HOVON 158 CLL: First line treatment with VeNEtoclaX and ibruTinib induction followed by obinutuzumab intenSificaTion Exclusively in CLL/SLL Patients not in complete remission and/or with detectable bone marrow minimal residual disease (NEXT STEP trial)
- Trial ID
- 2022-502808-72-00
- Protocol
- HO158
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of six cycles of ibrutinib/obinutuzumab in converting patients with Chronic Lymphocytic Leukemia (CLL) who are not in complete remission (CR) or who have detectable minimal residual disease (MRD) on combination ibrutinib and venetoclax into undetectable MRD (uMRD) in the bone marrow (BM) and achieve CR. This is clinically relevant as achieving uMRD and CR is associated with improved patient outcomes and prolonged survival in CLL.
Secondary objectives include:
- Exploring the kinetics of CLL clearance in different compartments (peripheral blood, bone marrow, lymph nodes) using regular test methods (MRD, PET-CT, and BM).
- Measuring the conventional response and outcomes of the combination ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab.
- Evaluating prognostic parameters for response to ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab.
- Assessing the safety of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab.
- Exploring the kinetics of CLL clearance using novel test methods (MRD, PET-CT, fine needle aspiration of lymph nodes).
- Evaluating the impact on immunity, such as the expression of CD20 and CXCR4/CD5, of ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab.
- Assessing the quality of life during and after treatment with ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab.
Participants
The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia** (CLL) or Small Lymphocytic Lymphoma (SLL) who require treatment according to the IWCLL criteria. The study population includes both male and female subjects, aged 18 years and older, with a **WHO performance status** of 0-3, specifically stage 3 if attributable to CLL/SLL. Participants must have adequate bone marrow function, liver function, and renal function, as defined by specific laboratory criteria. The trial does not include individuals with prior treatment for CLL/SLL. The selection process ensures that participants are capable of providing informed consent and are willing to adhere to the study protocol. The trial population includes vulnerable groups, and lifestyle factors such as diet and physical activity are not specified. The sponsor has not provided the total number of participants involved in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a treatment regimen for **Chronic Lymphocytic Leukemia** (CLL) using a combination of venetoclax, ibrutinib, and obinutuzumab. This is a Phase 4, randomized, double-blind, controlled trial. The trial aims to assess the conversion of patients who are not in complete remission (CR) or who have detectable minimal residual disease (MRD) into undetectable MRD (uMRD) CR after treatment intensification. The trial is expected to run from October 15, 2020, to December 15, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented CLL requiring treatment, adequate bone marrow function, and liver function, among others. Following the screening, participants will be randomized to receive the study medications. The treatment phase includes an induction period with venetoclax and ibrutinib, followed by an intensification phase with obinutuzumab for those not achieving CR or uMRD. Follow-up visits will be scheduled to monitor the primary endpoint, which is the achievement of uMRD CR three months post-intensification, and secondary endpoints, including progression-free survival and overall survival.
The expected length of participant involvement is up to 616 days, depending on individual response and treatment tolerability. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or disease progression. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Venclyxto** is provided in three different dosages: 10 mg, 50 mg, and 100 mg, all in the form of film-coated tablets. The active substance in Venclyxto is **venetoclax**, a chemical compound. The tablets are administered orally, with a maximum daily dose of 400 mg and a total maximum dose of 136,990 mg over a treatment period of up to 364 days. The manufacturer of Venclyxto is AbbVie Deutschland GmbH & Co. KG.
Another experimental medication used in the trial is **Gazyvaro**, which contains the active substance **obinutuzumab**. This medication is a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 1,000 mg, with a total maximum dose of 8,000 mg over a treatment period of up to 9 days. Gazyvaro is of biological/biotechnological origin and is produced by Roche Registration GmbH.
