A Multi-Center, Open-Label, Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Surufatinib (HMPL-012), Previously Named Sulfatinib in Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Hutchmed
- 入组人数
- 130
- 试验地点
- 12
- 主要终点
- Dose-Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)
研究概览
简要总结
Primary Objective Dose Escalation:
To evaluate the safety and tolerability of surufatinib in patients with advanced solid tumors and to determine the maximum tolerable dose (MTD) or recommended phase II dose (RP2D).
Primary Objective Dose Expansion:
To evaluate the anticancer activity of surufatinib in patients with advanced Biliary Tract Cancer (BTC), patients with advanced pancreatic neuroendocrine tumors (pNETs), patients with locally advanced, unresectable, metastatic extra-pancreatic neuroendocrine tumors (EP-NETs), and patients with soft tissue sarcomas (STS) treated at a dose of 300 mg QD.
Secondary Objective:
To evaluate the pharmacokinetic profile of multiple dose surufatinib in patients with advanced solid tumors and to evaluate the anti cancer activity of surufatinib in patients with advanced solid tumors.
详细描述
The study is an open-label, dose escalation and expansion clinical trial of surufatinib orally once daily (QD) in patients with advanced solid tumors.
The study consists of two phases:
Dose escalation phase - A 3+3 design will be used for this portion of the study.
- Approximately 15 to 35 evaluable patients will be enrolled. The actual number of patients depends on the Dose-limiting toxicity (DLT) situation as well as the RP2D dose level reached in this trial.
- The trial will approximately evaluate five surufatinib dose levels at 50,100, 200, 300 and 400 mg/day.
Expansion phase:
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
- •Fully understand the study and voluntarily sign the informed consent form;
- •At least 18 years old;
- •Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type during the dose escalation phase, that has progressed on available standard systemic therapy, and for whom no effective therapy or standard of care exists; and locally advanced or metastatic BTC that has progressed on standard first-line chemotherapy; locally advanced or metastatic pNET that has progressed on everolimus, sunitinib or both; locally advanced or metastatic EP-NET that has progressed on everolimus; advanced STS that has progressed on at least one line of standard therapy or refused standard frontline cytotoxic chemotherapy during the expansion phase;
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
排除标准
- •Hypertension that is not controlled by antihypertension medication, defined as: systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg;
- •History or presence of digestive tract diseases, including active gastric/duodenal ulcer or ulcerative colitis, or active hemorrhage of an unresected gastrointestinal tumor, or an evaluation by investigators of having any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation;
- •History or presence of serious hemorrhage , hemoptysis or hematemesis within 3 months or a thromboembolic event (including Deep Vein Thrombosis (DVT), stroke and/or transient ischemic attack) within 6 months;
- •Patients with squamous Non Small Cell Lung Cancer (NSCLC) should be excluded;
- •Clinically significant cardiovascular disease, including but not limited to, acute myocardial infarction within 6 months prior to enrollment, severe/unstable angina pectoris or coronary artery bypass grafting, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment or left ventricular ejection fraction (LVEF) < 50%;
- •Systemic anti-neoplastic therapies within 4 weeks prior to the initiation of investigational treatment, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
- •Palliative radiotherapy for bone metastasis/lesion within 2 weeks;
- •Known Human immunodeficiency virus (HIV) infection;
- •Known clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis;
- •Women who are pregnant or lactating;
- •Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; Subjects requiring steroids within 4 weeks prior to start of study treatment will be excluded;
- •Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
- •Received investigational treatment in another clinical study within 4 weeks prior to the initiation of investigational treatment;
- •Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at high risk.
研究组 & 干预措施
Escalation 50 mg
Escalation cohort at 50 mg/day
干预措施: surufatinib (Drug)
Escalation 100mg
Escalation cohort at 100 mg/day
干预措施: surufatinib (Drug)
Escalation 200 mg
Escalation cohort at 200 mg/day
干预措施: surufatinib (Drug)
Escalation 300 mg
Escalation cohort at 300 mg/day
干预措施: surufatinib (Drug)
Escalation 400 mg
Escalation cohort at 400 mg/day
干预措施: surufatinib (Drug)
Expansion
Subjects will receive RP2D surufatinib daily treatment continuously with every 28-day treatment cycle. Four expansion cohorts will enroll BTC, pNET, EP-NET, and STS patients, respectively.
