An Open Label, Phase I Study to Assess the Effect of Itraconazole (CYP3A4 and P-gp Inhibitor) on the Pharmacokinetics of Anetumab Ravtansine and to Assess the ECG Effects, Safety and Immunogenicity of Anetumab Ravtansine Given as a Single Agent and Together With Itraconazole in Subjects With Mesothelin-expressing Advanced Solid Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 63
- 试验地点
- 18
- 主要终点
- QTcF (QT interval, corrected for heart rate according to Fridericia's formula) interval duration
研究概览
简要总结
Characterize the safety, tolerability, ECG effects, pharmacokinetics and immunogenicity of anetumab ravtansine given as single agent and after inhibition of CYP3A4 and P-gp by concomitant administration of itraconazole in subjects with mesothelin-expressing advanced solid cancers
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Subjects must have histologically confirmed, locally advanced or metastatic solid cancers of the following histological types:
- •predominantly epithelial (≥50% tumor component) pleural or peritoneal mesothelioma
- •epithelial ovarian cancer (fallopian tube and primary peritoneal cancers are eligible)
- •adenocarcinoma of the pancreas,
- •triple-negative adenocarcinoma of the breast
- •non-small-cell adenocarcinoma of the lung
- •gastric cancer (including gastro-esophageal junction)
- •colon cancer
- •cholangiocarcinoma
- •Thymic carcinoma
- •Subjects must have no standard therapy available, or have actively refused standard therapy
- •Subjects must provide samples of archival tumor tissue collected and submitted anytime during the study
- •Subjects must have a life expectancy of at least 12 weeks
- •Subjects must have ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1
- •Subjects must have adequate bone marrow, renal and hepatic function and coagulation
- •Subjects must have normal or clinically insignificant ECG at screening
- •Women of reproductive potential must have a negative serum pregnancy test obtained within 3 days before the start of anetumab ravtansine
- •Women of childbearing potential and fertile men must agree to use adequate contraception when sexually active. This applies from the time period between signing of the informed consent until at least 6 months after the last administration of the last study drug. Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until 6 months after last study drug administration.
排除标准
- •Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study, except cervical carcinoma in situ, treated basal cell carcinoma, superficial noninvasive bladder tumors or any previous cancer curatively treated ≥ 3 years before the start of anetumab ravtansine
- •New or progressive brain or meningeal or spinal metastases
- •Corneal epitheliopathy or any eye disorder that may predispose the subjects to drug-induced corneal epitheliopathy, or may interfere with diagnosis of treatment-emergent corneal epitheliopathy at the ophthalmologist's or the investigator's discretion
- •History or current evidence of
- •biliary cirrhosis
- •malignant biliary obstruction unless the bile flow to the gastrointestinal tract is maintained by a fully operational biliary stent
- •CTCAE (Common Terminology Criteria for Adverse Events) Grade ≥2 bleeding disorder within 4 weeks before the start of anetumab ravtansine
- •uncontrolled cardiovascular disease or uncontrolled hypertension
- •Long QT Syndrome
- •HIV infection
- •Hepatitis B or C infection
- •Had a major surgery or significant trauma within 4 weeks before the start of anetumab ravtansine
- •Had solid organ or bone marrow transplantation
- •Have LVEF (left ventricular ejection fraction) <50% at screening
- •Have QTc >450 ms or heart rate ≥100 bpm or ≤45 bpm at screening
- •Poor CYP2D6 metabolizers based on the screening test for genetic polymorphisms in CYP2D6 metabolizing capacity
研究组 & 干预措施
Anetumab ravtansine
The evaluation of multiple ECG parameters and the drug-drug interaction (DDI) potential of anetumab ravtansine parameters when administered alone and together with itraconazole 100 mg oral capsules will be conducted in 2 sequential parts. On Cycle 1 Day 1, anetumab ravtansine will be given alone at a dose of 6.5 mg/kg in Part 1 and Part 2. On Cycle 2 Day 1, anetumab ravtansine will be given together with itraconazole at a dose of 0.6 mg/kg in Part 1, and at a dose of 6.5 mg/kg (planned) in Part 2.
干预措施: Anetumab ravtansine (BAY94-9343) (Drug)
Anetumab ravtansine
The evaluation of multiple ECG parameters and the drug-drug interaction (DDI) potential of anetumab ravtansine parameters when administered alone and together with itraconazole 100 mg oral capsules will be conducted in 2 sequential parts. On Cycle 1 Day 1, anetumab ravtansine will be given alone at a dose of 6.5 mg/kg in Part 1 and Part 2. On Cycle 2 Day 1, anetumab ravtansine will be given together with itraconazole at a dose of 0.6 mg/kg in Part 1, and at a dose of 6.5 mg/kg (planned) in Part 2.
干预措施: Itraconazole (Drug)
结局指标
主要结局
QTcF (QT interval, corrected for heart rate according to Fridericia's formula) interval duration
时间窗: Up to 2 months per patient
ECG evaluation
QT interval duration
时间窗: Up to 2 months per patient
ECG evaluation
Cycle 1+2 AUC (area under the plasma concentration vs. time curve from zero to infinity after single (first) dose) of BAY94-9343 analytes
时间窗: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
Cycle 1+2 Cmax (maximum drug concentration in plasma after the first dose administration) of BAY94-9343 analytes
时间窗: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
PR interval duration
时间窗: Up to 2 months per patient
ECG evaluation
Cycle 1+2 AUC(0-tlast) (AUC from time zero to the last data point > LLOQ [lower limit of quantification]) of BAY94-9343 analytes
时间窗: At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 10h, 24h, 48h, 168h, 336h, 480h and 504h after each dose during first 42 days of the study
Abnormal T/U waves
时间窗: Up to 2 months per patient
ECG evaluation
QRS interval duration
时间窗: Up to 2 months per patient
ECG evaluation
Heart rate
时间窗: Up to 2 months per patient
ECG evaluation
QTcP (QT interval, corrected for heart rate using a population-specific correction) interval duration
时间窗: Up to 2 months per patient
ECG evaluation
次要结局
- Incidence of non-serious adverse events(Up to 6 months per patient)
- Incidence of serious adverse events(Up to 6 months per patient)
- Incidence of positive anti-drug antibody titer(Up to 6 months per patient)
- Cycle 3 Cmax,md (Cmax after multiple-dose administration) of BAY94-9343 analytes(At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study)
- Cycle 3 AUC(0-tlast)md (AUC(0-tlast) after multiple-dose administration) of BAY94-9343 analytes(At pre-dose, 0.5h, 1h, 1.5h, 2h, 3h, 5h, 8h, 168h, 336h and 504h between 43rd and 64th days of the study)
- Incidence of neutralizing antibody titers(Up to 6 months per patient)