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 or CD25-positive Acute Lymphoblastic Leukemia
The goal of this clinical research study is to find the highest tolerable dose of ADCT-301 that can be given to patients with AML or ALL. Researchers also want to learn if the study drug can affect the disease. This is the first study using ADCT-301 in patients with AML or ALL.
Disease Group: Leukemia
Treatment Agent: ADCT-301
Treatment Location: Both at MDACC & and Other Sites
Sponsor: ADC Therapeutics SA
Primary Objectives Primary objectives for Part 1 (dose escalation) and Part 2 (expansion) of the study are: Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of ADCT-301 in patients with CD25-positive relapsed or refractory acute myeloid leukemia (AML) or CD25-positive acute lymphoblastic leukemia (ALL) (Part 1). Determine the recommended dose of ADCT-301 for Part 2 (expansion). Evaluate the safety and tolerability of ADCT-301 in Part 2 at the dose level recommended in Part 1. Secondary Objectives: The secondary objectives for Part 1 and Part 2 of the study are: Evaluate the clinical activity of ADCT-301, based on the patient’s response to treatment (complete recovery (CR), CR with incomplete blood count recover (CRi), partial response (PR), progressive disease (PD), no response (NR)) and determination of the overall duration of response (DOR), overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Characterize the pharmacokinetic (PK) profile of ADCT-301 (total antibody, drug-to-antibody ratio (DAR) >/=0), PBD-conjugated antibody (DAR >/=1), and free warhead SG3199. Evaluate anti-drug antibodies (ADAs) to ADCT-301 in blood before, during, and after treatment with ADCT-301. Exploratory Objectives Obtain preliminary data on the correlation between the clinical activity of ADCT-301 with the baseline expression of CD25 in blast cells from whole blood and bone marrow. Obtain preliminary data on the correlation between clinical activity and DNA cross-links in blood. Obtain preliminary data on the influence of ADAs (to ADCT-301) and soluble CD25 on the clinical activity and PK profile of ADCT-301. Explore the influence of ADCT-301 and free warhead SG3199 concentration on the QTc interval. Determine the baseline expression of other cell surface antigens/biomarkers (e.g., CD34) on blast cells within whole blood and bone marrow and explore the correlation with CD25 expression. Explore the correlation of FMS-like tyrosine kinase 3 (FLT3) related mutations, specifically FLT3 internal tandem duplications (FLT3-ITD), when available from patient’s medical history, with CD25 expression. Evaluate the change in peripheral blood white blood cell (WBC) populations before, during, and after treatment with ADCT-301 (Cycles 1 and 2, Part 2 only).
IRB Review and Approval Date: 08/16/2016
Recruitment Status: Open
Projected Accrual: 80
1) Male or female age 18 years or older.
2) Patients with relapsed or refractory CD25-positive* AML** who have failed, or are intolerant to, any established therapy known to provide clinical benefit at current state of disease. Patients with myelodysplastic syndrome who have received treatment with hypomethylating agents and subsequently present with CD25-positive* AML** and who failed, or are ineligible for standard induction therapy. Patients with relapsed or refactory CD25-positive* ALL** who have failed, or are intolerant to any established therapy; or for whom no other treatment options are available, in the opinion of the Investigator. NOTE: *CD25-positive is defined as determination of CD25 expression by >/= 5% of blast cells within bone marrow (aspirate or biopsy), assessed at an approved clinical laboratory. **Diagnosis and classification as per World Health Organization (WHO) classification of acute leukemias.
3) Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
4) Serum/plasma creatinine </= 1.5mg/dL, or if the patient has a serum/plasma creatinine >1.5mg/dL, creatinine clearance must be >60 mL/min/1.73m^2, as calculated by the Cockcroft and Gault equation.
5) 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.
6) Total serum/plasma bilirubin </= 1.5 times the upper limit of normal (ULN). Patients with known Gilbert’s syndrome may have a total bilirubin up to </= 3 times ULN.
7) Women of childbearing potential must have a negative urine or serum beta-human chorionic gonadotropin (Beta-HCG) pregnancy test within 7 days prior to the Day 1 visit.
8) 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-301. 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 patient receives his last dose of ADCT-301. * Defined as: Sexually mature women who have not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not been postmenopausal (i.e., who have not menstruated at all) for at least 1 year.
9) (Continuation of # 8) Defined as: ** Hormonal contraceptives (oral, injectable, patch, intrauterine devices), male partner sterilization, or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the patient. NOTE: The double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, post-ovulation), withdrawal (coitus interruptus), lactational amenorrhea method, and spermicide-only are not acceptable as highly effective methods of contraception.
10) WBC value of <15,000 cells/uL prior to C1D1.
1) Patients who have an option for any treatment with proven clinical
benefit for CD25-positive AML or CD25-positive ALL at current state of disease.
2) 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. Note: Patients may have a history of CNS leukemic involvement if they have received prior treatment for CNS involvement and no evidence of active disease (defined as >/= 2 consecutive spinal fluid assessments with no evidence of disease) is present at Screening. Prophylactic intrathecal chemotherapy is not a criterion for exclusion.
3) Active graft-versus-host disease.
4) Autologous or allogenic transplant within the 60 days prior to Screening.
5) Known history of immunogenicity or hypersensitivity to a CD25 antibody.
6) Known history of positive serum human anti-drug antibody (ADA), or known allergy to any component of ADCT-301.
7) Active autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, Sjögren's syndrome, autoimmune vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré syndrome and myasthenia gravis); other CNS autoimmune disease (e.g., poliomyelitis, multiple sclerosis). 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. Note: Testing is not mandatory to be eligible. Testing for HCV should be considered if the patient is at risk for having undiagnosed HCV (e.g., history of injection drug use).
8) History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
9) Pregnant or breastfeeding women.
10) 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.
11) Use of any other experimental medication(s) within 14 days or 5 half-lives but in no case </= 14 days prior to start of the study treatment on Cycle 1, Day 1, except if approved by the sponsor.
12) 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 Cycle 1, Day 1 treatment, except if approved by the Sponsor.
13) Failure to recover (to Common Terminology Criteria for Adverse Events (CTCAE Version 4.01) 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.
14) Isolated extramedullary relapse (i.e., testicular, CNS).
15) Congenital long QT syndrome or a corrected QTc interval >/= 450 ms at Screening (unless secondary to pacemaker or bundle branch block).
16) 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 that the Sponsor’s medical monitor and the Investigator agree and document should not be exclusionary.
17) Any other significant medical illness, abnormality, or condition that would, in the Investigator’s judgment, make the patient inappropriate for study participation or put the patient at risk.
Information and next steps
For general questions about clinical trials: