None listed
Conditions
Brief summary
The primary purpose of this study is to evaluate the efficacy and safety of combining a T-cell engager epcoritamab with venetoclax in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This combination therapy aims to address the unmet clinical need for novel treatment strategies in these patients. Who is it for? This study is for patients with documented relapsed or refractory CLL or SLL patients that have received at least one initial treatment that works throughout the entire body. Study details Venetoclax is taken by mouth once a day. After gradually increasing the venetoclax dose up to 35 days, all patients will receive 26 cycles of venetoclax. Each cycle has a duration of 28 days. All patients will then begin treatment with epcoritamab. Epcoritamab is given as an injection under the skin. All patients will receive weekly injections for the first 3 cycles. For patients receiving 6 cycles, it will be given every two weeks during cycles 4-6. For patients receiving 12 cycles, it will be given every two weeks during cycles 4-9 and every four weeks during cycles 10-12. It is hoped this research will identify the most effective and safest dosage for patients, improving overall survival and molecular response rates, while reducing treatment-related complications and deaths for those with CLL and SLL.
Interventions
Epcoritamab is supplied as a concentrate for solution for intended subcutaneous injection.
Venetoclax will be administered orally once a day. The initial venetoclax dose is 20 mg. After one week, it increases to 50 mg, then to 100 mg, 200 mg, and finally 400 mg, each after one week.. After venetoclax ramp-up of up to 35 days, all patients will receive 26 cycles of venetoclax. Each cycle has a duration of 28 days. All patients will commence treatment with epcoritamab after completion of the ve
Epcoritamab is supplied as a concentrate for solution for intended subcutaneous injection. Venetoclax will be administered orally once a day. The initial venetoclax dose is 20 mg. After one week, it increases to 50 mg, then to 100 mg, 200 mg, and finally 400 mg, each after one week.. After venetoclax ramp-up of up to 35 days, all patients will receive 26 cycles of venetoclax. Each cycle has a duration of 28 days. All patients will commence treatment with epcoritamab after completion of the venetoclax ramp-up phase. Epcoritamab will be administered as a subcutaneous injection over a period of 6 (Arm 1) or 12 (Arm 2) cycles, with each cycle lasting 28 days at a consistent assigned dose level. All patients will be treated with epcoritamab weekly during cycle 1-3. Patients in Arm 1 will be dosed biweekly during cycle 4-6, while patients in Arm 2 will be dosed biweekly during cycle 4-9 and every 4 weeks during cycles 10-12. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance. The approximate duration of study participation for patients is a maximum of 5 years (1 year treatment, 4 years follow up)
Sponsors
Australasian Leukaemia and Lymphoma Group
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment -Requiring treatment according to IWCLL criteria -Age at least 18 years; -ECOG/WHO performance status 0-2; -In case of prior venetoclax treatment, enrollment can only occur at least 24 months after end of treatment and patients must not have progressed during venetoclax treatment; - Adequate BM function defined as: - Hemoglobin higher than 5.6 mmol/l or Hb higher than 9 g/dL, unless low Hb is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy; -Absolute neutrophil count (ANC) higher than 1.0 x 109/L (1,000/µL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy; - Platelet count higher than 30 x 109/L (30,000/µL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM; - Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) higher or equal to 50ml/min (Cockcroft-Gault); - Adequate liver function as indicated: - Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) lower or equal to 3.0 x upper limit of normal (ULN); - Bilirubin lower or equal to 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia); - Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partial thromboplastin time (aPTT) lower than 1.5 x ULN; unless receiving anticoagulation; - Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks before enrollment. Those who are PCR positive will be excluded; Please note: For patients positive for anti-HBc or antibodies for hepatitis C, HBV-DNA or HCV-DNA PCR, respectively, has to be repeated every month until 12 months after last dose of study treatment; - Patient is able and willing to adhere to the study visit schedule and other protocol requirements; - Patient is capable of giving informed consent; - Written informed consent.
Exclusion criteria
-Active CLL/SLL directed therapy within the last 14 days; -Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy - Transformation of CLL (Richter’s transformation); - Prior allogeneic stem cell transplantation and/or solid organ transplantation; - Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML); - Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment; - Known allergy to xanthine oxidase inhibitors and/or rasburicase; - History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components); -Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease); -Active fungal, bacterial, and/or viral infection CTCAE grade higher than 1; Please note: active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment; - Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.); - Patient known to be HIV-positive; - Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer; -CTCAE grade III-IV cardiovascular disease including but not limited to: - Unstable or uncontrolled disease/condition related to or affecting cardiac function, eg, unstable angina, congestive heart failure grade III or IV as classified by the New York Heart Association, uncontrolled clinically significant cardiac arrhythmia (CTCAE grade II or higher), or clinically significant electrocardiogram (ECG) abnormalities. - Myocardial infarction within 6 months prior to registration. - Subject age higher or equal to 75 and 2 or more active grade higher or equal to 2 cardiovascular conditions. - Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) higher than 480 msec. NOTE: this criterion does not apply to subjects with a left bundle branch block. - Stroke or intracranial hemorrhage within 6 months prior to registration. -Severe pulmonary dysfunction (CTCAE grade III-IV); -Severe neurological or psychiatric disease (CTCAE grade III-IV); -Neuropathy greater than CTCAE grade II -Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication; - Vaccination with live vaccines within 28 days prior to registration; - Use of any other experimental drug or therapy within 28 days of registration; - Major surgery within 28 days prior to registration; -Pregnant women and nursing mothers; -Fertile men or women of childbearing potential (WOCBP) unless: (1) surgically sterile or higher or equal to 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device or sexual abstinence during study treatment and for 12 months after last dose of epcoritamab and 30 days after last dose of venetoclax; -Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial; -Current participation in other clinical trial with medicinal products; -Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Outcome results
None listed