A Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493, a Pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, in Subjects With Advanced or Refractory Solid Tumors or Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 188
- 试验地点
- 37
- 主要终点
- Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493
研究概览
简要总结
The purpose of this study is to evaluate the safety, pharmacokinetics (study of what the body does to a drug), and pharmacodynamics (study of what a drug does to the body) of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in adult participants with advanced or refractory solid tumors or lymphoma.
详细描述
This is a first-in-human, non-randomized (individuals will not be assigned by chance to study treatments), open-label (individuals will know the identity of study treatments), multicenter (more than 1 hospital work on a study), Phase 1 study. The study consists of 4 parts. Part 1 is the dose-escalation phase, which will be guided by pharmacokinetics, pharmacodynamics and safety. In part 1, safe and biologically active Phase 2 doses (recommended Phase 2 doses [RP2D]) for JNJ-42756493 will be primarily assessed. Participants will be enrolled in sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will receive increased doses of JNJ-42756493). Part 2 is the Dose Confirmation Phase, which consists of a pre and post treatment tumor biopsy cohorts to confirm the RP2D based on the pharmacodynamic effect of JNJ-42756493 on fibroblast growth factor receptor (FGFR) signaling pathway in tumor. Part 3 is the first Dose Expansion Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity at the first RP2D. It consists of 4 expansion cohorts, 1 each for squamous cell lung cancer, small cell lung cancer, breast cancer, other solid tumors (Cohorts A, B, C, and D). Part 4 is the second Dose Expansion Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity at the second RP2D. Biomarker eligibility has also been refined based on emerging data. It consists of 2 expansion cohorts, Cohort E for non-small cell lung cancer and Cohort F for select solid tumors including breast, urothelial, GBM, ovarian, head & neck, esophageal, gastric, and cholangiocarcinoma (Cohorts E and F). Enrollment of some cohorts may be discontinued due to lack of enrollment or for futility. The study is estimated to take approximately 48 months to complete. Participants' safety will be monitored throughout the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Histologically or cytologically confirmed: solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative treatment is no longer effective (Part 1); any type of advanced or refractory solid malignancy (excluding lymphoma) that is metastatic or unresectable and for which standard curative treatment is no longer effective (Part 2); advanced or refractory squamous non-small cell lung cancer (Cohort A, Part 3), advanced or refractory small cell lung cancer (Cohort B, Part 3), advanced or refractory breast cancer (Cohort C, Part 3), any type of advanced or refractory solid malignancy (excluding lymphoma) ([consisting of one of the following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma multiforme (GBM), ovarian or prostate]) (Cohort D, Part 3), advanced or refractory non small cell lung cancer(Cohort E, Part 4), any type of advanced or refractory solid malignancy (consisting of one of the following: Breast, Urothelial, GBM, Ovarian, Head & Neck, Esophageal, Gastric, and Cholangiocarcinoma) (Cohort F, Part 4)
- •Eastern Cooperative Oncology Group performance status score 0 or 1
- •Adequate bone marrow, liver, and renal function within the 14 days prior to Day 1 of Cycle 1 of study drug up until pre-dose of Cycle 1
- •Magnesium within 0.85 to 1.25 * institutional normal limits, Sodium greater than or equal to 130 milli equivalent per liter, Potassium within institutional normal limits (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1)
排除标准
- •Chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or at least 5 half-lives of the drug, whichever is longer and up to a maximum of 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) before the first administration of study drug. Localized radiation therapy and ongoing luteinizing hormone-releasing hormone (LHRH) agonists, bisphosphonates and denosumab, are permitted
- •Participants with GBM can be enrolled 2 weeks after last treatment
- •History or current condition of uncontrolled cardiovascular disease
- •Participants with persistent phosphate greater than upper limit of normal during screening (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1) and despite medical management of phosphate levels
- •Participants taking medications known to have a significant risk of causing QTc prolongation and Torsades de Pointes
- •Left ventricular ejection fraction (LVEF) less than 50 percent as assessed by echocardiography (or multi-gated acquisition) performed at screening
- •Any medical condition that requires intact wound healing capacity and is expected to endanger participant safety if wound healing capacity would be severely reduced during administration of the investigational agent
- •Participants not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, or Grade 1 neuropathy)
结局指标
主要结局
Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493
时间窗: Up to Part 1 Day 84 (Cycle 4, Day 21)
The maximum tolerated dose as determined in Part 1 of the study will be used as the recommended dose for Part 2, 3 and Part 4.
次要结局
- Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Number of Participants With Objective Tumor Response(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Duration of Objective Response(Up to Part 4 Day 84)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Total Clearance of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Accumulation Index (AI) of JNJ-42756493(Up to Part 4Day 84 (Cycle 4, Day 21))
- Progression Free Survival (PFS)(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Elimination Half Life of JNJ-42756493(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)(Up to Part 4 Day 84 (Cycle 4, Day 21))
- Number of Participants With an Adverse Event(Up to Part 4 Day 84 (Cycle 4, Day 21))