Phase 3 Multicenter Randomized Trial of Venetoclax, Obinutuzumab, and Pirtobrutinib in Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
- Trial ID
- 2023-510294-34-00
- Protocol
- CLL18/MOIRAI
- Sponsor
- University Of Cologne
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3 multicenter, randomized, prospective, open-label trial is to compare the efficacy of **MRD-guided** Venetoclax/Pirtobrutinib versus fixed-duration Venetoclax/Pirtobrutinib (15 cycles) and MRD-guided Venetoclax/Pirtobrutinib versus fixed-duration Venetoclax/Obinutuzumab (12 cycles) by measuring **progression-free survival** (PFS) in patients with previously untreated **chronic lymphocytic leukemia** (CLL) or **small lymphocytic lymphoma** (SLL). This objective is clinically relevant as it aims to establish the optimal treatment duration based on individual residual disease measurement, potentially improving patient outcomes by tailoring therapy to disease response.
Secondary objectives include:
- Evaluating **MRD levels** by different types of measurement from various materials at the final restaging and at selected time points.
- Assessing the **overall response rate** (ORR) and **complete response** (CR) rate as per iwCLL guidelines at the final restaging and other selected time points.
- Determining the **duration of response** (DOR) and **time to next treatment** (TTNT).
- Measuring **treatment-free survival** (TFS) and **overall survival** (OS).
- Evaluating the **safety and tolerability** of MRD-guided Venetoclax/Pirtobrutinib, fixed-duration Venetoclax/Pirtobrutinib, and fixed-duration Venetoclax/Obinutuzumab.
- Assessing the **best response** as per iwCLL guidelines until one year after the end of treatment.
Participants
The clinical trial involves a total of **67 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 no specific mention of an upper age limit. Participants were selected based on documented CLL/SLL requiring treatment according to iwCLL criteria, with adequate bone marrow, renal, and liver function, and a life expectancy of at least six months. The trial does not include a vulnerable population. Participants are required to have a negative serological test for hepatitis B, hepatitis C, and HIV. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have the ability and willingness to provide written informed consent and adhere to the study visit schedule and other protocol requirements.
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)** or **small lymphocytic lymphoma (SLL)**. The trial aims to compare the efficacy of MRD-guided Venetoclax/Pirtobrutinib versus fixed-duration Venetoclax/Pirtobrutinib and Venetoclax/Obinutuzumab by measuring progression-free survival (PFS). The study involves a fixed-duration of 12 cycles for Venetoclax/Obinutuzumab and 15 cycles for Venetoclax/Pirtobrutinib, with an MRD-guided approach for Venetoclax/Pirtobrutinib. The trial is expected to conclude by June 2031, with recruitment starting in June 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented CLL/SLL requiring treatment, adequate bone marrow, renal, and liver function, and negative serological testing for hepatitis B, C, and HIV. Following the screening, participants will be randomized into one of the treatment arms. Follow-up visits will be scheduled to monitor treatment response, safety, and adverse events. The end-of-study visit will occur three months after the completion of treatment, except for patients who show disease progression or transformation before this time.
The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period of 924 days for Venetoclax and 1008 days for Pirtobrutinib. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is progression-free survival, with secondary endpoints including measurable residual disease levels, overall response rate, duration of response, time to next treatment, treatment-free survival, overall survival, and safety parameters.
Treatment
The clinical trial involves the administration of **Venetoclax**, a film-coated tablet, as an experimental medication. Venetoclax is chemically synthesized and is provided by ABBVIE DEUTSCHLAND GMBH & CO. KG. The maximum daily dose of Venetoclax is 400 mg, with a total maximum dose of 360,990 mg over a treatment period of up to 924 days. The route of administration is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.
Another experimental medication used in the trial is **Gazyvaro**, a concentrate for solution for infusion containing the active substance **Obinutuzumab**. This medication is provided by ROCHE REGISTRATION GMBH 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 6 cycles. Specific labeling is applied for clinical trial use, and participant compliance is closely monitored to ensure proper administration.
**Pirtobrutinib** is also included in the trial as an experimental medication. It is a film-coated tablet with a chemical origin, and the maximum daily dose is 200 mg, with a total maximum dose of 201,600 mg over a treatment period of 1,008 days. The route of administration is oral, and the medication is not intended for pediatric use. The trial employs specific labeling and packaging for clinical trial purposes, and adherence to the dosing schedule is monitored to ensure participant compliance.
In addition to the experimental medications, the trial may involve the use of standard-of-care therapies as comparator treatments, depending on the specific study arm and protocol. The trial design includes fixed-duration and MRD-guided treatment arms to evaluate the efficacy of the experimental medications in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The primary objective is to measure progression-free survival (PFS) to determine the optimal treatment duration and improve patient outcomes.
