A phase 3 multicentre, randomized, prospective, open-label trial of Ibrutinib monotherapy versus fixed-duration Venetoclax plus Obinutuzumab versus fixed-duration Venetoclax plus Ibrutinib in patients with previously untreated chronic lymphocytic leukaemia (CLL) - CLL17
- Trial ID
- 2022-500439-35-00
- Protocol
- CLL17
- Sponsor
- University Of Cologne
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3 multicentre, randomized, prospective, open-label trial is to compare the efficacy of continuous **ibrutinib** monotherapy with fixed-duration **venetoclax** plus **obinutuzumab** and fixed-duration venetoclax plus ibrutinib by measuring progression-free survival (PFS) in patients with previously untreated chronic lymphocytic leukemia (CLL). This is clinically relevant as it aims to determine the most effective treatment regimen for improving PFS, a critical endpoint in the management of treatment-naive CLL.
Secondary objectives include:
- Rates of undetectable minimal residual disease (uMRD, i.e., <10-4) in peripheral blood (PB) and bone marrow (BM) at final restaging, which will be at cycle 18 after the start of treatment, and additional BM assessment approximately 12 months after restaging.
- MRD levels in PB at different time points (cycle 1 before the start of therapy, start of cycle 7, start of cycle 13 [end of VG treatment], start of cycle 16 [end of VI treatment], final restaging [cycle 18], and every 6 months thereafter until the end of the study).
- Duration of undetectable MRD (uMRD).
- Overall response rate (ORR; defined as the rate of a response of complete response [CR], CR with incomplete marrow recovery [CRi], or partial response [PR] as per iwCLL guidelines at final restaging).
- Duration of response.
- Complete response rate (CRR; defined as the rate of a response of CR or CRi) at final restaging as per iwCLL guidelines.
- Overall survival (OS).
- Event-free survival (EFS) (I vs VG and I vs VI).
- Time to next treatment (TTNT).
- PFS2 (i.e., PFS after second-line treatment).
Participants
The clinical trial involves a total of **68 participants** diagnosed with **treatment-naive chronic lymphocytic leukemia** (CLL). The study population includes both male and female subjects, aged 18 years and older, who have not previously received treatment for CLL. Participants were selected based on specific inclusion criteria, such as documented CLL requiring treatment according to iwCLL criteria, a life expectancy of at least six months, and adequate bone marrow, liver, and renal function. The trial does not include a vulnerable population. Participants are expected to have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration venetoclax plus ibrutinib by measuring progression-free survival in these patients.
Plans and Procedures
The clinical trial is a **phase 3**, multicenter, randomized, prospective, open-label study designed to evaluate the efficacy of different treatment regimens in patients with previously untreated **chronic lymphocytic leukemia (CLL)**. The trial compares continuous **ibrutinib** monotherapy with fixed-duration **venetoclax** plus **obinutuzumab** and fixed-duration venetoclax plus ibrutinib. The primary endpoint is progression-free survival (PFS), with secondary endpoints including rates of undetectable minimal residual disease (uMRD), overall response rate (ORR), and overall survival (OS). The trial is expected to conclude by September 2027, with recruitment having started in February 2021.
The trial design involves a randomized allocation of participants into one of the three treatment arms. The study is open-label, meaning both the researchers and participants are aware of the treatment being administered. The trial duration for each participant is determined by the specific treatment arm, with the maximum treatment period being 84 weeks for ibrutinib monotherapy and 12 months for the venetoclax-based regimens. Participants will be involved in the study until the end of the trial or until they meet criteria for early termination, such as disease progression, unacceptable toxicity, or withdrawal of consent.
Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will assess eligibility based on criteria such as documented CLL requiring treatment, age of at least 18 years, and adequate organ function. Follow-up visits will occur at regular intervals to monitor treatment response, adverse events, and laboratory parameters. The end-of-study visit will evaluate the final treatment outcomes and collect data on long-term efficacy and safety.
Participants are expected to remain in the study for the duration of their assigned treatment regimen, with follow-up extending until the end of the study. Conditions that may lead to early termination include disease progression, adverse events, or participant withdrawal. The trial aims to provide robust data on the comparative efficacy of the treatment regimens, contributing to optimized therapeutic strategies for CLL.
Treatment
The clinical trial involves the administration of several treatments for patients with previously untreated **chronic lymphocytic leukaemia (CLL)**. The first experimental medication is **IMBRUVICA** (ibrutinib), which is provided in the form of 140 mg hard capsules. This medication is a small molecule drug and a tyrosine kinase inhibitor. It is administered orally with a maximum daily dose of 420 mg and a total maximum dose of 987,840 mg over a treatment period of up to 84 days. The capsules are specifically labeled and packaged for clinical trial use by Clinigen Clinical Supplies Management.
