A Phase 1, Open-label, Adaptive Dose-escalation, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Anti-tumor Activity of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 35
- 试验地点
- 10
- 主要终点
- Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE)
研究概览
简要总结
This study evaluates ADCT-402 in participants with relapsed or refractory B-cell lineage acute lymphoblastic leukemia (B-ALL). Participants will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, participants will receive the dose level identified in Part 1.
详细描述
Study ADCT-402-102 is the first clinical study with ADCT-402 in participants with B-cell lineage acute lymphoblastic leukemia (B-ALL).
ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized antibody directed against human cluster of differentiation 19 (CD19), stochastically conjugated via a valine-alanine cleavable, maleimide linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin.
The study will be conducted in 2 parts. In Part 1 (dose escalation) participants will receive an infusion of ADCT-402 either on weekly administration or every 3-week administration. participants on weekly administration will receive an infusion of ADCT-402 on Days 1, 8, and 15 of each 3 week treatment cycle. Participants on 3-week administration will receive an infusion of ADCT-402 on Day 1, every 3 weeks. Dose escalation will continue until the maximum tolerated dose (MTD) is determined.
In Part 2 (expansion), all participants will be assigned to the recommended dose and/or schedule of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee.
For each patient, the study will include a screening period (up to 28 days), a treatment period (until withdrawal), and a follow-up period to assess disease progression and survival for up to 12 months after the last dose of study drug. The total study duration will be dependent on overall patient tolerability to the study drug and response to treatment. It is anticipated that the duration of the entire study (Parts 1 and 2) could be approximately 3 years from first patient treated to last patient completed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients, ages 12 years and older, with relapsed or refractory B-ALL who have failed, or are intolerant to, any established therapy; or for whom no other treatment options are available.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •Serum/plasma creatinine ≤1.5mg/dL.
- •Serum/plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2 times the upper limit of normal (ULN); ≤5 times ULN if there is liver or bone involvement.
- •Total serum/plasma bilirubin ≤1.5 times ULN.
- •White Blood Cell Count value of <15,000 cells/μL prior to Cycle 1 Day
- •Negative urine or serum beta-human chorionic gonadotropin (β-HCG) pregnancy test within 7 days prior to the Cycle 1, Day 1 visit, for women of childbearing potential.
- •Males, and female patients who are biologically capable of having children, must agree to use a medically acceptable method of birth control.
排除标准
- •Patients who have an option for other treatment for B-ALL at the current state of disease.
- •Known active central nervous system (CNS) leukemia.
- •Patients with Burkitt's leukemia/lymphoma.
- •Active graft-versus-host disease.
- •Autologous or allogenic transplant within the 60 days prior to Screening.
- •Known history of immunogenicity or hypersensitivity to a CD19 antibody.
- •Known history of positive serum human ADA.
- •Active autoimmune disease, motor neuropathy considered of autoimmune origin, or other central nervous system autoimmune disease.
- •Known seropositive for human immunodeficiency (HIV) virus, hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV).
- •History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
- •Pregnant or breastfeeding women.
- •Significant medical comorbidities, including uncontrolled hypertension (diastolic blood pressure >115 mm Hg), unstable angina, congestive heart failure (greater than New York Heart Association class II), severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, myocardial infarction within 6 months prior to Screening, or uncontrolled atrial or ventricular cardiac arrhythmias.
- •Use of any other experimental medication(s) within 14 days or 5 half-lives, but in no case <14 days prior to the start of treatment on Cycle 1, Day 1, except if approved by the Sponsor.
- •Major surgery, chemotherapy, systemic therapy (excluding hydroxyurea,steroids and any targeted small molecules or biologics), or radiotherapy, within 14 days or 5 half-lives (whichever is shorter) prior to the Cycle 1, Day 1 treatment, except if approved by the Sponsor.
- •Failure to recover from acute non hematologic toxicity (except alopecia or Grade 2 or lower neuropathy), due to previous therapy, prior to Screening.
- •Isolated extramedullary relapse.