Additionally, the trial includes the use of **IMBRUVICA**, which contains the active substance **ibrutinib**. This medication is also provided in the form of film-coated tablets, with each tablet containing 140 mg of ibrutinib. The tablets are administered orally, with a maximum daily dose of 420 mg and a total maximum dose of 70,560 mg over a treatment period of up to 616 days. IMBRUVICA is manufactured by Janssen-Cilag International NV.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of the experimental medications in achieving the trial's main objective.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the achievement of **bone marrow undetectable minimal residual disease complete remission (BM uMRD CR)** three months after the end of intensification with ibrutinib and obinutuzumab in patients who were not in complete remission (CR) or who had detectable minimal residual disease (MRD) on combination ibrutinib and venetoclax. Secondary endpoints include BM uMRD CR nine months after registration in all subjects, the best BM MRD level during the protocol, and MRD levels in bone marrow (BM) and peripheral blood (PB) at different time points during the protocol and follow-up.
Additional secondary endpoints involve the best response by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria during the protocol, response by IWCLL at different time points, and response by Deauville criteria on PET scans at various time points. Progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and treatment-free interval (TFI) will also be evaluated. The predictive value of prognostic markers at diagnosis on uMRD and overall response rate (ORR) by IWCLL and Deauville criteria at the end of ibrutinib/venetoclax and ibrutinib/obinutuzumab treatment will be assessed. Toxicities will be monitored using CTCAE grade ≥2 and IWCLL hematological grade ≥2 criteria.
Exploratory endpoints include MRD levels in BM and PB at different time points using novel techniques, quantification of lesions on 18F-FDG PET-CT, the amount of chronic lymphocytic leukemia (CLL) cells in lymph node biopsy and fine needle aspiration (FNA), immune cell subsets and function at various time points, and quality of life (QoL) assessments during the protocol and follow-up. These efficacy parameters will be measured and analyzed at specified intervals to determine the treatment's impact on patients with CLL/SLL.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented CLL or SLL requiring treatment according to IWCLL criteria, including minimal required markers (CD5/CD19/CD23 triple positive with light chain restriction)
- WHO performance status 0-3 stage 3 only if attributable to CLL/SLL
- No prior treatment for CLL/SLL
- Age at least 18 years
- Adequate BM function defined as: - Hb > 5 mmol/l or Hb > 8 g/dL. - Absolute neutrophil count (ANC) ≥ 0.75 x 109/L or 750/μL. - Platelet count ≥ 50 x 109/L or 50,000 /μL; Unless directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy.
- Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30 l/min (Cockcroft-Gault); Please note: in case eGFR or CrCl is <50ml/min the patient needs to be considered high risk for TLS
- Adequate liver function as indicated: - Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x ULN. - Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of nonhepatic origin)
- Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN
- Negative serological testing for hepatitis B virus (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded.
- Ability and willingness to adhere to the study visit schedule and other protocol requirements.
- Patient is capable of giving informed consent.
- Written informed consent.
Exclusion Criteria
- Transformation of CLL (Richter's transformation)
- Malignancies other than CLL/SLL currently requiring systemic therapy or not being treated incurative intention before or showing signs of progression after curative treatment
- Patient with CNS involvement
- Known allergy to xanthine oxidase inhibitors and/or rasburicase
- Intolerance of exogenous protein administration
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
- Active fungal, bacterial, and/or viral infection that requires systemic therapy
- 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 or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists
- History of stroke or intracranial hemorrhage within 6 months prior to registration
- Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade IIIIV);
- Severe pulmonary dysfunction (CTCAE grade III-IV)
- Patient with Child Pugh C
- Severe neurological or psychiatric disease (CTCAE grade III-IV);
- Vaccination with live vaccines within 28 days prior to registration
- Use of any other experimental drug or therapy within 28 days prior to registration
- Major surgery within 28 days prior to registration
- Steroid therapy within 10 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 20 mg of dose equivalents of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids
- Pregnant women and nursing mothers
- Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 2 years after the onset of menopause, and/or (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device, sexual abstinence or barrier method of contraception in conjunction with spermicidal jelly during study treatment and in female patients for 3 months after end of induction treatment and 18 months after end of treatment with obinutuzumab and male patients for 6 months after end of treatment
- Current participation in other clinical trial;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 15 Oct 2020 | 10 |
 The Netherlands | Not Recruiting | 15 Oct 2020 | — |
| Netherlands | — | — | 75 |
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 |
|---|---|---|---|---|---|---|
IMBRUVICA 140 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 420 | 616 | PRD7294186 |
Venclyxto 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 364 | PRD6353826 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 9 | PRD1753415 |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 364 | PRD6353834 |
Venclyxto 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 364 | PRD6353818 |