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

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

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.

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.

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.