Open-label, Randomized, Controlled, Multicenter Phase II Trial Investigating 2 Sym004 Doses Versus Investigator's Choice (Best Supportive Care, Capecitabine, 5-FU) in Subjects With Metastatic Colorectal Cancer and Acquired Resistance to Anti-EGFR Monoclonal Antibodies
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 254
- 试验地点
- 54
- 主要终点
- Overall Survival (OS) Time
研究概览
简要总结
This is a Phase 2, open-label, randomized, 3-arm trial investigating the efficacy of two Sym004 doses (Arm A and Arm B) compared with a control group (Arm C) in subjects with metastatic colorectal cancer (mCRC) and acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs).
详细描述
This trial assesses the efficacy of two different weekly dosing regimens of Sym004 (Arm A: 12 mg/kg/week versus Arm B: 9 mg/kg loading dose followed by 6 mg/kg/week) compared with investigator's choice in terms of overall survival time in subjects with mCRC. Subjects assigned to Arm C will receive best supportive care (BSC), Fluorouracil (5-FU), or Capecitabine, per local standard of care.
Subjects will receive treatment until unacceptable toxicity, disease progression, withdrawal of consent, or until the subject meets any of the criteria for treatment discontinuation or trial discontinuation. Therefore, the duration of treatment will differ among individuals and cannot be fixed in advance.
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
- 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
- •Written informed consent obtained before undergoing any study-related activities
- •Male or female, at least 18 years of age
- •Subjects with histologically or cytologically confirmed mCRC, Kirsten rat sarcoma wild-type (KRAS WT) at initial diagnosis
- •Failure of or intolerance to 5-FU, Oxaliplatin, and Irinotecan
- •Acquired resistance to marketed anti-EGFR mAbs as defined in the protocol
- •Measurable disease defined as one or more target lesions according to RECIST
- •Life expectancy of at least 3 months
- •Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
- •Other protocol defined inclusion criteria could apply
排除标准
- •Pretreatment with regorafenib.
- •Subjects who in the opinion of the subject and investigator would benefit more from regorafenib treatment (except where regorafenib is not reimbursed in the country)
- •Skin rash Common Terminology Criteria for AEs (CTCAE) Grade greater than 1 from previous anti-EGFR therapy at time of randomization
- •Magnesium less than 0.9 milligram per deciliter (mg/dL)
- •Known hypersensitivity to any of the treatment ingredients. Known previous Grade 3-4 infusion related reactions with anti-EGFR mABs
- •Other protocol defined exclusion criteria could apply
研究组 & 干预措施
Arm A: Sym004 (12 mg/kg)
Sym004 will be administered as an intravenous infusion at a dose of 12 milligrams per kilogram (mg/kg) weekly until unacceptable toxicity, disease progression, or consent withdrawal.
干预措施: Sym004 (12 mg/kg) (Drug)
Arm B: Sym004 (9/6 mg/kg)
Sym004 will be administered as an intravenous infusion at a loading dose of 9 mg/kg followed by 6 mg/kg weekly until unacceptable toxicity, disease progression, or consent withdrawal.
干预措施: Sym004 (9/6 mg/kg) (Drug)
Arm C: Investigator's Choice
Best supportive care (BSC) or Fluorouracil (5-FU) or Capecitabine will be given as per Investigator's discretion.
干预措施: Best Supportive Care (BSC) (Other)
Arm C: Investigator's Choice
Best supportive care (BSC) or Fluorouracil (5-FU) or Capecitabine will be given as per Investigator's discretion.
干预措施: Fluorouracil (5-FU) (Drug)
Arm C: Investigator's Choice
Best supportive care (BSC) or Fluorouracil (5-FU) or Capecitabine will be given as per Investigator's discretion.
干预措施: Capecitabine (Drug)
结局指标
主要结局
Overall Survival (OS) Time
时间窗: From randomization until the date of death (assessed up to 32 months).
OS based on product-limit (Kaplan-Meier) estimates. Confidence intervals for the median are calculated according to Brookmeyer and Crowley. If a subject had not died, survival time was censored at the last date the subject was known to be alive.
次要结局
- Pharmacokinetic (PK) Parameters: Sym004 Concentrations(Weeks 3, 5, and 7 and at the End of Treatment visit, including a Week 1 and Week 2 subset.)
- Best Overall Response (OR) According to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)(From randomization until first radiological confirmed or clinical progression event, or death due to any cause, within 12 weeks after last tumor assessment (assessed up to 32 months).)
- Occurrence and Nature of Adverse Events (AEs), as Assessed by the Common Terminology Criteria for AEs (Version 4.03) (CTCAE v4.03).(From Baseline up to 28 days after the last IMP administration.)
- Progression Free Survival (PFS) Time(From randomization until first event, where an event can be a progression (radiological confirmed or clinical progression) or death due to any cause (assessed up to 32 months).)
- Time to Treatment Failure (TTF)(From randomization until treatment discontinuation for any reason, including disease progression or death (assessed up to 32 months).)
- Relative Dose Intensity of Sym004(From first dose of study drug until disease progression (assessed up to 32 months).)
- Pharmacokinetic (PK) Parameters: Time of Maximum Plasma Concentration (Tmax)(Day 1 on Weeks 1-3 followed by Week 5 Day 1 and Week 7 Day 1.)
- Host Immune Response: Number of Subjects With Anti-drug Antibodies (ADAs) to Sym004 Over Time(Every two weeks (Days 15, 29, and 43) followed by every six weeks thereafter (Days 78, 120, 162, etc.) until the End of Treatment Visit)
- Quality of Life Assessed by FACT-EGFRI-18 for Skin Rash(Assessed every 3 weeks (week 1 and week 4 reported))
- Quality of Life Assessed by the EORTC QLQ-C30 (Version 3)(Assessed every 6 weeks (week 1 and week 7 reported))
- Quality of Life Assessed by EORTC QLQ-CR29(Assessed every 6 weeks (week 1 and week 7 reported))