干预措施: surufatinib (Drug)
结局指标
主要结局
Dose-Escalation Phase: Number of Patients With Dose-Limiting Toxicities (DLTs)
时间窗: From the first dose of study drug (Day 1) up to Day 28 of Cycle 1
A DLT was defined as any of the following toxicities determined by the Investigator to have a reasonable possibility of being related to surufatinib. Adverse events (AE) were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Any Grade 4 non-hematological toxicity; any Grade 3 non-hematological toxicity except for nausea/vomiting, diarrhea, constipation, electrolyte imbalances, or transient hypertension downgraded within 3 days with appropriate supportive treatment; Grade 4 neutropenia lasting \>7 days; Grade 3 febrile neutropenia (absolute neutrophil count \<1.0 × 10\^9/liter (L) with a single temperature of \>38.3 degree Celsius (°C) or a sustained temperature of \>=38°C for more than 1 hour; Grade 4 thrombocytopenia or \>=Grade 3 thrombocytopenia associated with tendency to bleed; dose interruption or delay for \>14 days due to toxicity; any life-threatening complication or abnormality not covered in NCI CTCAE v. 4.03.
Dose-Escalation Phase: Number of Patients With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
时间窗: From the first dose of study drug (Day 1) up to approximately 90 months
An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug or other protocol-imposed drug, regardless of attribution. An SAE was an AE that resulted in any of the following outcomes: was fatal; was life threatening; required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity; a congenital anomaly/birth defect in a neonate/infant born to a female patient or female partner of a male patient exposed to the study drug(s); was considered a significant medical event by the Investigator. TEAEs were defined as any AEs that started or worsened in severity on or after the first administration date of study drug and no later than 30 (+7) days after the last administration date of study drug or initiation of new anti-tumor therapy (whichever occurred first).
Dose-Expansion Phase: Arms A and D: Progression Free Survival (PFS) Rate at 16 Weeks
时间窗: At 16 weeks
The tumor response was determined according to the international Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 guideline. PFS is defined as the time (in months) from the start date of study medication (Day 1) until the date of objective disease progression as defined by RECIST Version 1.1 or death (by any cause in the absence of progression), whichever occurred earlier. PFS rate probability at 16 week was estimated. Progression is defined by RECIST v1.0 as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline or appearance of 1 or more new lesions.
Dose-Expansion Phase: Arms B and C: PFS Rate at 11 Months
时间窗: At 11 months
The tumor response was determined according to the RECIST v1.1 guideline. PFS is defined as the time (in months) from the start date of study medication (Day 1) until the date of objective disease progression as defined by RECIST Version 1.1 or death (by any cause in the absence of progression), whichever occurred earlier. PFS rate probability at 11 months was estimated. Progression is defined by RECIST v1.0 as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline or appearance of 1 or more new lesions.
次要结局
- Dose Escalation and Dose-Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Surufatinib(Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Days 1 and 15 of Cycle 1)
- Dose-Escalation and Dose-Expansion Phase: Objective Response Rate (ORR)(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months)
- Dose-Escalation and Dose-Expansion Phase: Maximum Percentage Change From Baseline in Tumor Size as Per RECIST v1.1(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months)
- Dose-Escalation and Dose-Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Surufatinib(Pre-dose and 1, 2, 4, 6, 8 hours post-dose on Days 1 and 15 of Cycle 1)
- Dose-Escalation and Dose-Expansion Phase: AUC Over the Dosing Interval (AUCtau) of Surufatinib(Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1)
- Dose-Escalation and Dose-Expansion Phase: Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h) of Surufatinib(Pre-dose and 1, 2, 4, 6, and 8 hours post-dose on Cycle 1 Day 1)
- Dose-Escalation and Dose-Expansion Phase: Disease Control Rate (DCR)(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months)
- Dose-Escalation and Dose-Expansion Phase: Duration of Response (DoR)(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 90 months)
- Dose-Escalation Phase: Progression-Free Survival (PFS)(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 53 months)
- Dose-Expansion Phase: Time to Response (TTR)(RECIST assessments performed at screening (within 28 days before start of study treatment), Day 1 of Cycle 2, and every 8 (+/-1 week) weeks afterwards until the occurrence of disease progression, up to a maximum of 53 months)