A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of ADCT-502 in Patients With Advanced Solid Tumors With HER2 Expression
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 21
- 试验地点
- 5
- 主要终点
- Number of Participants With Clinically Significant Physical Examination Results
研究概览
简要总结
This study evaluated ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression. Participants participated in a dose-escalation phase (Part 1) and were due to participate in the dose expansion phase (Part 2). In Part 2, patients were due to receive the dose level identified in Part 1, but the study was terminated prior to the beginning of Part 2.
详细描述
Study ADCT-502-101 was the first clinical study with ADCT-502 in participants with Advanced Solid Tumors with HER2 Expression.
ADCT-502 is an antibody drug conjugate (ADC) composed of an engineered version of the humanized monoclonal antibody trastuzumab, directed against the human HER2 receptor, conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. ADCT-502 specifically binds to HER2, and once internalized, releases the PBD dimer to allow cross-linking of DNA and eventually trigger cell death.
The study had 2 parts. In Part 1 (dose escalation) participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined. In Part 2 (expansion), participants were due to be assigned to the recommended dose level of ADCT-502 identified in Part 1 by the Dose Escalation Steering Committee, but the study was terminated prior to the beginning of Part 2.
For each participant, the study included a screening period (up to 28 days), a treatment period, and a follow-up period to assess disease progression and survival for up to 12 weeks after the last dose of study drug. The total study duration was dependent on overall participant tolerability to the study drug and response to treatment as participants were able to continue treatment until disease progression or unacceptable toxicity.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female age 18 years or older
- •Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.
- •Eastern Cooperative Oncology Group (ECOG) performance status: Part 1: 0-2, Part 2: 0-1
- •Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block or unstained slides to demonstrate HER2 expression.
- •Pathologic diagnosis of solid tumor malignancy that is locally advanced or metastatic at time of Screening with documented HER2 expression.
- •Part 2/Dose Expansion Only: Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
- •Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥1.5× 109/L).
- •Platelet count ≥100,000 //mm3 (≥100 × 109/L).
- •Hemoglobin ≥ 9 g/L (≥5.6 mmol/L).
- •Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); or ≤ 5.0 × ULN if liver metastases are present.
- •Total bilirubin ≤ 1.5× ULN (or ≤ 3× ULN, with direct bilirubin ≤1.5 × ULN, in participants with known Gilbert syndrome).
- •Creatinine ≤ 1.5× ULN; or, if serum creatinine > 1.5 × ULN, a measured creatinine clearance must be >60mL/min/1.73m2 as calculated by the Cockcroft and Gault equation for participants to be eligible.
- •Women of childbearing potential must agree to use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the last dose of ADCT-
- •Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception from the time of giving informed consent until at least 16 weeks after the participant receives his last dose of ADCT-
排除标准
- •Known history of ≥ Grade 3 hypersensitivity to a therapeutic antibody.
- •Known history of positive serum human anti-drug antibody (ADA) to trastuzumab.
- •Major surgical procedure or significant traumatic injury, radiotherapy, chemotherapy, targeted therapy, hormone therapy, or other anticancer therapy.
- •Failure to recover to Grade 0 or Grade 1 from acute non-hematologic toxicity due to previous therapy, prior to screening (with the exception of alopecia).
- •Central Nervous System (CNS) disease only.
- •Symptomatic CNS metastases or evidence of leptomeningeal disease.
- •Active cardiovascular disease or significant history thereof.
- •Other active disease including but not limited to ulceration of the upper gastrointestinal tract, autoimmune disease, HIV infection, active Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
- •Breastfeeding or pregnant.
- •Other concurrent severe and/or uncontrolled medical conditions.
研究组 & 干预措施
ADCT-502
Part 1 (dose escalation): Participants received an infusion of ADCT-502, at escalating doses. Part 1 continued until the maximum tolerated dose or the recommended dose(s) and schedule(s) for expansion were determined.
Part 2 (expansion): Participants were due to be assigned to the recommended dose level of ADCT-502 as identified in Part 1 by the Dose Escalation Steering Committee.
干预措施: ADCT-502 (Drug)
结局指标
主要结局
Number of Participants With Clinically Significant Physical Examination Results
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Clinical significance was determined by the investigator.
Number of Participants With Clinically Significant Vital Signs
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Vital sign measurements include arterial blood pressure, heart rate, respiratory rate, and body temperature. Clinical significance was determined by the investigator.
Number of Participants Who Experience Clinically Significant Electrocardiogram (ECG) Results
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Standard 12-lead ECG's will be used. Clinical significance was determined by the investigator.
Number of Participants Who Experience At Least One Treatment Emergent Serious Adverse Event (SAE)
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Number of Participants Who Experience a Clinically Significant Change in Eastern Cooperative Oncology Group (ECOG) Performance Status
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Performance status was assessed using the ECOG performance status grades. These range between Grade 0 (fully active) and Grade 5 (dead). Clinical significance was determined by the investigator.
Number of Participants Who Experienced Dose-Limiting Toxicities
时间窗: Day 1 to 3 Weeks (one cycle)
Number of Participants Who Experienced a Dose-Limiting Toxicity With a CTCAE Grade of 3 or Above
时间窗: Day 1 to 3 Weeks (one cycle)
The Common Terminology Criteria For Adverse Events (CTCAE) Version 4 will be used.
Number of Participants With Clinically Significant Clinical Laboratory Tests
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
Clinical significance was determined by the investigator.
Number of Participants Who Experience At Least One Treatment Emergent Adverse Event (TEAE)
时间窗: Day 1 to end of trial, a maximum of 168 days (+ 30 days)
An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.
次要结局
- Area Under the Plasma Concentration Versus Time Curve (AUC) of PBD-conjugated Antibody (DAR ≥1)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Maximum Observed Plasma Concentration (Cmax) for ADCT-502 (Total Antibody)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Overall Response Rate (ORR)(Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks)
- Disease Control Rate (DCR)(Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks)
- Area Under the Plasma Concentration Time Curve (AUC) of Drug To-antibody Ratio [DAR] ≥0(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Area Under the Plasma Concentration Versus Time Curve (AUC) of ADCT-502 (Total Antibody)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Free Warhead SG3199(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Maximum Observed Plasma Concentration (Cmax) for Free Warhead SG3199(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Progression-Free Survival (PFS)(Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks)
- Maximum Observed Plasma Concentration (Cmax) for PBD-conjugated Antibody (DAR ≥1)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Time to Reach the Maximum Plasma Concentration (Tmax) for Drug To-antibody Ratio [DAR] ≥0)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Overall Survival (OS)(Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks)
- Maximum Observed Plasma Concentration (Cmax) for Drug To-antibody Ratio [DAR] ≥0(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Anti-drug Antibody (ADA) Titers to ADCT-502(Blood sample collection before start of infusion in Cycles 1 and 2, and on Day 1 starting with Cycle 3 until disease progression, 30 days and 12 weeks after last dose)
- Duration of Response (DOR)(Screening, day 1 of cycle 3 and cycle 5, then every 4 cycles, approximately every 12 weeks)
- Time to Reach the Maximum Plasma Concentration (Tmax) for ADCT-502 (Total Antibody)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Time to Reach the Maximum Plasma Concentration (Tmax) for Free Warhead SG3199(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)
- Time to Reach the Maximum Plasma Concentration (Tmax) for PBD-conjugated Antibody (DAR ≥1)(Before infusion, End of Infusion, and 1, 3, 6, 24, 48, 96, 168 and 336 hours post infusion for Cycle 1 & 2. Before infusion and end of infusion of Cycle 3 to disease progression, and 30 days and 12 weeks after last dose)