Phase I/IIa, First-in-human, Open-label, Dose Escalation Trial With Expansion Cohorts to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of BNT141 as a Monotherapy and in Combination With Other Anti-cancer Agents in Patients With CLDN18.2-positive Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- BioNTech SE
- 入组人数
- 13
- 试验地点
- 7
- 主要终点
- Occurrence of Treatment-emergent Adverse Events (TEAEs) Within a Patient Including Grade ≥ 3, Serious, Fatal TEAE by Relationship
研究概览
简要总结
This study was planned as an open-label, multi-site, Phase I/IIa dose escalation, safety, and pharmacokinetic (PK) trial of BNT141 followed by expansion cohorts in patients with Claudin 18.2 (CLDN18.2)-positive tumors.
The sponsor decided to stop the development of BNT141 on 24 July 2023 and the study was terminated early.
详细描述
The study design consisted of three parts:
- Part 1A was a dose escalation of BNT141 as monotherapy in patients with advanced unresectable or metastatic CLDN18.2-positive solid tumors for which there was no available standard therapy considered to confer clinical benefit, or the patient was not a candidate for such available therapy. The dose of BNT141 was planned to be escalated until the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of BNT141 as monotherapy was defined. However, due to the early study termination, the dose of BNT141 was not fully escalated as planned per protocol (i.e., only four doses were tested, i.e., 0.15 mg/kg, 0.30 mg/kg, 0.45 mg/kg, and 0.60 mg/kg). Once the MTD was reached, up to 10 additional patients with CLDN18.2 expressing pancreatic and biliary tract cancers were planned to be enrolled at the MTD level to obtain additional data on safety, PK and pharmacodynamics (PD). Eligible tumor types were gastric cancer, gastroesophageal junction (GEJ) and esophageal adenocarcinoma, pancreatic, biliary tract (cholangiocarcinoma and gallbladder cancer), and mucinous ovarian cancers. Additionally, patients with specific tumors (including colorectal cancer, non-small-cell lung cancer, gastric subtype of endocervical adenocarcinoma) where there is scientific evidence that the CLDN18.2 could be elevated could be tested for CLDN18.2 expression.
- Part 1B was planned to be a dose escalation of BNT141 in combination with nab-paclitaxel and gemcitabine in patients with locally advanced unresectable or metastatic CLDN18.2-positive pancreatic adenocarcinoma or cholangiocarcinoma who were eligible for treatment with nab-paclitaxel and gemcitabine. Part 1B intended to define the MTD and/or RP2D of the combination. Once the MTD was reached, up to 10 additional patients with CLDN18.2-expressing pancreatic adenocarcinoma or cholangiocarcinoma were planned to be enrolled at the MTD level to obtain additional data on safety, PK and PD. The MTD of BNT141 in combination with nab-paclitaxel and gemcitabine in Part 1B was planned to not exceed the monotherapy BNT141 MTD determined in Part 1A.
- Part 2 (Expansion) was planned to consist of two predefined expansion cohorts in patients with CLDN18.2-positive solid tumors eligible for treatment with nab-paclitaxel and gemcitabine.
Part 1B and Part 2 did not proceed and no participant was enrolled in Part 1B and Part 2.
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
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part 1A - BNT141 monotherapy escalation
Administration once every three weeks (Q3W)
干预措施: BNT141 (Drug)
Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine
BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle.
干预措施: BNT141 (Drug)
Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine
BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle.
干预措施: Nab-paclitaxel (Drug)
Part 1B - BNT141 in combination with nab-paclitaxel and gemcitabine
BNT141 was planned to be administered Q3W. Nab-paclitaxel and gemcitabine was planned to be administered on three days of each 28-day cycle.
干预措施: Gemcitabine (Drug)
Part 2 - predefined expansion cohorts
BNT141 in combination with nab-paclitaxel and gemcitabine
干预措施: BNT141 (Drug)
Part 2 - predefined expansion cohorts
BNT141 in combination with nab-paclitaxel and gemcitabine
干预措施: Nab-paclitaxel (Drug)
Part 2 - predefined expansion cohorts
BNT141 in combination with nab-paclitaxel and gemcitabine
干预措施: Gemcitabine (Drug)
结局指标
主要结局
Occurrence of Treatment-emergent Adverse Events (TEAEs) Within a Patient Including Grade ≥ 3, Serious, Fatal TEAE by Relationship
时间窗: From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks.
All TEAEs are included, i.e., AEs with an onset date on or after the first dose of BNT141 (if the AE was absent before the first dose) or worsened after the first dose of BNT141 (if the AE was present before the first dose). AEs with an onset date \>60 days after the last dose of BNT141 are included only if assessed as related to BNT141 by the investigator. Intensity of AEs was graded according to the NCI CTCAE v5.0, i.e.,: Grade 1 - Mild, Grade 2 - Moderate, Grade 3 - Severe, Grade 4 - Life-threatening consequences; urgent urgent intervention indicated, Grade 5 - Death related to AE
Occurrence of Dose Reductions and Discontinuation of BNT141 Due to TEAEs
时间窗: From start of BNT141 treatment until the second Safety Follow-up Visit (60 ± 7 days after last dose), up to 30 weeks.
All TEAEs are included, i.e., AEs with an onset date on or after the first dose of BNT141 (if the AE was absent before the first dose) or worsened after the first dose of BNT141 (if the AE was present before the first dose). AEs with an onset date \>60 days after the last dose of BNT141 are included only if assessed as related to BNT141 by the investigator
Occurrence of Dose-limiting Toxicities (DLTs) Within a Patient During the DLT Evaluation Period
时间窗: First treatment cycle (From first dose up to 21 days after first dose)
Serious AEs, non-serious Grade ≥ 3 non-hematological and hematological AEs as defined per DLT criteria and clinically significant abnormal laboratory values Grade ≥ 3 were collected and considered a DLT if assessed by the investigator to be at least possibly related to BNT141. Toxicities clearly not related to BNT141 (e.g., progressive disease, comorbidity, etc.) were not considered a DLT. The NCI CTCAE v.5.0 was used to grade the intensity of AEs.
次要结局
- RiboMab PK Parameter - Area Under the Concentration Time Curve (AUC)(First treatment cycle (From first dose up to 21 days after first dose))
- RiboMab PK Parameter - Clearance(First treatment cycle (From first dose up to 21 days after first dose))
- RiboMab PK Parameter - Volume of Distribution at Steady State (Vss)(First treatment cycle (From first dose up to 21 days after first dose))
- RiboMab PK Parameter - Maximum Serum Drug Concentration (Cmax)(First treatment cycle (From first dose up to 21 days after first dose))
- RiboMab PK Parameter - Time to Reach Cmax (Tmax)(First treatment cycle (From first dose up to 21 days after first dose))
- RiboMab PK Parameter - Concentration at the End of a Dosing Interval (Taken Directly Before Next Administration) (Ctrough)(Before start of Cycle 3 (plasma sample taken directly before BNT141 Cycle 3 administration))
- RiboMab PK Parameter - Half-time (t½)(First treatment cycle (From first dose up to 21 days after first dose))
- Objective Response Rate (ORR)(From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks)
- Disease Control Rate (DCR)(From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks)
- Duration of Response (DoR)(From start of first dose of BNT141 until end of trial or start of a new anti-cancer therapy, up to 30 weeks)