HOVON 165 CLL: A prospective randomized phase I/II trial of venetoclax treatment (26 cycles) with 6 cycles or 12 cycles of epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia or Small Lymphocytic Lymphoma. AETHER study (ABT199 + Epcoritamab THErapy for Relapsed/refractory CLL/SLL)
- Trial ID
- 2022-500305-40-00
- Protocol
- HO165
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the recommended phase II dose level (RP2D) of **epcoritamab** when used in combination with **venetoclax** for the phase II part of the trial. Additionally, the study aims to evaluate the efficacy of venetoclax treatment (26 cycles) in combination with 6 cycles or 12 cycles of epcoritamab in patients with relapsed or refractory **Chronic Lymphocytic Leukemia** (CLL) or **Small Lymphocytic Lymphoma** (SLL) in terms of achieving undetectable minimal residual disease (uMRD4) in the bone marrow after treatment for the two treatment groups separately. This is clinically relevant as achieving uMRD4 is associated with improved patient outcomes and may indicate a deeper response to therapy.
Secondary objectives include: - Evaluating the efficacy of epcoritamab in combination with venetoclax in terms of minimal residual disease (MRD) depth in peripheral blood, progression-free survival (PFS), overall survival (OS), event-free survival (EFS), overall response rate (ORR), and time to next treatment (TTNT) for the two treatment groups separately. - Assessing the safety and tolerability of the combination therapy. - Evaluating quality of life (QoL) with the combination therapy. - Investigating the incidence, severity, and type of infections. - Exploring the association between MRD in peripheral blood and bone marrow, and PFS/OS. - Evaluating the value of different techniques for MRD testing. - Assessing the impact on immunological function of the combination therapy. - Evaluating circulating tumor DNA (ctDNA) at several time points.
Participants
The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia** (CLL) or Small Lymphocytic Lymphoma (SLL). The study population includes both male and female subjects, aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of self-care. Participants are required to have adequate bone marrow, liver, and renal function, as well as a negative serological status for hepatitis B and C, unless specific conditions are met. The trial includes individuals who have experienced relapsed or refractory CLL or SLL following at least one systemic first-line treatment. The sponsor has not provided the total number of participants. The trial population was selected based on their ability to adhere to the study protocol and provide informed consent. Lifestyle considerations such as diet and physical activity are not specified. The study includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **venetoclax** in combination with **epcoritamab** in patients with relapsed or refractory **Chronic Lymphocytic Leukemia** (CLL) or **Small Lymphocytic Lymphoma** (SLL). The trial is divided into two phases: Phase I aims to determine the recommended Phase II dose level of epcoritamab when used with venetoclax, while Phase II evaluates the efficacy of the combination treatment in achieving undetectable minimal residual disease in the bone marrow. The trial is expected to conclude by December 2032, with recruitment starting in December 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as documented relapsed or refractory CLL or SLL, negative serological testing for hepatitis B and C, and adequate bone marrow and liver function. Following successful screening, participants will be randomized into treatment groups. The study involves multiple follow-up visits to monitor minimal residual disease status, progression-free survival, overall survival, and other secondary endpoints. These visits will occur at specified intervals, including every three months for the first year and every six months thereafter until relapse or six years post-randomization.
The expected length of participant involvement is up to six years, depending on individual response and disease progression. Conditions that may lead to early termination from the study include disease progression, withdrawal of consent, or adverse events that compromise participant safety. The trial's primary endpoints include determining the recommended Phase II dose and achieving undetectable minimal residual disease in the bone marrow. Secondary endpoints encompass various measures of treatment efficacy, safety, and quality of life, as well as exploratory analyses of immune markers and molecular characteristics.
Treatment
**Venetoclax** is an experimental medication used in this clinical trial, formulated as a **film-coated tablet**. It is administered orally. The specific dosage and frequency of administration are determined based on the trial protocol, which aims to evaluate its efficacy in combination with other treatments. Venetoclax is a chemical substance developed by ABBVIE DEUTSCHLAND GMBH & CO. KG, and it is identified by the sponsor product code ABT-199. The trial involves multiple cycles of administration, with participant compliance monitored throughout the study period.
**Epcoritamab (GEN3013)** is another experimental medication included in the trial, provided as a **solution for injection**. It is administered subcutaneously. The trial seeks to determine the recommended phase II dose level of Epcoritamab when used in combination with Venetoclax. Epcoritamab is a protein-based substance developed by GENMAB. The administration schedule involves either 6 or 12 cycles, depending on the treatment group, with careful monitoring of participant compliance and response to the treatment.
No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided. The focus of the study is on the combination of Venetoclax and Epcoritamab to assess their efficacy in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The trial's objective is to achieve undetectable minimal residual disease in the bone marrow after treatment.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Phase II is the achievement of **undetectable minimal residual disease (uMRD4)** in the bone marrow, defined as less than 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes, at 12 weeks after the last day of cycle 26. This endpoint will be evaluated in the absence of disease progression according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.
Secondary endpoints include the assessment of minimal residual disease (MRD) status in peripheral blood at various cycles (4, 6, 9, 12, 15, 18, 21, 24) and 12 weeks after day 28 of cycle 26. MRD will also be monitored every 3 months for the first year post-treatment, then every 6 months until relapse or up to 6 years after randomization. Additional secondary endpoints encompass progression-free survival (PFS), overall survival (OS), best overall response rate (ORR), event-free survival (EFS), time to next CLL treatment (TTNT), treatment-free survival (TFS), and duration of response (DOR). The depth of MRD in both bone marrow and peripheral blood will be measured at specified intervals to provide further insights into treatment efficacy.
Safety parameters will be evaluated by documenting the type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI), using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Health-related quality of life will be assessed using the EORTC QLQ-C30, QLQ-CLL17, and PRO-CTCAE questionnaires. The study will also explore the relationship between baseline markers and clinical outcomes, including response and MRD status, as well as conduct immunophenotyping, functional T cell studies, and circulating tumor DNA analysis at several time points.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment
- 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
- Requiring treatment according to IWCLL criteria
- Age at least 18 years
- ECOG/WHO performance status 0-2
- Adequate BM function defined as: - Hemoglobin >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; - Absolute 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; - Platelet count >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) ≥ 50ml/min (Cockcroft-Gault)
- Adequate liver function as indicated: - Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upper limit of normal (ULN); - Bilirubin ≤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) <1.5 x ULN; unless receiving anticoagulation;
Exclusion Criteria
- 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;
- 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;
- 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 ≥75 and 2 or more active grade ≥2 cardiovascular conditions. - Screening 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. - 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 > 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
- Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy
- 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 ≥ 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
- 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 and using study medication
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- 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)
- Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Dec 2023 | 11 |
 Denmark | Recruiting | 01 Dec 2023 | 16 |
 Germany | Recruiting | 01 Dec 2023 | 30 |
 The Netherlands | Recruiting | 01 Dec 2023 | — |
| Netherlands | — | — | 55 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | — | — | PRD2186236 |
EpcoritamabGEN3013 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD10556500 |
EpcoritamabGEN3013 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS | — | — | PRD10556501 |
Venetoclax | Test | FILM-COATED TABLET | ORAL | — | — | PRD2186234 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | — | — | PRD2186235 |