A Phase I Safety and Bioimaging Trial of DS-8895a in Patients With Advanced or Metastatic EphA2 Positive Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Number of Patients With Treatment-emergent Adverse Events
研究概览
简要总结
This was a Phase 1, dose-escalation, non-randomized, open-label, single-center study of DS-8895a in patients with advanced or metastatic Ephrin type-A receptor 2 (EphA2)-positive cancers. The primary study objective was to determine the safety of DS-8895a, with secondary objectives of determining the biodistribution, tumor uptake (bioimaging), pharmacokinetics (PK), antitumor and pharmacodynamic response, and correlations between pharmacodynamics and clinical outcomes, as appropriate.
详细描述
Patients received an initial ^89Zr trace-labelled infusion of DS-8895a on Day 1, followed by safety assessments, positron emission tomography (PET) imaging, and PK sampling over a 1-week period. DS-8895a was infused again on Days 8, 22, and 36. The Day 36 infusion of DS-8895a was also trace labelled with ^89Zr, with subsequent PET imaging and PK sampling. Four dose levels (1, 3, 10 and 20 mg/kg) were to be evaluated, with 3 to 6 patients entered at each dose level. Patients who responded or had stable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at the Day 50 restaging may have continued to receive biweekly treatment with DS-8895a until disease progression, with restaging performed by computed tomography (CT) scans every 6 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Advanced or metastatic EphA2 positive cancer (based on immunohistochemistry of archived or fresh tumor tissue).
- •Malignant tumor that was refractory to standard treatment.
- •At least one reference tumor > 1 cm in size for assessment of tumor uptake of ^89Zr-Df-DS-8895a.
- •Expected survival of at least 3 months.
- •Eastern Cooperative Oncology Group performance status ≤
- •Within the last week prior to the first study drug administration, laboratory parameters for vital functions were to be in the normal range. Out-of-range values that were not clinically significant were permitted, except that the following parameters were to be in the specified ranges:
- •Neutrophil count ≥ 1.5 x 10^9/L
- •Platelet count ≥ 90 x 10^9/L
- •International normalized ratio ≤ 1.5
- •Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the upper limit of normal (ULN); ≤ 5 x ULN if liver metastases
- •Serum bilirubin ≤ 1.5 x ULN
- •Calculated creatinine clearance ≥ 55 mL/min.
- •Age ≥ 18 years.
- •Able and willing to give valid written informed consent.
排除标准
- •Active central nervous system metastases. Definitively treated metastases were allowed if stable for 6 weeks off therapy.
- •Known immunodeficiency or human immunodeficiency virus positivity.
- •Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the patient to fulfill the study requirements.
- •Other malignancy, apart from non-melanoma skin cancer, within 3 years prior to the first study drug administration that in the opinion of the investigator had > 10% risk of relapse within 12 months.
- •Significant allergic reaction to prior antibody infusions.
- •Chemotherapy, radiotherapy, or investigational agent within 4 weeks prior to the first study drug administration.
- •Regular corticosteroid, non-steroidal anti-inflammatory drug (other than paracetamol or low-dose aspirin) or other immunosuppressive treatment within 3 weeks prior to the first study drug administration (intermittent dosing permitted if less than 4 doses within a 3-day period).
- •Mental impairment that could have compromised the ability to give informed consent and comply with the requirements of the study.
- •Lack of availability for clinical follow-up assessments.
- •Pregnancy or breastfeeding.
- •Women of childbearing potential: Refusal or inability to use effective means of contraception.
研究组 & 干预措施
DS-8895a
Patients received infusions with DS-8895a on Days 1, 8, 22, and 36. Infusions on Days 1 and 36 were trace labelled with ^89Zr (^89Zr-Df-DS-8895a). The Day 1 dose was 0.2 mg/kg, followed by subsequent doses calculated based on individual patient body weight and dosing cohort assignment.
干预措施: DS-8895a 1 mg/kg (Drug)
DS-8895a
Patients received infusions with DS-8895a on Days 1, 8, 22, and 36. Infusions on Days 1 and 36 were trace labelled with ^89Zr (^89Zr-Df-DS-8895a). The Day 1 dose was 0.2 mg/kg, followed by subsequent doses calculated based on individual patient body weight and dosing cohort assignment.
干预措施: DS-8895a 3 mg/kg (Drug)
DS-8895a
Patients received infusions with DS-8895a on Days 1, 8, 22, and 36. Infusions on Days 1 and 36 were trace labelled with ^89Zr (^89Zr-Df-DS-8895a). The Day 1 dose was 0.2 mg/kg, followed by subsequent doses calculated based on individual patient body weight and dosing cohort assignment.
干预措施: DS-8895a 10 mg/kg (Drug)
结局指标
主要结局
Number of Patients With Treatment-emergent Adverse Events
时间窗: Continuously for up to 58 weeks
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period.
次要结局
- Number of Patients With Tumor Uptake of ^89Zr-Df-DS-8895a(Up to Day 43)
- Number of Patients With Best Overall Tumor Response(Up to 58 weeks)
- Mean Area Under the Serum Concentration Curve of ^89Zr-Df-DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Volume of Distribution at Steady State of ^89Zr-Df-DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Total Serum Clearance of ^89Zr-Df-DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Maximum Serum Concentration of ^89Zr-Df-DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Elimination Half-life of ^89Zr-Df-DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Area Under the Serum Concentration Curve of DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Volume of Distribution at Steady State of DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Total Serum Clearance of DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Maximum Serum Concentration of DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Mean Elimination Half-life of DS-8895a Following the First Infusion(Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion))
- Number of Patients With Pharmacodynamic (Metabolic) Response(Day 29 and Day 50)
- Number of Patients With Human Anti-Human Antibody Positivity(Up to 43 Weeks)