Study of ADCT-301 in Patients With Relapsed/Refractory CD25-positive Acute Myeloid Leukemia (AML) or CD25-positive Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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This study evaluates ADCT-301 in participants with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL). Participants will participate in a dose-escalation phase (Part 1) and receive ADCT-301 either weekly or once every 3 weeks. In Part 2 of the study, participants will receive a recommended dose of ADCT-301 as determined by a Dose Escalation Steering Committee.

Detailed Description
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This is a Phase 1 study with ADCT-301 to evaluate the safety, tolerability and pharmacokinetics of ADCT-301 in participants with Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL). ADCT-301 is a human monoclonal antibody attached via a cleavable linker to a pyrrolobenzodiazepine (PBD) warhead which, when internalized by antigen expressing cells, covalently cross links deoxyribonucleic acid (DNA) preventing replication. The study will be conducted in 2 parts: In Part 1 (dose escalation) participants will either be on weekly administration or every 3-week administration. Participants on weekly administration will receive an infusion of ADCT-301 on Days 1, 8, and 15 of each 3 week treatment cycle. Participants on 3-week administration will receive an infusion of ADCT-301 on Day 1, every 3 weeks. Dose escalation will continue until the maximum tolerated dose (MTD) is determined. In Part 2 (expansion), participants will be assigned to receive a recommended dose and/or schedule of ADCT-301 as determined by a Dose Escalation Steering Committee. For each participant, the study will include 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 months after the last dose of study drug. The total study duration will be dependent on overall participant tolerability to the study drug and response to treatment. It is anticipated that the entire study (Parts 1 and 2) will enroll a maximum of 80 participants and could last approximately 3 years from first participant treated to last participant completed.

Official Title
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A Phase 1, Open-label, Dose-escalation, Multicenter Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Activity of ADCT 301 in Patients With Relapsed or Refractory CD25-positive Acute Myeloid Leukemia (AML) or CD25-positive Acute Lymphoblastic Leukemia

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: ADCT-301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory CD25-positive AML [per World Health Organization (WHO)]. Relapsed or refractory CD25-positive ALL [per World Health Organization (WHO)]. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 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 the upper limit of normal. Women of childbearing potential must have a negative urine or serum beta-human chorionic gonadotropin pregnancy test within 7 days prior to Day 1. Women of childbearing potential must agree to use a highly effective method of contraception. Men with female partners who are of childbearing potential must agree that they or their partners will use a highly effective method of contraception. White Blood Cell Count value of <15,000 cells/μL prior to Cycle 1 Day 1. Exclusion Criteria: Participants who have an option for any treatment with proven clinical benefit for CD25-positive AML or CD25-positive ALL at current state of disease. Known active central nervous system (CNS) leukemia, defined as morphologic evidence of leukemic blasts in the cerebrospinal fluid (CSF), use of CNS directed intrathecal treatment for active disease within 28 days prior to Screening, or symptomatic CNS leukemia (i.e., cranial nerve palsies or other significant neurologic dysfunction) within 28 days prior to Screening. Active graft versus host disease. Autologous or allogenic transplant within the 60 days prior to Screening. Known history of immunogenicity or hypersensitivity to a CD25 antibody. Known history of positive serum human anti-drug antibodies (ADA), or known allergy to any component of ADCT-301. Active autoimmune disease; other CNS autoimmune disease. Known seropositive for human immunodeficiency (HIV) virus, hepatitis B surface antigen (HbsAg), or antibody to hepatitis C virus (anti-HCV) with confirmatory testing and requiring anti-viral therapy. 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 the study treatment on Cycle 1, Day 1. Major surgery, chemotherapy, systemic therapy (excluding hydroxyurea, steroids, and any targeted small molecules or biologics), or radiotherapy, or biotherapy targeted therapies within 14 days or 5 half-lives (whichever is shorter) prior to Cycle 1, Day 1 treatment, except if approved by the Sponsor. Failure to recover (to CTCAE Version 4.0 Grade 0 or Grade 1) from acute non hematologic toxicity (except all grades of alopecia or Grade 2 or lower neuropathy), due to previous therapy, prior to Screening. Isolated extramedullary relapse (i.e., testicular, CNS). Congenital long QT syndrome or a corrected QT interval (QTc) ≥450 ms at Screening (unless secondary to pacemaker or bundle branch block). 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. Any other significant medical illness, abnormality, or condition.

Ages Eligible for Study
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Minimum Age: 18 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-301 (dose escalation)<br>Weekly administration - Participants will receive an IV infusion of ADCT-301, on Days 1, 8, and 15 of each 3-week (21-day) cycle. 3-week administration - Participants will receive an IV infusion of ADCT-301, on Day 1 of each 3-week (21-day) cycle. The dose escalation will be conducted according to a 3+3 design. | Drug: ADCT-301<br>* Intravenous infusion<br>* Other names: Camidanlumab tesirine;|
| Experimental: Part 2: ADCT-301 (dose expansion)<br>Participants will be assigned to receive the recommended dose and/or schedule of ADCT-301 as determined by the Dose Escalation Steering Committee. | Drug: ADCT-301<br>* Intravenous infusion<br>* Other names: Camidanlumab tesirine;|

