Phase 1/2a Open-Label, Dose-Escalation, Multicenter, FIH, Consecutive-Cohort, Clinical Trial of BI-1808, a Monoclonal Antibody to TNFR 2 as a Single Agent and in Combination With Pembrolizumab (MK-3475-D20) in Subjects With Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 250
- 试验地点
- 27
- 主要终点
- Occurrence of adverse events (AEs)
研究概览
简要总结
The goal of this first in human clinical trial is to test BI-1808 administered as single agent and in combination with pembrolizumab in subjects with advanced malignancies whose disease has progressed after standard therapy.
The main questions it aims to answer are:
- how safe and tolerable is BI-1808
- what is maximum tolerated or administrated dose
- to determine recommended dose for further clinical trials. Participants will receive infusions of with BI-1808 as a single agent, BI-1808 in combination with pembrolizumab and BI-1808 in combination with pembrolizumab and paclitaxel every 3 weeks.
For the purpose of this study, subjects with advanced malignancies includes subjects with advanced solid tumors and subjects with T-cell lymphoma (TCL),
详细描述
This is a Phase 1/2a, dose-escalation, multicenter, first-in-human, consecutive-cohort, open-label study of BI-1808, as a single agent, in combination with pembrolizumab, and in BI-1808 in combination with pembrolizumab and paclitaxel in subjects with advanced malignancies, whose disease has progressed after standard therapy.
The study will consist of 2 phases: a Phase 1 with Parts A and B, and a Phase 2a with Parts A , B and C.
Phase 1 Part A consists of a dose escalation of BI-1808 as a single agent to evaluate safety and tolerability and to determine the RP2D as a single agent (sRP2D) in subjects with advanced malignancies whose disease has progressed after standard therapy.
Phase 1 Part B consists of a dose escalation of BI-1808 in combination with pembrolizumab to evaluate the safety and tolerability of the combination treatment and to allow selection of the RP2D for BI-1808 in combination with pembrolizumab (cRP2D) in subjects with advanced malignancies whose disease has progressed after standard therapy.
Phase 2a will assess BI-1808 administered as a single agent (Part A), in combination with pembrolizumab (Part B), and in combination with pembrolizumab and paclitaxel (Part C) at the respective hypothesized RP2D(s) determined in Phase 1. Phase 2a expansion will be conducted in indication specific signal seeking cohorts and indication specific Dose Optimization Cohorts) of subjects. The Phase 2a study aims to further evaluate the safety and tolerability of BI-1808 as monotherapy (Part A), in combination with pembrolizumab (Part B), and in combination with pembrolizumab and paclitaxel (Part C). Including characterization of the PK and PD profiles of BI-1808, evaluation of preliminary antitumor activity based on ORR, DoR, and progression-free survival (PFS) as assessed by RECIST v1.1 and iRECIST, and determination of the recommended Phase 2 dose (RP2D).
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
- •Able and willing to provide written informed consent.
- •Aged 18 years or older.
- •Histologically confirmed advanced or metastatic malignancy eligible for an enrolling study cohort.
- •Disease progression following, intolerance of, ineligibility for, or refusal of applicable standard therapy.
- •At least one measurable lesion according to the response criteria specified in the protocol.
- •Eastern Cooperative Oncology Group performance status of 0 or
- •Life expectancy of at least 12 weeks.
- •Adequate organ function.
- •Willing and medically suitable to provide required tumor or skin biopsies.
- •Meets the disease-specific and treatment-history requirements of the applicable Phase 2a cohort.
- •For Phase 2a Part C: Histologically confirmed platinum-resistant high-grade serous or clear-cell ovarian carcinoma, prior platinum-based treatment as specified in the protocol, and suitability for paclitaxel treatment.
排除标准
- •1. Active central nervous system metastases or carcinomatous meningitis.
- •Active or clinically significant autoimmune disease, immunodeficiency, or use of prohibited immunosuppressive treatment.
- •Prior treatment-related toxicity not recovered to the level specified in the protocol.
- •Prior anticancer therapy, radiotherapy, immunotherapy, investigational treatment, or live vaccine within the protocol-defined washout period.
- •History of clinically significant immune-mediated toxicity, including pneumonitis, associated with previous immune-checkpoint inhibitor treatment.
- •Uncontrolled or clinically significant cardiovascular disease, serious infection, or another condition that could compromise safety or study participation.
- •Major surgery without adequate recovery.
- •Prior allogeneic tissue or solid-organ transplantation or active graft-versus-host disease.
