临床试验/NCT04322539

NCT04322539已完成3 期

A Global Multicenter Randomized Placebo-Controlled Phase 3 Trial To Compare The Efficacy And Safety Of Fruquintinib Plus Best Supportive Care To Placebo Plus Best Supportive Care In Patients With Refractory Metastatic Colorectal Cancer

Hutchison Medipharma Limited153 个研究点分布在 2 个国家目标入组 691 人开始时间: 2020年8月12日最近更新: 2025年4月4日

适应症

干预措施

试验速览

阶段: 3 期
状态: 已完成
发起方
入组人数: 691
试验地点: 153
主要终点: Overall Survival (OS)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验相关资讯

研究概览

简要总结

This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best supportive care (BSC) versus placebo plus BSC in participants with refractory metastatic colorectal cancer (mCRC). 691 participants were randomized to one of the following treatment arms in a 2:1 ratio, fruquintinib plus BSC or placebo plus BSC.

详细描述

This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in combination with BSC in metastatic colorectal cancer participants who have progressed on, or were intolerant to, chemotherapy, anti-VEGF and anti-EGFR biologics, and TAS-102 or regorafenib. Participants with MSI-H/MMR deficient tumors must have also received an immune checkpoint inhibitor if approved and available and if deemed appropriate. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available and if deemed appropriate.

Metastatic colorectal cancer cannot be cured by surgery. Therefore, treatment principals are primarily aimed at controlling disease progression and prolonging survival. Standard first- and second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy. After the first two lines of chemotherapy, standard third-line treatment is either TAS-102 or regorafenib. There are currently no effective treatments for patients who have progressed on standard, approved therapies, and treatment options include reuse of prior therapies, clinical trials or BSC. Consequently, there is an unmet medical need for additional safe and effective treatment.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

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

•Provide written informed consent;
•Age ≥18 years;
•Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
•Participants must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Participants are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Participants who have been treated with both TAS-102 and regorafenib are permitted. Participants must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
•Participants with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the participant's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
•Participants who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Participants who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
•Body weight ≥40kg;
•Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
•Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
•Expected survival >12 weeks.
•For female participants of childbearing potential and male participants with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the participant. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male participants involved in this clinical trial if they have a partner of childbirth potential, and male participants must always use a condom.
•Participants with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the participant's home country unless the patient is ineligible for treatment with a BRAF inhibitor.

排除标准

•Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
•Serum total bilirubin >1.5 × the upper limit of normal (ULN). Participants with Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;
•Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in participants without hepatic metastases; ALT or AST >5 × ULN in participants with hepatic metastases;
•Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockroft-Gault equation.
•Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Participants with greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess urine protein level;
•Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management. Participants were required to have blood pressure values below both limits. Repeated assessments were permitted;
•International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to receive anticoagulants for prophylactic purposes;
•History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
•History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
•History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
•Stroke and/or transient ischemic attack within 12 months prior to screening;
•Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram;
•Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
•Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
•Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
•Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
•Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
•Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
•Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
•Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision;
•Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0 Grade 1 (except for alopecia or neurotoxicity grade≤2);
•Known human immunodeficiency virus (HIV) infection;
•Known history of active viral hepatitis. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
•Clinically uncontrolled active infection requiring IV antibiotics;
•Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava;
•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; participants requiring steroids within 4 weeks prior to start of study treatment are excluded;
•Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
•Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
•Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment;
•Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
•Participants who have received prior fruquintinib;
•Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

研究组 & 干预措施

Fruquintinib Plus Best Supportive Care (BSC) Group

Experimental

Participants will be orally administered Fruquintinib 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).

干预措施: Fruquintinib (Drug)

Placebo Plus BSC Group

Placebo Comparator

Participants will be orally administered Placebo 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days).

干预措施: Placebo (Drug)

结局指标

主要结局

Overall Survival (OS)

时间窗: From date of randomization to death from any cause (up to 22 months)

OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive - date of randomization + 1)/30.4375. Participants without report of death at the time of analysis will be censored at the date last known alive.

次要结局

Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1(From randomization until the first documentation of objective progression or death, whichever comes first (up to 22 months))
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(From randomization until the first documentation of best overall response (up to 22 months))
Observed Plasma Concentrations of Fruquintinib and Metabolite M11(Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 (Day 21): Predose and 2 hours, Cycle 3 (Day 1): Pre-dose, Cycle 3 (Day 21): Pre-dose and 2 hours, Cycle 5, 7, 9, 11, 13, 15 and 17 (Day 1): Pre-dose (Each cycle = 28 days))
Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(From randomization until the first documentation of best overall response (up to 22 months))
Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula(Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days))
Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)(From first occurrence of PR or CR until the first documentation progression or death, whichever comes first (up to 22 months)
Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS)(Up to 22 months)
Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ (Gr3+): Dermatological Toxicity, Proteinuria and Gr Hemorrhage)(Up to 22 months)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs(From start of study drug administration up to approximately 40 months)
Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula(Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days))
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score(Baseline, Cycle 2, 3 and 4 (Each cycle=28 days))
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score(Baseline, Cycle 2, 3 and 4 (Each cycle=28 days))
Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores(Baseline, Cycle 2, 3 and 4 (Each cycle=28 days))
Health Care Resource Utilization: Duration of Hospital Visits by Participants(From start of study drug administration up to 22 months)
Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed(From start of study drug administration up to 22 months)

研究者

发起方

Hutchison Medipharma Limited

申办方类型

Industry

责任方

Sponsor

研究点 (153)

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