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 (DLT) | 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 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. Peripheral sensory or motor neuropathy ≥ Grade 2. | Day 1 to Day 21 (Cycle 1) | 
| Recommended Dose of ADCT-301 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 Day 21 (Cycle 1) | 
| Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) | A TEAE is defined as any adverse 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. | Day 1 to a maximum of 24 weeks (+ 30 days) | 
| Number of Participants Reporting One or More Treatment Emergent Serious Adverse Event (SAE) | 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. Hospitalization for elective procedures or for protocol compliance is not considered an SAE. | Day 1 to a maximum of 24 weeks (+ 30 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR is defined among responders (complete response [CR], CR with incomplete blood count recover [CRi], or 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. A summary of antitumor activity was not conducted due to a limited number of responders. CR: 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: 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. | Screening, Day 19 visit (+/- 3 days) of Cycle 2 and each subsequent cycle up to 12 months after the last dose of study drug (1 cycle = 21 days) | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants with a best overall response of CR, CRi, or PR at the time each participant discontinues treatment with ADCT-301. A summary of antitumor activity was not conducted due to a limited number of responders. | Screening, Day 19 visit (+/- 3 days) of Cycle 2 and each subsequent cycle up to 12 months after the last dose of study drug (1 cycle = 21 days) | 
| Overall Survival (OS) | OS is defined as the time from the first dose of study drug treatment until the date of death due to any cause. A summary of antitumor activity was not conducted due to a limited number of responders. | Screening, Day 19 visit (+/- 3 days) of Cycle 2 and each subsequent cycle up to 12 months after the last dose of study drug (1 cycle = 21 days) | 
| Number of Participants With Progression Free Survival (PFS) | PFS is defined as the time from first dose of study drug until the first date of either disease progression or death due to any cause. A summary of antitumor activity was not conducted due to a limited number of responders. | Screening, Day 19 visit (+/- 3 days) of Cycle 2 and each subsequent cycle up to 12 months after the last dose of study drug (1 cycle = 21 days) | 
| Maximum Observed Serum Concentration (Cmax) of ADCT-301 for the Q3W Dosing Schedule | Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohorts. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Maximum Observed Serum Concentration (Cmax) of ADCT-301 for the QW Dosing Schedule | Cmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Time to Reach the Maximum Observed Serum Concentration (Tmax) for ADCT-301 for the Q3W Dosing Schedule | Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Time to Reach the Maximum Observed Serum Concentration (Tmax) for ADCT-301 for the QW Dosing Schedule | Tmax for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-301 for the Q3W Dosing Schedule | AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for ADCT-301 for the QW Dosing Schedule | AUClast for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau) for ADCT-301 for the Q3W Dosing Schedule | AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-time Curve From Time 0 to the End of the Dosing Interval (AUCtau) for ADCT-301 for the QW Dosing Schedule | AUCtau for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for ADCT-301 for the Q3W Dosing Schedule | AUCinf for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) for ADCT-301 for the QW Dosing Schedule | AUCinf for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Accumulation Index (AI) for ADCT-301 for the Q3W Dosing Schedule | AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. AI is the ratio of area under the serum concentration-time curve (AUC) from 0 to 21 days for Cycle 2 divided by AUC from 0 to 21 days for Cycle 1. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Accumulation Index (AI) for ADCT-301 for the QW Dosing Schedule | AI for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. AI is the ratio of area under the serum concentration-time curve (AUC) from 0 to 7 days divided by AUC from 7 to 14 days for Cycle 1. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Volume of Distribution at Steady-state (Vss) for ADCT-301 for the Q3W Dosing Schedule | Vss for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Volume of Distribution at Steady-state (Vss) for ADCT-301 for the QW Dosing Schedule | Vss for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Mean Residence Time (MRT) for ADCT-301 for the Q3W Dosing Schedule | MRT analysis was planned for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Mean Residence Time (MRT) for ADCT-301 for the QW Dosing Schedule | MRT analysis was planned for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Terminal Elimination Phase Rate Constant (λz) for ADCT-301 for the Q3W Dosing Schedule | λz analysis was planned for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Terminal Elimination Phase Rate Constant (λz) for ADCT-301 for the QW Dosing Schedule | λz analysis was planned for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Apparent Terminal Phase Elimination Half-life (Thalf) for ADCT-301 for the Q3W Dosing Schedule | Thalf for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Apparent Terminal Phase Elimination Half-life (Thalf) for ADCT-301 for the QW Dosing Schedule | Thalf for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Clearance (CL) for ADCT-301 for the Q3W Dosing Schedule | CL for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for Q3W cohort. | Before infusion, end of infusion, 1, 3, 6, 24, 48, and 96 hours after infusion, and on Days 8 and 19 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Clearance (CL) for ADCT-301 for the QW Dosing Schedule | CL for Pyrrolobenzodiazepine (PBD) conjugated antibody (Ab), total Ab and free warhead (SG3199) for QW cohort. | Before infusion, end of infusion, 5, 24, 48, and 96 hours after infusion on days 1 and 8, and before and after infusion on Day 15 of Cycle 1 and 2 (1 cycle = 21 days) | 
| Number of Participants With Anti-drug Antibody Response (Against ADCT-301) | Blood serum samples were collected and analysed to determine the presence or absence of ADA. Results were pooled for Part 1 participants as specified in the protocol. | Day 1 to the end of Cycle 2 (6 weeks) | 

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