A Phase Ia/Ib, Open-label, Multicentre Dose-escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of BI 1823911 as a Monotherapy and in Combination With Other Anti-cancer Therapies in Patients With Advanced or Metastatic Solid Tumours Expressing KRAS G12C Mutation
概览
- 阶段
- 1 期
- 干预措施
- BI 1823911
- 疾病 / 适应症
- Solid Tumors, KRAS Mutation
- 发起方
- Boehringer Ingelheim
- 入组人数
- 30
- 试验地点
- 16
- 主要终点
- Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Objective response (OR) defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR)
- 状态
- 进行中（未招募）
- 最后更新
- 2个月前
概览
简要总结
This study is open to adults with different types of advanced or metastatic cancer (including lung cancer, colorectal cancer, pancreatic cancer, and bile duct cancer). This study is for people for whom previous treatment was not successful or no treatment exists.
People who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes tumours grow faster. BI 1823911 and BI 1701963 are medicines that may turn off KRAS, each in a different way. In this study, BI 1823911 is given to people for the first time.
The purpose of this study is to find the highest dose of BI 1823911 that people can tolerate when taken alone and together with BI 1701963. The most suitable dose is used to find out whether BI 1823911 alone and in combination with BI 1701963 can make tumours shrink.
Participants can stay in the study as long as they benefit from treatment and can tolerate it.
During this time, participants take tablets of BI 1823911 alone or in combination with BI 1701963 once a day. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participant's health.
研究者
入排标准
入选标准
- •Pathologically confirmed diagnosis of locally advanced or metastatic solid tumours, e.g. adenocarcinoma of the lung, colorectal cancer, pancreatic cancer or cholangiocarcinoma. Non-small cell lung cancer (NSCLC) patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
- •Documented disease progression despite appropriate prior standard therapies or for whom no standard therapy exists for their tumour type and disease stage.
- •KRAS mutation status: Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation in tumour tissue or blood based on previously performed local testing using a validated test.
- •Provision of archival tumour tissue, if available, to confirm retrospectively KRAS G12C mutation status and for biomarker assessment.
- •At least one target lesion that can be measured per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (radiated lesions do not qualify as target lesions). In patients who only have one target lesion, and a biopsy of the lesion is required, the baseline imaging must be performed before the biopsy or at the earliest two weeks after the biopsy.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Adequate organ function as follows:
- •Absolute neutrophil count (ANC) ≥1.5 x 10\^9/L (equivalent values: ≥ 1.5 x 10³/μL or ≥ 1500/mm³); hemoglobin ≥9.0 g/dL (equivalent values: ≥ 90 g/L or ≥ 5.6 mmol/L); platelets ≥100 x 10\^9/L (equivalent values: ≥ 100 x 10³/μL or ≥ 100 x 10³/mm³) without the use of haematopoietic growth factors.
- •Total bilirubin ≤1.5 times the upper limit of normal (ULN), or ≤4 x ULN for patients who are known to have Gilbert's syndrome.
- •Creatinine ≤1.5 x ULN. If creatinine is \>1.5 x ULN, patient is eligible if concurrent creatinine clearance ≥50 mL/min (equivalent value: 0.84mL/s) (measured or calculated by Cockcroft-Gault formula).
排除标准
- •Previous anticancer chemotherapy within 3 weeks of the first administration of trial drug. Previous anticancer hormonal treatment or anticancer immunotherapy within 2 weeks of the first administration of trial drug.
- •Previous treatment with Rat Sarcoma (RAS), Mitogen-activated protein kinase (MAPK) or Son of sevenless 1 (SOS1) targeting agents (only for monotherapy Parts A, B, and C).
- •Radiotherapy within 2 weeks prior to start of treatment, provided recovery from related toxicity.
- •Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to start of treatment or planned during the projected course of the trial, e.g. hip replacement.
- •Previous treatment with any investigational agent(s) or targeted treatment within 28 days prior to start of treatment or 5 half-lives, whichever is shorter.
- •Known history of hypersensitivity to any of the excipients of BI 1823911 tablets, or any contraindication to Midazolam (for Monotherapy Part B only).
- •History or presence of cardiovascular abnormalities such as congestive heart failure New York Heart Association (NYHA) classification of ≥3, unstable angina or poorly controlled arrhythmia which are considered clinically relevant by the Investigator. Myocardial infarction within 6 months prior to start of treatment. Uncontrolled hypertension defined as: Blood pressure (BP) measured in a rested and relaxed condition, where systolic BP \>=140 mmHg, or diastolic BP \>= 90 mmHg, with or without medication.
- •Left ventricular ejection fraction (LVEF) \<50%. Further exclusion criteria apply.
研究组 & 干预措施
Monotherapy Arm
Each arm consists of three parts (dose escalation (A), dose confirmation (B), and dose expansion (C).
干预措施: BI 1823911
Monotherapy Arm
Each arm consists of three parts (dose escalation (A), dose confirmation (B), and dose expansion (C).
干预措施: Midazolam
Combination Therapy Arm
Will be started after confirmation of safety in the Monotherapy Arm. Each arm consists of three parts (dose escalation (A), dose confirmation (B), and dose expansion (C).
干预措施: BI 1823911
Combination Therapy Arm
Will be started after confirmation of safety in the Monotherapy Arm. Each arm consists of three parts (dose escalation (A), dose confirmation (B), and dose expansion (C).
干预措施: BI 1701963
结局指标
主要结局
Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Objective response (OR) defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR)
时间窗: up to 39 months
BOR is determined according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. BOR will consider all tumour assessments from first treatment administration until the earliest of disease progression, death, or last evaluable tumour assessment before start of subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent.
Dose escalation (Part A) - Monotherapy and combination therapy: Number of patients experiencing Dose limiting toxicities (DLTs) during the Maximum tolerated dose (MTD) evaluation period for BI 1823911 in monotherapy and in each combination
时间窗: up to 28 days
DLTs are graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
次要结局
- All study parts, BI 1823911: Maximum concentration (Cmax)(up to 24 hours)
- All study parts, BI 1701963: Maximum concentration (Cmax)(up to 24 hours)
- Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Objective response (OR)(up to 39 months)
- Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Progression-free survival (PFS) rate(at month 6)
- All study parts, BI 1823911: Area under the plasma concentration-time curve from time zero to time t (AUCτ)(up to 24 hours)
- All study parts, BI 1701963: Area under the plasma concentration-time curve at steady state (AUCss)(up to 24 hours)
- Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Tumour shrinkage (in millimetres)(up to 39 months)
- All study parts, BI 1701963: Steady state concentration (Css)(up to 24 hours)
- Dose escalation (Part A) - Monotherapy and combination therapy: Number of patients experiencing DLTs during all treatment cycles for BI 1823911 in monotherapy and in each combination(up to 39 months)
- Dose confirmation (Part B) and expansion (Part C) - Monotherapy and combination therapy: Duration of OR(up to 39 months)
- All study parts: Number of patients with adverse events during the on-treatment period(up to 39 months)
- All study parts, BI 1823911: Area under the plasma concentration-time curve at steady state (AUCss)(up to 24 hours)
- All study parts, BI 1701963: Area under the plasma concentration-time curve from time zero to time t (AUCτ)(up to 24 hours)
- All study parts, BI 1823911: Steady state concentration (Css)(up to 24 hours)