A Two-part Phase I, Open Label, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Pyrotinib in Patients With HER2-positive Solid Tumors Whose Disease Progressed on Prior HER2 Targeted Therapy
试验速览
- 阶段
- 1 期
- 入组人数
- 50
- 试验地点
- 10
- 主要终点
- Part 1 Maximum Tolerated Dose (MTD)
研究概览
简要总结
Part 1: to assess the safety and tolerability of pyrotinib and to define the maximum tolerated dose (MTD) of pyrotinib in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive advanced solid tumors (metastatic breast cancer, gastric cancer, or other solid tumors that have no targeted agent as standard of care).
Part 2: to estimate the overall response rate (ORR) for patients with HER2-positive metastatic breast cancer (mBC) and HER2 mutant non-small cell lung cancer (NSCLC) treated at the RP2D (or MTD).
详细描述
This is an open-label, dose escalation study of repeated doses of pyrotinib in patients with HER2-positive advanced solid tumors, including breast cancer, non small cell lung cancer.
Part 1 of the trial is dose escalation and is designed to enroll 3 to 6 patients in each dose group. Adverse events (AEs) will be assessed and monitored throughout the study. Dose-limiting toxicities (DLT) will be assessed from the first dose of study drug through day 28 in the first cycle of treatment.
Part 2 of the trial will consist of two independent arms: arm A for HER2 positive mBC and arm B for NSCLC with documented HER2 mutation will be investigated to further evaluate safety and the preliminary effectiveness and clinical benefits of pyrotinib as a single agent.
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
- 未提供
排除标准
- •Patients who meet any of the criteria listed below will not be eligible for participation in this study. A patient will not be eligible for study participation if:
- •is unable or unwilling to swallow pyrotinib;
- •has been < 2 weeks since the last radiotherapy, chemotherapy, hormone therapy, surgery or molecule-target therapy (< 6 weeks if chemotherapy included nitrosoureas or mitomycin);
- •the bone or skin is the only site of disease (for Part 2 extension only);
- •has pleural or peritoneal only disease;
- •has uncontrolled ≥ grade 2 hypokalemia and hypomagnesemia;
- •has had other cancer(s) within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin;
- •has active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with a history of CNS metastases or cord compression are allowable if they have been definitively treated and have been clinically stable for at least 4 weeks, and off steroids and anticonvulsants, before first dose of study drug);
- •has either QTcF prolongation (> 470 ms for female and > 450 ms for male), a known history of QTcF prolongation or Torsade de Pointes; or is on drugs that are required for existing medical conditions and that may result in QT prolongation (e.g., anti-arrhythmic drugs); patients who use medications that have a minimal impact on the QTcF interval in the Arizona-CERT criteria are allowed to participate in this study at Investigator's discretion based on his/her clinical assessment);
- •has a significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or ≥ grade 2 diarrhea of any etiology at baseline);
- •has participated in any other investigational drug clinical studies within the last 4 weeks;
- •is concurrently receiving other anti-tumor therapies at time of study screening visit;
- •has an active infection (per Investigator judgment);
- •has a history of immunodeficiency including seropositive for human immunodeficiency virus, or has other acquired or congenital immunodeficient disease;
- •has evidence of uncontrolled heart disease, including (1) congestive heart failure (New York Heart Association functional classification) of ≥ 2), (2) angina requiring treatment (3) myocardial infarction within the past 12 months, or (4) any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention;
- •has allergies or a known history of hypersensitivity to any components of the pyrotinib;
- •is female and of childbearing potential (WOCBP) who is unwilling or unable to use an acceptable method (barrier methods only) to avoid pregnancy for the entire study period and for up to 28 days post last dose;
- •is female and pregnant (or found to be pregnant at screening) or breastfeeding;
- •evidence of significant medical illness or an abnormal laboratory finding, which according to the Investigator's judgment, will substantially increase the risk of participation in and completion of the study. Including, but not limited to, serious ongoing infection (ie, requiring intravenous antibiotic or antiviral agent), uncontrolled major seizure disorder, or significant pulmonary disorder (e.g. interstitial pneumonitis, pulmonary hypertension); hypertension (> grade 3), severe diabetes (uncontrolled > grade 3 hyperglycemia), serious ongoing infection or thyroid disease;
- •has a known history of neurological psychiatric disease including epilepsy or dementia that would interfere with patient's ability to participate in the study or to provide consent;
- •has had prior exposure to any other investigational HER2 targeted agents within 4 weeks of screening visit.
- •is currently taking strong CYP3A4 inhibitor or concomitant meds.
研究组 & 干预措施
Pyrotinib
A two-part Phase I, open-label, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of pyrotinib in patients with HER2-positive solid tumors whose disease progressed on prior HER2 targeted therapy
干预措施: Pyrotinib (Drug)
结局指标
主要结局
Part 1 Maximum Tolerated Dose (MTD)
时间窗: Day 1 to 28 ( Cycle 1)
to assess safety and tolerability of pyrotinib with a maximum tolerated dose (MTD) of pyrotinib in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive advanced solid tumors (metastatic breast cancer, gastric or other solid tumors with no targeted agent as standard of care).
Part 2 Overall Response Rate (ORR)
时间窗: up to 24 months after the first dose
to estimate the overall response rate (ORR) for patients with HER2-positive metastatic breast cancer (mBC) and HER2 mutant non-small cell lung cancer (NSCLC) treated at the RP2D (or MTD).
次要结局
- Maximum plasma concentration(Cmax)(Up to 3 cycles(each cycle 28 days))
- Time to Cmax(Up to 3 cycles(each cycle 28 days))
- Terminal half life (t1/2)(Up to 3 cycles(each cycle 28 days))
- Area under the plasma concentration-time curve(Up to 3 cycles(each cycle 28 days))
- Progression Free Survival (PFS)(up to 24 months after the first dose)
- Volume of distribution(V/F)(Up to 3 cycles(each cycle 28 days))
- Plasma Clearance(CL/F)(Up to 3 cycles(each cycle 28 days))