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) or small lymphocytic lymphoma (SLL). This primary endpoint will compare the efficacy of MRD-guided Venetoclax/Pirtobrutinib against fixed-duration Venetoclax/Pirtobrutinib and Venetoclax/Obinutuzumab regimens. Secondary endpoints include measurable residual disease (MRD) levels at final restaging, overall response rate (ORR), complete response (CR) rate, duration of response (DOR), time to next treatment (TTNT), treatment-free survival (TFS), overall survival (OS), and safety parameters such as the type, frequency, and severity of adverse events (AEs) and adverse events of particular interest (AEPI).
These efficacy parameters will be collected and analyzed at various time points, including the final restaging, which occurs three months after the end of treatment, except for patients showing disease progression or Richter transformation before this time. Additional assessments will be conducted at selected time points during and after treatment. The trial aims to establish the measurement of individual residual disease for adjusting treatment duration to improve patient outcomes. The study is designed as a phase 3 multicenter, randomized, prospective, open-label trial, with an estimated end date of June 2031.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented CLL/SLL requiring treatment according to iwCLL criteria with a CLL phenotype cell count >10-2 tracked by flow cytometry at screening.
- Adequate bone marrow function as indicated by: - an absolute neutrophil count ≥ 1 x 10⁹/l - a hemoglobin value ≥8.0 g/dL without transfusions during the last 7 days unless directly attributable to CLL/SLL (e.g. bone marrow infiltration) and - a platelet count ≥ 25 x 10⁹/l unless due to the CLL/SLL, in this case, platelet count should be ≥ 10.000/µl without transfusion during the last 7 days.
- Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the MDRD-formula or an equally accurate method (e.g. 24 hr. urine collection)
- Adequate liver function as indicated by: - a total bilirubin≤ 2 x the institutional upper limit of normal (ULN) value, and - AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL/SLL 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 until 12 months after last dosage of obinutuzumab), negative testing for hepatitis-C (HCV-RNA PCR) and negative HIV test within 6 weeks prior to registration
- Age ≥ 18 years
- Eastern Cooperative Oncology Group Performance Status (ECOG) performance status
- Life expectancy ≥ 6 months
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
Exclusion Criteria
- Any prior CLL- or SLL-specific therapies, except for 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 per day are permitted).
- Decompensated auto-immune cytopenia (defined as ongoing drop in hemoglobin (AIHA) or in platelets (ITP) in spite of prednisolone and/or intravenous immunoglobulins treatment).
- (Suspicion of) transformation of CLL/SLL (i.e. Richter`s transformation) or central nervous system (CNS) involvement.
- (Suspicion of) progressive multifocal leukoencephalopathy (PML).
- Malignant neoplasm other than CLL/SLL unless in remission and unlikely to adversely impact on patient´s life expectancy, defined as curatively treated non-melanoma skin cancer or other neoplasias treated curatively ≥1 year ago, without signs of progression and not currently requiring systemic therapies (with the exception of ongoing anti-hormonal therapy).
- Active infection requiring systemic treatment, including HIV, HBV and HCV
- Increased risk of bleeding, e.g. due to: - known bleeding disorder - anticoagulant therapy with phenprocoumon or other vitamin K antagonists (anticoagulation with a direct oral Xa or thrombin inhibitor (DOAC) or heparin) is permitted) - major surgery ≤4 weeks prior to randomization - stroke or intracranial hemorrhage ≤ 6 months of randomization
- Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4 or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion - could compromise the patient`s safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tab-lets or impaired resorption in the gastrointestinal tract)
- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
- Fertile men or women of childbearing potential unless: - surgically sterile or ≥ 2 years after the onset of menopause, or - willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for the required time period thereafter (at least one and up to 18 months after end of study treatment depending of study drug(s) used, see chapter 2.2.2.1 Known risks relevant with all study drugs).
- Vaccination with a live vaccine ≤ 28 days prior to registration
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration
- 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 | Recruiting | 01 Jun 2025 | 17 |
 Belgium | Recruiting | 01 Jun 2025 | 34 |
 Czechia | Recruiting | 01 Jun 2025 | 67 |
 Denmark | Recruiting | 01 Jun 2025 | 60 |
 Finland | Recruiting | 01 Jun 2025 | 11 |
 France | Recruiting | 01 Jun 2025 | 94 |
 Germany | Recruiting | 01 Jun 2025 | 109 |
 Ireland | Recruiting | 01 Jun 2025 | 38 |
 Italy | Recruiting | 01 Jun 2025 | 42 |
 The Netherlands | Recruiting | 01 Jun 2025 | — |
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 | 924 | PRD2186234 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 400 | 924 | PRD2186236 |
Venetoclax | Test | FILM-COATED TABLET | ORAL USE | 400 | 924 | PRD2186235 |
PIRTOBRUTINIB | Test | — | ORAL USE | 200 | 1008 | SUB215610 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 6 | PRD1753415 |