VENETOCLAX for Small lymphocytic lymphoma | Chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"- Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment\n- Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 50ml/min (Cockcroft-Gault)\n- Adequate liver function as indicated: -\tSerum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upper limit of normal (ULN); -\tBilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia);\n- Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN; unless receiving anticoagulation;\n- 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;\n- Patient is able and willing to adhere to the study visit schedule and other protocol requirements;\n- Patient is capable of giving informed consent;\n- Written informed consent\n- Requiring treatment according to IWCLL criteria\n- Age at least 18 years\n- ECOG/WHO performance status 0-2\n- Adequate BM function defined as: -\tHemoglobin >5.6 mmol/l or Hb > 9 g/dL, unless low Hb is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy; -\tAbsolute neutrophil count (ANC) >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; -\tPlatelet count >30 x 109/L (30,000/μL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM;"}

Exclusion criteria

• {"criterion_text":"- Patient received treatment with anti-cancer agent as follows: a. Standard agents within 2 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of epcoritamab (excluding anti-CD20 mAbs and BTKi, which can be administered until first full dose of epcoritamab); OR b. Patient received treatment with an investigational drug, within 4 weeks or 5 half-lives, whichever is shorter, prior to the planned first dose of Venetoclax;\n- Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication\n- Vaccination with live vaccines within 28 days prior to registration\n- Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy\n- Major surgery within 28 days prior to registration\n- Pregnant women and nursing mothers\n- Fertile men or women of childbearing potential (WOCBP) unless: (1) surgically sterile or ≥ 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 4 months after last dose of epcoritamab and 30 days after last dose of venetoclax\n- Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial\n- Current participation in other clinical trial and using study medication\n- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule\n- Transformation of CLL (Richter’s transformation)\n- a. Ongoing active bacterial, viral, fungal, mycobacterial, parasitic or other infection requiring systemic treatment (excluding prophylactic treatment) at the time of enrollment or within the previous 2 weeks prior to the planned first dose of trial drug, including COVID-19 infection. Note that a past COVID-19 infection may be a risk factor, but if resolved and the subject is vaccinated, it may be allowable to enroll the subject. b. Has suspected active or inadequately treated latent tuberculosis;\n- Prior allogeneic stem cell transplantation and/or solid organ transplantation\n- Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML)\n- Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment\n- Known allergy to xanthine oxidase inhibitors and/or rasburicase\n- History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components)\n- Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease)\n- Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment\n- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)\n- Patient known to be HIV-positive\n- Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer\n- CTCAE grade III-IV cardiovascular disease including but not limited to: -\tUnstable 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. -\tMyocardial infarction within 6 months prior to registration. -\t Subject age ≥75 and 2 or more active grade ≥2 cardiovascular conditions. -\tScreening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) >480 msec. NOTE: this criterion does not apply to subjects with a left bundle branch block. -\tStroke or intracranial hemorrhage within 6 months prior to registration.\n- Severe pulmonary dysfunction (CTCAE grade III-IV)\n- Severe neurological or psychiatric disease (CTCAE grade III-IV)\n- Neuropathy > CTCAE grade II"}

Primary endpoints

• {"endpoint_text":"- Phase I: recommended Phase 2 Dose (RP2D) for the combination of venetoclax and epcoritamab based on dose limiting toxicity (DLT).","definition_or_measurement_approach":"Determination of RP2D based on observed dose limiting toxicities (DLTs) during Phase I."}
• {"endpoint_text":"- Phase II: undetectable minimal residual disease <10-4 (uMRD4) in the bone marrow (BM), i.e., less than 1 CLL cell per 10 000 leukocytes (equivalently: <0.01%, or <10-4), in absence of progression according to the IWCLL criteria, at 12 weeks after the last day, i.e., day 28, of cycle 26.","definition_or_measurement_approach":"uMRD4 measured in bone marrow at 12 weeks after day 28 of cycle 26; defined as <1 CLL cell per 10,000 leukocytes (<10-4) in absence of progression per IWCLL criteria."}