Another treatment used in the trial is **Gazyvaro** (obinutuzumab), which is a concentrate for solution for infusion. This medication is a protein-based therapeutic agent and is 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 6 days. The product is labeled for clinical trial use.
**Venetoclax** is also included in the trial, provided in the form of film-coated tablets. This synthetic chemical compound is administered orally. The maximum daily dose is 400 mg, with a total maximum dose of 125,790 mg over a treatment period of up to 12 months. Venetoclax is identified by the sponsor product code ABT-199 and is manufactured by AbbVie Deutschland GmbH & Co. KG.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration venetoclax plus ibrutinib by measuring progression-free survival in patients with CLL.
Efficacy
The efficacy of the clinical trial will be assessed primarily by measuring **progression-free survival (PFS)** in patients with previously untreated chronic lymphocytic leukemia (CLL). This primary endpoint will compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration venetoclax plus ibrutinib. Secondary endpoints include rates of undetectable minimal residual disease (uMRD) in peripheral blood and bone marrow at final restaging, which occurs at cycle 18 after the start of treatment, and additional bone marrow assessment approximately 12 months after restaging. Other secondary endpoints are MRD levels in peripheral blood at various time points, duration of uMRD, overall response rate (ORR) as per iwCLL guidelines, duration of response, complete response rate (CRR), overall survival (OS), event-free survival (EFS), time to next treatment (TTNT), and PFS after second-line treatment (PFS2).
The collection and analysis of these efficacy parameters will be conducted at specified time points throughout the trial, including cycle 1 before the start of therapy, start of cycle 7, start of cycle 13, start of cycle 16, final restaging at cycle 18, and every 6 months thereafter until the end of the study. The trial is designed to ensure rigorous assessment of the efficacy of the treatment regimens, with a focus on both immediate and long-term outcomes in the patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented CLL/ Small lymphocytic lymphoma (SLL) requiring treatment according to iwCLL criteria
- Age at least 18 years.
- Life expectancy ≥ 6 months
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
- Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL: a) Absolute neutrophil count ≥ 1.0 × 10E9/L, b) Platelet counts ≥ 30 × 10E9/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 10E9/L , c) Total haemoglobin ≥ 8 g/dL (without transfusion support, unless anaemia is due to CLL)
- GFR >30ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method. a) For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.
- Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
- Negative serological testing for hepatitis B (HbsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month/ every three month if persistently negative until 12 months after last treatment cycle), and for hepatitis C (anti-HCV-ab negative; in case of positive HCV antibody test, negative HCV-PCR is required).
- Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
Exclusion Criteria
- Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
- Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
- Patients with a history of PML.
- An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
- Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician or showing signs of progression after curative treatment.
- Uncontrolled or active infection.
- Patients with known infection with human immunodeficiency virus (HIV).
- Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).
- Anticoagulant therapy with warfarin or phenprocoumon (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
- History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
- Known bleeding disorders.
- Child B / C liver cirrhosis.
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
- Vaccination with live vaccines 28 days prior to registration for study screening.
- Major surgery less than 30 days before start of study treatment.
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
- Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
- Fertile men or women of childbearing potential unless a) surgically sterile or ≥ 2 years after the onset of menopause or b) willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
- Legal incapacity.
- Prisoners or subjects who are institutionalized by regulatory or court order.
- Persons who are in dependence to the sponsor or an investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 26 Feb 2021 | 48 |
 Belgium | Not Recruiting | 26 Feb 2021 | 29 |
 Denmark | Not Recruiting | 26 Feb 2021 | 53 |
 Finland | Not Recruiting | 26 Feb 2021 | 15 |
 Germany | Not Recruiting | 26 Feb 2021 | 169 |
 Ireland | Not Recruiting | 26 Feb 2021 | 86 |
 Italy | Not Recruiting | 26 Feb 2021 | 63 |
 The Netherlands | Not Recruiting | 26 Feb 2021 | — |
 Norway | Not Recruiting | 26 Feb 2021 | 32 |
 Spain | Not Recruiting | 26 Feb 2021 | 109 |
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 | 400 | 12 | PRD2186234 |
IMBRUVICA 140 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 420 | 84 | PRD1729387 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 400 | 12 | PRD2186236 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 400 | 12 | PRD2186235 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 6 | PRD1753415 |