A Phase 1, Open-label, 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)
If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant. The goal of this clinical research study is to find the highest tolerable dose level of ADCT-402 that can be given to patients with acute lymphoblastic leukemia (ALL). Researchers also want to learn if that dose level can help to control ALL. The safety of ADCT-402 will also be studied. This is the first study using ADCT-402 in humans.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: ADCT-402
Treatment Location: Both at MDACC & and Other Sites
Sponsor: ADC Therapeutics Sàrl
Primary Objectives Evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of ADCT-402 in patients with relapsed or refractory B-ALL in Part 1. Determine the recommended dose of ADCT-402 for Part 2 (expansion). Evaluate the safety and tolerability of ADCT-402 in Part 2 (expansion) at the dose level recommended in Part 1. Secondary Objectives Evaluate the clinical activity of ADCT-402, based on the patient's response to treatment (complete response [CR], CR with incomplete blood count recovery [CRi], partial response [PR], progressive disease [PD], no response [NR]) and determination of the overall response rate (ORR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS). Characterize the pharmacokinetic (PK) profile of ADCT-402 (total antibody, drug-to-antibody ratio [DAR] >0), PBD-conjugated antibody (DAR >1), and free warhead SG3199. Evaluate anti-drug antibodies (ADAs) against ADCT-402 in serum before, during, and after treatment with ADCT-402. Exploratory Objectives Obtain preliminary data on the correlation between the clinical activity and PK profile of ADCT-402 with the baseline expression of CD19 and other CD markers in bone marrow and peripheral blood. Evaluate the change in peripheral blood white blood cell (WBC) populations and expression of CD markers (e.g., CD19, CD20, CD21, CD22) before, during, and after treatment with ADCT-402 (Cycles 1 and 2). Obtain preliminary data on the influence of ADAs (to ADCT-402) on the clinical activity and PK profile of ADCT-402. Explore the influence of ADCT-402 and free warhead SG3199 concentrations on the QTc interval. Evaluate minimal residual disease (MRD) in the bone marrow and its correlation with PFS and OS.
IRB Review and Approval Date: 05/05/2016
Recruitment Status: Open
Projected Accrual: 70
1) 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, in the
opinion of the Investigator. Note: Diagnosis and classification as per
World Health Organization (WHO) classification of B-ALL.
2) Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
3) Serum/plasma creatinine </=1.5mg/dL. If the patient has a serum/plasma creatinine >1.5mg/dL, creatinine clearance must be >60 mL/min/1.73m2, as calculated by the Cockcroft and Gault equation.
4) 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.
5) Total serum/plasma bilirubin </=1.5 times ULN. Patients with known Gilbert’s syndrome may have a total bilirubin up to </=3 times ULN).
6) Negative urine or serum beta-human chorionic gonadotropin (beta-HCG) pregnancy test within 7 days prior to the Cycle 1, Day 1 visit for women of childbearing potential.
7) 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-402. 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-402. Defined as: Sexually mature women who have not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or who have not been naturally postmenopausal (i.e., who have not menstruated at all) for at least 1 year.
8) (continuation of #7) ** Defined as: Hormonal contraceptives (oral, injectable, patch, intrauterine devices), double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), male partner sterilization, or total abstinence from heterosexual intercourse, when this is the preferred and usual lifestyle of the patient. 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.
9) White blood cell (WBC) value of <15,000 cells/uL prior to Cycle 1 Day 1.
1) Patients who, in the opinion of the Investigator, have an option for
other treatment for B-ALL at the current state of disease.
2) Known active central nervous system (CNS) leukemia, defined as morphologic evidence of lymphoblasts 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) Patients with Burkitt’s leukemia/lymphoma.
4) Active graft-versus-host disease.
5) Autologous or allogenic transplant within the 60 days prior to the Screening visit.
6) Known history of immunogenicity or hypersensitivity to a CD19 antibody.
7) Known history of positive serum human ADA.
8) 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).
9) 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).
10) History of Stevens-Johnson syndrome or toxic epidermal necrolysis syndrome.
11) Pregnant or breastfeeding women.
12) 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.
13) Use of any other experimental medication(s) within 14 days or 5 half-lives but in no case less than 14 days prior to the start of study treatment on Cycle 1, Day 1, except if approved by the Sponsor.
14) 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.
15) Failure to recover (to Common Terminology Criteria for Adverse Events [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.
16) Isolated extramedullary relapse (i.e., testicular, CNS).
17) Congenital long QT syndrome, or a corrected QTc interval of >/=450 ms, at the Screening visit (unless secondary to pacemaker or bundle branch block).
18) 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.
19) 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
Malignant neoplasms stated as primary lymphoid haematopoietic
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