A Phase 1 Adaptive Dose-Escalation Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of ADCT-301 in Patients with Relapsed or Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma
Michelle A. Fanale
The goal of this clinical research study is to find the highest tolerable dose level of ADCT-301 that can be given to patients with different types of lymphoma. Researchers also want to learn if the highest dose found can help to control the disease. The safety of ADCT-301 will also be studied. This is the first study using ADCT-301 in humans.
Disease Group: Lymphoma
Treatment Agent: ADCT-301
Treatment Location: Both at MDACC & and Other Sites
Sponsor: ADC Therapeutics SARL
Primary Objectives -The 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 AML (Part 1). • Determine the recommended dose of ADCT-301 for Part 2. • 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 activity of ADCT-301 measured by overall response rate, duration of response, progression-free survival, and overall survival. Characterize the pharmacokinetic (PK) profile of HuMax-TAC (total antibody drug-toantibody ratio [DAR] >/= 0), PBD-conjugated HuMax-TAC (DAR >/= 1), and free warhead SG3199. - Evaluate anti-drug antibodies (ADAs) in blood before, during, and after treatment with ADCT-301. Exploratory Objectives The exploratory objectives for Part 1 and Part 2 of the study are: - Evaluate the pharmacodynamic (PD) profile of ADCT-301 as measured by correlation between clinical activity and CD25 expression level in tumor tissue, and soluble CD25. - Evaluate the pharmacokinetic (PK) and PD relationship of ADCT-301. - Evaluate the change in white blood cell populations (such as activated T -cells) before, during, and after treatment with ADCT-301 (Study Part 2 only). - Explore the ADCT-301 and free warhead SG3199 concentration-QTc interval relationship.
IRB Review and Approval Date: 12/16/2015
Recruitment Status: Open
Projected Accrual: 90
1) Male or female age 18 years or older
2) Refractory or relapsed lymphoma (per World Health Organization WHO Classification system) defined as: • Non-Hodgkin lymphoma (NHL): Patients with histologically confirmed NHL (including stage >/= Ib cutaneous T-cell lymphoma [CTCL]) who have failed or are intolerant to any established therapy known to provide clinical benefit at current state of disease. There is no upper limit to the number of prior therapies. • Hodgkin lymphoma: Patients with histologically confirmed classical Hodgkin lymphoma who have failed or intolerant to any established therapy known to provide clinical benefit at current state of disease. There is no upper limit to the number of prior therapies.
3) Pathologically confirmed relapsed or refractory lymphoma; a biopsy at any relapse is acceptable
4) Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block. An FFPE block from a current biopsy is preferred; however archival tissue taken at any prior relapse is acceptable. If tissue block is not available, slides from a FFPE block may be acceptable for eligibility upon consultation with the sponsor.
5) Measurable disease, defined by the 2014 Lugano Classification Criteria (including CTCL patients without evidence of skin disease). CTCL patients with skin disease and modified Severity-Weighted Assessment Tool (mSWAT) criteria > 0, or absolute Sezary count >/= 1000 cells/µL are eligible.
6) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
7) Absolute neutrophil count (ANC) >/= 1500/uL.
8) Platelet count of >/= 75000/uL.
9) Hemoglobin >/= 9.0 g/dL without transfusion within the 2 weeks prior to Day 1.
10) Serum/plasma creatinine </= 1.5 mg/dL, or if the patient has a creatinine > 1.5mg/dL, a measured creatinine clearance must be > 80 mL/min/1.73m2 as calculated by the Cockcroft and Gault equation.
11) Serum/plasma alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase </=2 times the upper limit of normal (ULN); </= 5 times ULN if there is liver or bone involvement.
12) Total serum/plasma bilirubin </=1.5 times ULN (patients with known Gilbert’s syndrome may have a total bilirubin up to </= 3 times ULN).
13) Women of childbearing potential must have a negative blood beta-human chorionic gonadotropin pregnancy test within 7 days prior to Day 1.
14) 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.
15) 14. Continued **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.
1) Patients who have an option for any treatment with proven clinical
benefit for their lymphoid malignancy at current state of disease.
2) Active graft-versus-host disease.
3) Autologous or allogenic transplant within the 60 days prior to Cycle 1 Day 1.
4) Evidence of myelodysplasia or myeloid leukemia by morphology, immunostains, flow cytometry, or cytogenetics on a bone marrow aspirate or biopsy.
5) Known history of positive serum human ADA or known allergy to any component of ADCT-301.
6) History of symptomatic 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 central nervous system autoimmune disease (e.g., poliomyelitis, multiple sclerosis).
7) 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. If patient is at risk for having undiagnosed HCV (e.g., history of injection drug use), HCV testing should be considered.
8) History of Steven's Johnson's 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, or electrocardiographic evidence of acute ischemia, poorly controlled diabetes, severe chronic pulmonary disease, coronary angioplasty, or 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 the start of study treatment on Cycle 1, Day 1, except if approved by the Sponsor.
12) Steroid use equivalent to >/= 20 mg of prednisone within 4 weeks prior to Day 1, except for the use of short course systemic corticosteroids (</= 7 days), with a wash-out of 1 week prior to Day 1.
13) Major surgery, chemotherapy, systemic therapy (excluding steroids and including 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.
14) 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.
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 sponsor medical monitor and 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
Michelle A. Fanale
For general questions about clinical trials: