Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: ADCT-402


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 0-2. 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 1. 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: ADCT-402 dose escalation<br>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. | Drug: ADCT-402<br>* Intravenous infusion<br>* Other names: Zynlonta;|
| Experimental: Part 2: ADCT-402 expansion<br>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 | Drug: ADCT-402<br>* Intravenous infusion<br>* Other names: Zynlonta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | 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. | Day 1 to End of Cycle 1 (3 weeks) | 
| Recommended Dose of ADCT-402 for Part 2 | The recommended dose was to be established by the dose escalation steering committee and based on safety findings during part 1 of the study. | Day 1 to End of Cycle 1 (3 weeks) | 
| Number of Participants Reporting at Least One Treatment Emergent Adverse Event (TEAE) | 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. | From first dose of study drug up to 12 weeks after last dose (up to 39 weeks) | 
| Number of Participants Reporting at Least One Treatment Emergent Serious Adverse Event (SAE) | 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. | From first dose of study drug up to 12 weeks after last dose (up to 39 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the number of participants with a best overall response of complete response (CR), complete response with incomplete blood count recovery (Cri) or partial response (PR) at the time each participant discontinues treatment with ADCT-402. CR is defined as achieving each of the following: Bone marrow differential showing ≤5% blast cells. Absolute neutrophil count (ANC) ≥1.0 x 10^9/L and platelet count ≥100 x 10^9/L. Absence of extramedullary disease. Participant is independent of red blood cell transfusions. Cri is defined as achieving all CR criteria except that values for ANC may be <1.0 x 10^9/L and/or values for platelets may be <100 x 10^9/L. PR is defined as achieving each of the following: ANC ≥1.0 x 10^9/L and platelet count ≥100 x 10^9/L. Bone marrow differential showing a ≥50% decrease from baseline in the percentage of bone marrow blast cells to a level >5% and ≤25%, or bone marrow differential showing <5% blast cells. | 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 | 
| Duration of Response | Duration of response is defined among responders (complete response [CR], complete response with incomplete blood count recovery [Cri], and partial response [PR]) as the time from the earliest date of first response until the first date of either disease progression or death due to any cause. Disease progression is defined as: For participants with CR or CRi, the first date of reappearance of blast cells in bone marrow and/or peripheral blood to a level ≥5%, or development of extramedullary disease. For participants with PR, the first date of an increase in blast cells in bone marrow and/or peripheral blood such that the patient does not continue to meet the criteria for PR. | 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 | Overall survival is defined as the time from the first dose of study drug treatment until the date of death due to any cause. | 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 | Progression-free survival is defined among the efficacy population as the time from first dose of study drug until the first date of either disease progression or death due to any cause. | 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) | Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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 | 
| Maximum Observed Serum Concentration (Cmax) for ADCT-402 Administered Every Week (QW) | Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | AUC∞ for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | AUC∞ for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. AI is the ratio of AUC 0-24 after multiple doses versus a single dose. It is the increase in drug plasma concentration after multiple dosing until a steady state is reached. | 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 Weekly (QW) | AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. AI is the ratio of AUC 0-24 after multiple doses versus a single dose. It is the increase in drug plasma concentration after multiple dosing until a steady state is reached. | 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 | 
| 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 | 
| 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 | 
| Apparent Terminal Phase Elimination Half-life (T1/2) for ADCT-402 Administered Every 3 Weeks (Q3W) | T1/2 for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | T1/2 for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | Apparent clearance for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | Apparent clearance for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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) | Vd beta for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the Q3W cohorts. | 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) | Vd beta for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for the QW cohort. | 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 | Blood serum samples were collected and analysed to determine the presence or absence of ADA. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Loncastuximab tesirine