Secondary endpoints

• {"endpoint_text":"- MRD status in PB at cycle 4, 6, 9, 12, 15, 18, 21, 24 and 12 weeks after day 28 of cycle 26; following treatment: every 3 months for the first year, then every 6 months until relapse or until 6 years after randomization.","definition_or_measurement_approach":"MRD measured in peripheral blood at specified cycles and during follow-up as described."}
• {"endpoint_text":"- Progression free survival (PFS), defined as time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first.","definition_or_measurement_approach":"Time-to-event analysis from randomization to progression or death."}
• {"endpoint_text":"- Overall survival (OS), defined as the time from randomization to death from any cause.","definition_or_measurement_approach":"Time-to-event analysis from randomization to death."}
• {"endpoint_text":"- Best overall response rate (ORR) defined as the proportion of patients with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria.","definition_or_measurement_approach":"Response assessment per IWCLL 2018 criteria; proportion of patients achieving CR/CRi/PR."}
• {"endpoint_text":"- Event free survival (EFS), defined as time from randomization to date of start of next CLL treatment, progression or death, whichever comes first.","definition_or_measurement_approach":"Time-to-event from randomization to next treatment start, progression, or death."}
• {"endpoint_text":"- Time to next CLL treatment (TTNT), defined as time from randomization to next new line of treatment.","definition_or_measurement_approach":"Time-to-event from randomization to initiation of a subsequent CLL therapy."}
• {"endpoint_text":"- Treatment free survival (TFS), defined as time from date of last protocol treatment to date start of next (new) line of treatment, or death from any cause, whichever comes first.","definition_or_measurement_approach":"Time from last protocol treatment to next treatment or death."}
• {"endpoint_text":"- Duration of response (DOR), defined as time from first response (i.e., ≥PR and CR) to progressive disease (PD) or death from any cause..","definition_or_measurement_approach":"Time from first documented response to progression or death."}
• {"endpoint_text":"- Depth (level) of MRD measured in BM after cycle 9 and 12 weeks after day 28 of cycle 26.","definition_or_measurement_approach":"MRD depth measured in bone marrow at specified timepoints."}
• {"endpoint_text":"- Depth (level) of MRD measured in PB at cycle 4, 6, 9, 12, 15, 18, 21, 24, 12 weeks after day 28 of cycle 26 and thereafter every 3 months for the first year, then every 6 months until relapse or until 6 years after registration.","definition_or_measurement_approach":"MRD depth measured in peripheral blood at specified timepoints and during follow-up."}
• {"endpoint_text":"- Safety parameters: Type, frequency, and severity of- adverse events (AEs) and- adverse events of special interest (AESI) and their relationship to study treatment (determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0).","definition_or_measurement_approach":"AE and AESI reporting graded per NCI CTCAE v5.0 and assessment of relationship to study treatment."}
• {"endpoint_text":"- Health-related quality of life (QoL) by EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE questionnaires.","definition_or_measurement_approach":"QoL assessed using EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE instruments."}
• {"endpoint_text":"- Evaluation of relationship between various baseline markers and clinical outcome parameters (response, MRD, EFS, etc)","definition_or_measurement_approach":"Exploratory correlation analyses between baseline biomarkers and clinical outcomes."}
• {"endpoint_text":"- Immunophenotyping and functional T cell studies.","definition_or_measurement_approach":"Laboratory immunophenotyping and functional assays for T cells."}
• {"endpoint_text":"- Circulating tumor DNA study on several time points.","definition_or_measurement_approach":"ctDNA analysis at multiple timepoints."}
• {"endpoint_text":"- Baseline molecular characteristics (IGHV mutation status, TP53 mutations, genomic complexity).","definition_or_measurement_approach":"Baseline molecular profiling including IGHV, TP53 and genomic complexity assessments."}
• {"endpoint_text":"- Retrospective exploratory analysis to investigate the effect of epcoritamab in combination with venetoclax on immune composition, genomic and transcriptomic profiles and clonal repertoire.","definition_or_measurement_approach":"Retrospective exploratory genomic, transcriptomic and immune composition analyses."}
• {"endpoint_text":"- Association between MRD (after cycle 9 and 12 weeks after cycle 26) in PB and BM, and PFS/OS.","definition_or_measurement_approach":"Association analyses between MRD measures in PB/BM and survival endpoints."}
• {"endpoint_text":"- Immune markers in relation to CRS and infections.","definition_or_measurement_approach":"Assessment of immune markers and correlation with CRS events and infections."}

Netherlands

Earliest CTIS Part Ii Submission Date

05-12-2023

Latest Decision Or Authorization Date

25-06-2025

Processing Time Days

568

Number Of Sites

12

Number Of Participants

55

Belgium

Earliest CTIS Part Ii Submission Date

01-12-2023

Latest Decision Or Authorization Date

26-06-2025

Processing Time Days

573

Number Of Sites

2

Number Of Participants

11

Denmark

Earliest CTIS Part Ii Submission Date

15-12-2023

Latest Decision Or Authorization Date

26-06-2025

Processing Time Days

559

Number Of Sites

3

Number Of Participants

16

Germany

Earliest CTIS Part Ii Submission Date

05-12-2023

Latest Decision Or Authorization Date

30-06-2025

Processing Time Days

573

Number Of Sites

7

Number Of Participants

30

Primary sponsor

Full Name

Stichting Hemato-Oncologie voor Volwassenen Nederland (Hovon)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands

Contract research organisations

Name

Labcorp Central Laboratory Services S.a.r.l.

Responsibilities

Central laboratory services

Name

Clinigen Clinical Supplies Management

Responsibilities

Clinical supplies management

Third parties

• {"country":"United States","full_name":"Adaptive Biotechnologies Corp.","duties_or_roles":"code 4","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"AbbVie Biotechnology GmbH","duties_or_roles":"code 4","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"IKNL","duties_or_roles":"On site data management (code 15)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"code 1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"code 1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Netherlands","full_name":"Amsterdam UMC","duties_or_roles":"code 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"code 4 (central laboratory services)","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Clinigen Clinical Supplies Management","duties_or_roles":"code 14 (clinical supplies management)","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Sanquin Blood Supply Foundation","duties_or_roles":"code 4","organisation_type":"Patient organisation/association"}