An Open-label, Multicenter, Phase 1a/2a Trial Investigating the Safety, Tolerability and Antitumor Activity of Multiple Doses of Sym013, a mAb Mixture Targeting EGFR, HER2 and HER3, in Patients With Advanced Epithelial Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 32
- 试验地点
- 3
- 主要终点
- Part 2: Evaluate the Antitumor Effect of Sym013 When Administered at the RP2D and Regimen to Patients.
研究概览
简要总结
This is the first study to test Sym013 (Pan-HER) in humans. The primary purpose of this study is to see if Sym013 is safe and effective for patients with advanced epithelial malignancies without available therapeutic options.
详细描述
This is an open-label, multicenter trial composed of 2 parts in which Sym013 will be evaluated when administered by intravenous infusion in patients with advanced epithelial malignancies without available therapeutic options.
Part 1 is a Phase 1a dose-escalation evaluating weekly (Q1W) and every second week (Q2W) schedules of administration in separate dose-escalation cohorts to determine the recommended phase 2 dose (RP2D) and regimen of Sym013.
Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) dose-expansion cohorts will be evaluated in this part of the trial and will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets. Patients will be entered, depending upon either a defined molecular profile or profiles, or their underlying malignancy, to 1 of 4 corresponding expansion cohorts: Cohort A, Cohort B, Cohort C, or Cohort D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Main inclusion criteria all patients, Part 1 and Part 2:
- •Male or female, at least 18 years of age at the time of informed consent
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- •Life expectancy >3 months assessed during Screening
- •Documented (histologically- or cytologically-proven) epithelial malignancy that is locally advanced or metastatic, having received all therapy known to confer clinical benefit
- •Additional inclusion criteria applicable to Part 2 ONLY:
- •Epithelial malignancy (tumor types to be determined), measurable according to RECIST v1.1 that has been confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks prior to C1/D1
- •Willingness to undergo a pre-and post-dosing biopsy (total of 2 biopsies) from primary or metastatic tumor site(s) considered safe for biopsy
排除标准
- •Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed toxicity within 4 weeks or 5 plasma half-lives (whichever is shortest) prior to C1/D1, except nitrosoureas and mitomycin C within 6 weeks prior to C1/D
- •Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there is documented progression of the lesion following radiotherapy
- •Immunosuppressive or systemic hormonal therapy (>10 mg daily prednisone equivalent) within 2 weeks prior to C1/D1 with exceptions
- •Use of hematopoietic growth factors within 2 weeks prior to C1/D1
- •Active second malignancy or history of another malignancy within the last 3 years, with allowed exceptions
- •Central nervous system (CNS) malignancies including:
- •Primary malignancies of the CNS
- •Known, untreated CNS or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or symptoms suggesting CNS metastatic involvement for which treatment is required
- •Inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy
- •Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any prior surgical procedure
- •Non-healing wounds on any part of the body
- •Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to C1/D1, unless adequately treated and stable
- •Active uncontrolled bleeding or a known bleeding diathesis
- •Significant gastrointestinal abnormalities
- •Significant cardiovascular disease or condition
- •Abnormal hematologic, renal or hepatic function
研究组 & 干预措施
1 mg/kg Q1W
Phase 1a: Patients are administered a weekly dose of 1 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
干预措施: Sym013 (Drug)
2 mg/kg Q1W
Phase 1a: Patients are administered a weekly dose of 2 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
干预措施: Sym013 (Drug)
4 mg/kg Q1W
Phase 1a: Patients are administered a weekly dose of 4 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
干预措施: Sym013 (Drug)
6 mg/kg Q1W + Prophylaxis
Phase 1a: Patients are administered a weekly dose of 6 mg/kg of Sym013 + premedication until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.
干预措施: Sym013 (Drug)
9 mg/kg Q1W + Prophylaxis
Phase 1a: Patients are administered a weekly dose of 9 mg/kg of Sym013 + premedication until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.
干预措施: Sym013 (Drug)
6 mg/kg Q2W
Phase 1a: Patients are administered a dose of 6 mg/kg of Sym013 every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
干预措施: Sym013 (Drug)
9 mg/kg Q2W
Phase 1a: Patients are administered a dose of 9 mg/kg of Sym013 every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
干预措施: Sym013 (Drug)
9 mg/kg Q2W + Prophylaxis
Phase 1a: Patients are administered a dose of 9 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.
干预措施: Sym013 (Drug)
12 mg/kg Q2W + Prophylaxis
Phase 1a: Patients are administered a dose of 12 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.
干预措施: Sym013 (Drug)
15 mg/kg Q2W + Prophylaxis
Phase 1a: Patients are administered a dose of 15 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.
Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.
干预措施: Sym013 (Drug)
Phase 2a Dose-Expansion Cohort A
Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.
干预措施: Sym013 (Drug)
Phase 2a Dose-Expansion Cohort B
Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.
干预措施: Sym013 (Drug)
Phase 2a Dose-Expansion Cohort C
Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.
干预措施: Sym013 (Drug)
Phase 2a Dose-Expansion Cohort D
Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.
干预措施: Sym013 (Drug)
结局指标
主要结局
Part 2: Evaluate the Antitumor Effect of Sym013 When Administered at the RP2D and Regimen to Patients.
时间窗: 24 months
No data were collected for this Outcome Measures as Part 2 of the trial was never initiated.
Part 1: Assess the Safety and Tolerability of Sym013 When Administered Either Q1W or Q2W to Separate Dose-escalation Cohorts of Patients.
时间窗: 24 months
Assess the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 of Sym013 administration.
次要结局
- Part 1: Determine the RP2D and Regimen of Sym013.(24 months)
- Parts 1 and 2: Evaluate the Immunogenicity of Sym013.(42 months)
- Parts 1 and 2: Maximum Concentration (Cmax) and Trough Concentration (Ctrough) - Mean Values.(0, 2, 4, 8, 24, 48, 168 hours and 336 hours if Q2W)
- Parts 1 and 2: Elimination Half-life (T½).(0, 2, 4, 8, 24, 48, 168 hours and 336 hours if Q2W)
- Parts 1 and 2: Area Under the Concentration-time Curve Extrapolated to Infinity (AUC).(0, 2, 4, 8, 24, 48, 168 hours and 336 hours if Q2W)
- Parts 1 and 2: Time to Reach Maximum Concentration (Tmax).(0, 2, 4, 8, 24, 48, 168 hours and 336 hours if Q2W)
- Parts 1 and 2: Clearance (CL).(0, 2, 4, 8, 24, 48, 168 hours and 336 hours if Q2W)