort 4: RP2D of BNT324 + BNT327
In subpopulation 2 of NSCLC AGA negative, 1L
干预措施: BNT327 (Biological)
Part 2 - Cohort 2: RP2D of BNT324 + BNT327 and RP2D-1 of BNT324 + BNT327
In SCLC, second-line plus (2L+)
干预措施: BNT327 (Biological)
Part 2 - Cohort 4: RP2D of BNT324 + BNT327
In subpopulation 2 of NSCLC AGA negative, 1L
干预措施: BNT324 (Biological)
Part 2 - Cohort 7: RP2D of BNT324 + BNT327
In SCLC, 1L
干预措施: BNT327 (Biological)
Part 2 - Cohort 5: RP2D of BNT324 + BNT327
In subpopulation 2 of NSCLC AGA negative, 2L+
干预措施: BNT327 (Biological)
Part 1 - BNT324 + BNT327 combination therapy
Escalating combination dose levels of BNT324 and BNT327 to define RP2D and RP2D-1 for NSCLC and SCLC.
干预措施: BNT324 (Biological)
Part 2 - Cohort 5: RP2D of BNT324 + BNT327
In subpopulation 2 of NSCLC AGA negative, 2L+
干预措施: BNT324 (Biological)
Part 2 - Cohort 7: RP2D of BNT324 + BNT327
In SCLC, 1L
干预措施: BNT324 (Biological)
Part 2 - Cohort 6: RP2D of BNT324 + BNT327
In NSCLC AGA positive
干预措施: BNT324 (Biological)
Part 2 - Cohort 6: RP2D of BNT324 + BNT327
In NSCLC AGA positive
干预措施: BNT327 (Biological)
结局指标
主要结局
Part 1 - Occurrence of dose limiting toxicities (DLTs) by dose level
时间窗: During the DLT evaluation period, i.e., the time of initiation of the first dose of investigational medicinal product (IMP) up to 21 days]
Part 1 - Occurrence of Treatment-emergent adverse events (TEAEs), serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by dose level
时间窗: From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 1 - Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs by dose level
时间窗: From the time of the first dose of IMP to 90 days after the last dose of IMP or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm
时间窗: From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm
时间窗: From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first
Part 2 cohorts 1 and 2 - Objective response rate (ORR) by cohort and treatment arm
时间窗: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
ORR defined as the proportion of participants in whom a confirmed complete response (CR) or partial response (PR) is observed as best overall response (per response evaluation criteria in solid tumors \[RECIST\] version 1.1 based on the investigator's assessment).
Part 2 cohorts 3-7 - ORR by cohort
时间窗: From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months
ORR, defined as the proportion of participants in whom a confirmed CR or PR is observed as best overall response (per RECIST version 1.1 based on the investigator's assessment).
次要结局
- Part 1 - ORR by dose level(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 1 - Disease control rate (DCR) by dose level(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 all cohorts - (PFS) by cohort and treatment arm(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 all cohorts - Duration of response (DOR) by cohort and treatment arm(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 all cohorts - Overall survival (OS) by cohort and treatment arm(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 all cohorts - DCR by cohort and treatment arm(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 all cohorts - Time to response (TTR) by cohort and treatment arm(From the time of initiation of the first dose of IMP to end of study, i.e., up to 87 months)
- Part 2 cohorts 3-7 - Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs by cohort and treatment arm(From the time of the first dose of IMPs to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first)
- Part 2 cohorts 3-7 - Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs by cohort and treatment arm(From the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first)