- •Congenital long QT syndrome or a corrected QTc interval of ≥450 ms at the Screening visit.
- •Active second primary malignancy other than non-melanoma skin cancers, nonmetastatic prostate cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast, or other malignancy determined not be exclusionary.
- •Any other significant medical illness, abnormality, or condition that would make the patient inappropriate for study participation or put the patient at risk.
研究组 & 干预措施
Part 1: ADCT-402 dose escalation
Weekly administration - Participants will receive an intravenous (IV) infusion of ADCT-402, on Days 1, 8, and 15 of each 3-week (21-day) cycle.
3-week administration - Participants will receive an IV infusion of ADCT-402, on Day 1 of each 3-week (21-day) cycle.
The dose escalation will be conducted according to a 3+3 design.
干预措施: ADCT-402 (Drug)
Part 2: ADCT-402 expansion
All participants will be assigned to the recommended dose and/or schedule of ADCT-402 identified in Part 1 by the Dose Escalation Steering Committee
干预措施: ADCT-402 (Drug)
结局指标
主要结局
Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE)
时间窗: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks)
An adverse event (AE) is defined as any untoward medical occurrence in a participants enrolled into this study regardless of its causal relationship to study drug. A TEAE is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug.
Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs)
时间窗: Day 1 to End of Cycle 1 (3 weeks)
A DLT is defined as any of the following events, except those that are clearly due to underlying disease or extraneous causes: A hematologic DLT is defined as: - Grade 3 or higher event of neutropenia or thrombocytopenia, or a Grade 4 anemia, with a hypocellular bone marrow lasting for 6 weeks or more after the start of a cycle, in the absence of residual leukemia (i.e., with \<5% blasts). In case of a normocellular bone marrow with \<5% blasts, 8 weeks with ≥Grade 3 pancytopenia will be considered a DLT. A non-hematologic DLT is defined as: * Grade 4 tumor lysis syndrome (Grade 3 TLS will not constitute DLT unless it leads to irreversible end-organ damage). * Grade 3 or higher AE (including nausea, vomiting, diarrhea, and electrolyte imbalances lasting more than 48 hours despite optimal therapy; excluding all grades of alopecia). * CTCAE Grade 3 or higher hypersensitivity reaction (regardless of premedication). * CTCAE Grade 3 or higher skin ulceration.
Recommended Dose of ADCT-402 for Part 2
时间窗: Day 1 to End of Cycle 1 (3 weeks)
The recommended dose was to be established by the dose escalation steering committee and based on safety findings during part 1 of the study.
Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE)
时间窗: From first dose of study drug up to 12 weeks after last dose (up to 39 weeks)
An adverse event (AE) is defined as any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study drug. A treatment-emergent AE (TEAE) is defined as any event not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug. An SAE is defined as any event that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
次要结局
- Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-tau) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Accumulation Index (AI) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Volume of Distribution at Steady State for ADCT-402(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Duration of Response(From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug)
- Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Overall Response Rate (ORR)(From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug)
- Overall Survival(From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug)
- Progression-free Survival(From 6 days prior to Day 1 of Cycle 3 and 5, and at each subsequent cycle, until discontinuation, assessed up to 12 months after last dose of study drug)
- Accumulation Index (AI) for ADCT-402 Administered Weekly (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Mean Residence Time for ADCT-402(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Number of Participants With Anti-drug Antibody Response (ADA) Against ADCT-402(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUC0-tau) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Clearance at Steady State for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Volume of Distribution (Vd Beta) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Time to Reach the Maximum Serum Concentration (Tmax) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Terminal Elimination Phase Rate Constant for ADCT-402(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUC∞) for ADCT-402 Administered Weekly (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Clearance at Steady State for ADCT-402 Administered Every Week (QW)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)
- Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every 3 Weeks (Q3W)(Day 1 (before infusion, end of infusion, and 1, 3 and 6 hours after infusion) and Days 2, 3, 5, 8 and 15 for Cycles 1 and 2)