A Japanese Phase I Open-label Dose-escalation Trial of Sym004 Administered as Monotherapy in Japanese Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 1
- 主要终点
- Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
研究概览
简要总结
This trial is to assess the safety and tolerability of Sym004, administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors.This study consisted of two parts, a dose-escalation part ("Part-A") and a dose-expansion part ("Part-B"). In Part-A, Sym004 will be administered weekly or biweekly as monotherapy in Japanese subjects with advanced solid tumors. In Part-B, Sym004 will be administered weekly as monotherapy to Japanese subjects with advanced esophageal squamous cell carcinoma (ESCC) as dose-expansion. A subject will receive Sym004 administration weekly at a dose that will determined to be the MTD or a dose that will lower than the MTD and determined to be appropriate with recommendation by Safety monitoring committee (SMC). The dose going to used in Part-B will be determined after safety confirmation of weekly regimens in Part-A of this trial.
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
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Japanese male or female subjects aged greater than or equal to 20 years at the time of informed consent signature
- •Histologically or cytologically confirmed cancer
- •Refractory or recurrent advanced late stage solid tumors without available therapeutic options which are likely to provide patient benefit (failure and/or intolerance to standard anti-cancer therapy)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy of at least 3 months
- •Written informed consent given before any trial-related activities are carried out
- •Other protocol defined inclusion criteria could apply
排除标准
- •Subjects with symptomatic brain metastases
- •Subjects who received total resection or irradiation of the target lesion
- •Received any of the following medications within 4 weeks before the first administration of Sym004 at Week 1: cytotoxic or cytostatic anti-cancer therapy, antibody therapy, tyrosine kinase inhibitors, and any investigational agent
- •Received vaccine therapy as anticancer treatment within 12 weeks before the first administration of Sym004 at Week 1
- •Diarrhea of greater than Grade 1 according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (v4.03)
- •Skin manifestation of greater than Grade 1 according to NCI-CTCAE (v4.03)
- •Magnesium of less than 0.9 milligram per deciliter (mg/dL)
- •Abnormal organ or bone marrow function as defined in the protocol
- •Received immunosuppressive agents (including systemic corticosteroids used at doses above 20 milligram per day (mg/day) of prednisolone or equivalent) within 4 weeks before the first administration of Sym004 at Week 1
- •Active severe infection, any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the trial as judged by the Investigator
- •Known human immunodeficiency virus (HIV) positive, active Hepatitis B or C, or uncontrolled allergic conditions or allergy to Sym004 or its components
- •Clinically significant cardiac disease or concurrent, uncontrolled medical condition
- •Known previous Grade 3 to 4 infusion-related reactions, according to NCI-CTCAE (v4.03), with chimeric monoclonal antibodies
- •Other protocol defined exclusion criteria could apply
研究组 & 干预措施
Sym004
干预措施: Sym004 (Drug)
结局指标
主要结局
Number of Subjects With Treatment-emergent Adverse (TEAEs), Serious TEAEs, TEAEs Leading to Discontinuation or TEAEs Leading to Death
时间窗: Baseline up to 4 weeks after the last Sym004 administration, up to a maximum of 41.1 weeks
An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AEs were considered treatment emergent if they started on or after the day of first administration of the Sym004 or if they started prior to administration but worsened after receiving the first dose of treatment.
Number of Subjects With Dose Limiting Toxicities (DLTs) Determined in Part-A
时间窗: Week 1 up to Week 4 (Part A)
DLT: any of the following National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Grade 4 hematologic or Grade 3/4 non-hematologic toxicities that occurred during DLT observation period of Part A, and were considered by Investigator to be at least possibly related to study treatment, and confirmed by Safety Monitoring Committee. Hematological toxicities: Grade 4 neutropenia, febrile neutropenia, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding episodes. Nonhematological toxicities: Grade 3 or higher non-hematological toxicity with exception of Grade 3 fatigue/skin toxicity; Grade 3 nausea/vomiting without appropriate prophylactic therapy; Grade 3 diarrhoea recovered within 2 days with adequate treatment or did not accompany fever/dehydration; Grade 3 or 4 laboratory liver parameter abnormalities with duration of less than 3 days.
次要结局
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1)
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5)
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1)
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12 and 24 hours post-infusion at Week 5)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 and 168 hours post-infusion at Week 1)
- Dose Nornamized Area Under Concentration-time Curve (AUC) From Start of First Infusion to 168 Hours (AUC0-168h) for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, and 168 hours post-infusion at Week 4)
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48, 168, 336 hours post-infusion at Week 1)
- Area Under Concentration-time Curve (AUC) From Start of First Infusion to 336 Hours (AUC0-336hours) For the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 168 and 336 hours post-infusion at Week 5)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, and 48 hours post-infusion at Week 1)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Dose Normalized Area Under Concentration-time Curve (AUC) From Start of First Infusion to Infinity (AUC0-inf) For the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Terminal Half-life (t1/2) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Terminal Half-life (t1/2) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Terminal Half-life (t1/2) of Sym004 For the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Clearance (CL) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Clearance at Steady-state (CLss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Clearance at Steady-state (CLss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Volume of Distribution at the Elimination Phase (Vz) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Volume of Distribution at Steady State (Vss) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Volume of Distribution at Steady State (Vss) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Dose Nornamized Maximum Serum Concentration (Cmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Dose Normalized Maximum Serum Concentration (Cmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Trough Concentrations (Ctrough) of Sym004(Pre-infusion at Week 2, 3, 5, 6, 7, 8, End of Trial (up to 41.1 weeks) and Follow up (up to 45.1 Weeks))
- Time to Reach Maximum Concentration (Tmax) of Sym004 at Week 1: Single Dose(Pre-infusion, end of infusion, 4, 8, 12, 24, 48 hours post-infusion at Week 1)
- Time to Reach Maximum Concentration (Tmax) of Sym004 for the Weekly Regimen at Week 4: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 4)
- Time to Reach Maximum Concentration (Tmax) of Sym004 for the Biweekly Regimen at Week 5: Multiple Dose(Pre-infusion, end of infusion, 4, 8, 12, 24 hours post-infusion at Week 5)
- Percentage of Subjects With Best Overall Response(Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks))
- Duration of Overall Response(Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 Weeks)
- Percentage of Subjects With Disease Control(Week 7 and thereafter every 6 weeks, up to 4 weeks after last dose for Part A or up to 8 weeks after the last dose for Part B (up to 45.1 Weeks))
- Duration of Disease Control(Week 7 and thereafter every 6 weeks until the first date of objectively documented recurrent or progressive disease, up to 45.1 weeks)
- Time to Progression(Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks)
- Progression-free Survival Time(Time from enrollment until the date of objectively documented disease progression or death, up to 45.1 Weeks)
- Anti-drug Antibody Titers(Week 1 (pre-dose) up to Follow-up assessment (up to maximum 45.1 Weeks))
- Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Expression in Skin Tissues by Immunohistochemistry (IHC)(Week 1 (pre-dose), Week 4 and Week 5)
- Percentage of Participants With EGFR Amplification Using Fluorescent in Situ Hybridization (FISH) Method.(Week 1 (pre-dose) and Week 4.)