- •Pregnancy or breastfeeding, or unwillingness to comply with protocol-defined contraceptive requirements.
- •Known hypersensitivity to a study treatment or its components.
- •Another active malignancy, except for protocol-defined permitted malignancies.
- •Participation in another interventional clinical trial that conflicts with this study.
- •Unable or unlikely to comply with study procedures and requirements.
- •For Phase 2a Part C: Receipt of prohibited colony-stimulating factors within the protocol-defined period before treatment.
研究组 & 干预措施
Phase I, Part A - Dose escalation and safety of BI-1808 as single agent
Dose escalation of BI-1808 administrated a single agent
干预措施: BI-1808 (Drug)
Phase I, Part B - Dose escalation and Safety of BI-1808 in combination with pembrolizumab
Dose escalation of BI-1808 in combination with pembrolizumab.
干预措施: Pembrolizumab (KEYTRUDA® ) 25 Mg/mL Solution for Injection (Drug)
Phase 2a, Part B - Dose expansion of BI-1808 in combination with pembrolizumab
BI-1808 administered in combination with pembrolizumab at the respective hypothesized recommended phase 2 doses determined in Phase 1
干预措施: BI-1808 (Drug)
Phase 2a, Part C - Dose expansion of BI-1808 in combination with pembrolizumab and paclitaxel
BI-1808 administered in combination with pembrolizumab and paclitaxel at the respective hypothesized recommended phase 2 doses determined in Phase 1.
干预措施: Pembrolizumab (KEYTRUDA® ) 25 Mg/mL Solution for Injection (Drug)
Phase 2a, Part C - Dose expansion of BI-1808 in combination with pembrolizumab and paclitaxel
BI-1808 administered in combination with pembrolizumab and paclitaxel at the respective hypothesized recommended phase 2 doses determined in Phase 1.
干预措施: BI-1808 (Drug)
Phase 2a, Part C - Dose expansion of BI-1808 in combination with pembrolizumab and paclitaxel
BI-1808 administered in combination with pembrolizumab and paclitaxel at the respective hypothesized recommended phase 2 doses determined in Phase 1.
干预措施: Paclitaxel 80 mg/m2 weekly (Drug)
Phase I, Part B - Dose escalation and Safety of BI-1808 in combination with pembrolizumab
Dose escalation of BI-1808 in combination with pembrolizumab.
干预措施: BI-1808 (Drug)
Phase 2a - Part A dose expansion of BI-1808 as a single agent
BI-1808 administered as a single agent at the hypothesized recommended phase 2 dose determined in Phase 1
干预措施: BI-1808 (Drug)
Phase 2a, Part B - Dose expansion of BI-1808 in combination with pembrolizumab
BI-1808 administered in combination with pembrolizumab at the respective hypothesized recommended phase 2 doses determined in Phase 1
干预措施: Pembrolizumab (KEYTRUDA® ) 25 Mg/mL Solution for Injection (Drug)
结局指标
主要结局
Occurrence of adverse events (AEs)
时间窗: From the start of the study treatment for up to 2 years and 90 days.
AEs will be assessed by the investigators by severity and will be graded according to the NCI CTCAE v5.0 or higher and causality between AEs and the exposure to the study treatment.
Identify DLTs, determine the maximum tolerated dose and select a recommended Phase 2 dose (RP2D) of BI-1808, given via intravenous (IV) infusion, as a single agent (Phase 1, Part A), and in combination with pembrolizumab (Phase 1, Part B)
时间窗: Up to 104 weeks (2 years)
Determine the hypothesized RP2D dose for BI-1808 Phase 2a according to mTPI-2 design
Occurrence of serious adverse events (SAEs)
时间窗: Up to 104 weeks (2 years)
SAEs will be assessed by the investigators by severity and will be graded according to the NCI CTCAE v5.0 or higher and causality between SAEs and the exposure to the study treatment
To identify the recommended Phase 2 dose (RP2D) of BI-1808,
时间窗: up to 104 weeks (2 years)
Select the RP2D dose for BI-1808 derived from the totality of PK, PD, clinical response, safety,and tolerability observed in signal seeking and dose optimization cohorts.
次要结局
- Evaluation of PK parameters for BI-1808. Maximum observed plasma concentration (Cmax)(Up to 104 weeks (2 years))
- Evaluation of ADA response to BI-1808 in serum with validated method(Up to 104 weeks (2 years))
- Measurement of TNFR2 receptor occupancy on CD14+ and/CD16+ cells in serum with validated method(Up to 104 weeks (2 years))