Phase 3 Randomized Trial of Acalabrutinib, Obinutuzumab, and Venetoclax in High-Risk Chronic Lymphocytic Leukemia Patients
- Trial ID
- 2023-506414-46-00
- Protocol
- CLL16
- Sponsor
- University Of Cologne
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this multicenter, prospective, open-label, randomized, superiority phase 3 study is to demonstrate that treatment with a triple combination of **acalabrutinib**, obinutuzumab, and venetoclax (GAVe) prolongs the progression-free survival (PFS) compared to the combination of obinutuzumab and venetoclax (GVe) in patients with high-risk chronic lymphocytic leukemia (CLL). High-risk CLL is defined by the presence of at least one of the following risk factors: 17p-deletion, TP53-mutation, or complex karyotype. Prolonging PFS is clinically relevant as it may delay disease progression and improve patient outcomes in this high-risk population.
Secondary objectives include evaluating measurable residual disease (MRD) levels in the peripheral blood (PB) and bone marrow (BM) at final restaging, MRD in PB at cycle 27 day 1 for all patients, overall response rate (ORR) and complete response rate (CRR) at cycle 15, overall survival (OS), event-free survival (EFS), duration of response (DOR), and time to next treatment (TTNT). These secondary endpoints provide a comprehensive assessment of the treatment's efficacy and its impact on disease management and patient quality of life.
Participants
The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older, who are diagnosed with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The trial does not include a vulnerable population. Participants are required to have at least one high-risk factor, such as 17p-deletion, TP53-mutation, or a complex karyotype. The total number of participants is not provided by the sponsor. The selection criteria ensure that participants have a life expectancy of at least six months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Additionally, participants must demonstrate adequate bone marrow, renal, and liver function, and have negative serological testing for hepatitis B and C. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
This clinical trial is a **randomized**, open-label, multicenter, phase 3 study designed to evaluate the efficacy of a combination therapy in patients with high-risk **chronic lymphocytic leukemia** (CLL). The trial aims to compare the progression-free survival (PFS) of patients treated with a combination of acalabrutinib, obinutuzumab, and venetoclax (GAVe) against those treated with obinutuzumab and venetoclax (GVe). The study targets patients with high-risk CLL, characterized by the presence of at least one of the following risk factors: 17p-deletion, TP53-mutation, or complex karyotype. The trial is expected to conclude by June 2025, with recruitment having commenced in June 2022.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as documented CLL/SLL requiring treatment, negative serological testing for hepatitis B and C, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments of measurable residual disease (MRD) levels, overall response rate, and complete response rate, among other secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.
The expected duration of participant involvement varies depending on the treatment arm, with a maximum treatment period of 24 months for the GAVe arm and 12 months for the GVe arm. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of the study is the investigator-assessed PFS, with secondary endpoints including MRD levels, overall survival, event-free survival, and duration of response. The trial is designed to provide robust data on the efficacy and safety of the GAVe regimen compared to the GVe regimen in this high-risk patient population.
Treatment
The clinical trial involves the administration of **Acalabrutinib**, a **BTK Inhibitor**, which is provided in the form of a hard capsule. The active substance, acalabrutinib, is of chemical origin. Participants will receive a maximum daily dose of 200 mg, administered orally. The total maximum dose over the treatment period is 134,400 mg, with a treatment duration of up to 24 months. Compliance with the dosing schedule will be monitored throughout the trial.
**Venetoclax**, a **BCL2 Inhibitor**, is another experimental medication used in this study. It is available as a film-coated tablet, with the active substance also being of chemical origin. The maximum daily dose for venetoclax is 400 mg, administered orally. The total maximum dose is 114,590 mg, with a treatment period of up to 12 months. Participant adherence to the dosing regimen will be closely monitored.
**Obinutuzumab** is included as a non-experimental treatment in the trial. It is a monoclonal anti-CD20 antibody provided as a concentrate for solution for injection. The administration route is intravenous, with a maximum daily dose of 1000 mg and a total maximum dose of 8000 mg over a 6-month treatment period. The administration schedule and participant compliance will be documented and monitored throughout the study.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, as evaluated by investigators. This endpoint is designed to demonstrate the superiority of the treatment regimen consisting of acalabrutinib, obinutuzumab, and venetoclax (GAVe) over the combination of obinutuzumab and venetoclax (GVe) in patients with high-risk chronic lymphocytic leukemia (CLL), characterized by the presence of at least one risk factor such as 17p-deletion, TP53-mutation, or complex karyotype.
Secondary endpoints include the assessment of measurable residual disease (MRD) levels in both peripheral blood and bone marrow at specified timepoints, such as final restaging and at the end of maintenance for patients in the GAVe study arm. Additional secondary endpoints encompass overall response rate (ORR), complete response rate (CRR), overall survival (OS), event-free survival (EFS), duration of response (DOR), and time to next treatment (TTNT). These parameters will be measured using established guidelines, such as the iwCLL criteria, at various cycles throughout the trial.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Documented CLL/SLL3 requiring treatment according to iwCLL criteria as of 2018.
- Age at least 18 years.
- At least one of the following risk factors: 17p- deletion, TP53 mutation, complex karyo-type (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases), or an unmutated IGHV status.
- Life expectancy ≥ 6 months.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2.
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
- Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy).
- GFR >30 ml/min directly measured with 24hr urine collection, 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. 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 institu-tional 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; pa-tients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every cycle until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.
Exclusion Criteria
- Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention (after start of study treatment only continuous treatment with dose equivalents up to 20 mg prednisolone is permitted) and short-termed treatment with Rituximab because of auto-immune cytopenia .
- Transformation of CLL (Richter‘s transformation).
- Known central nervous system involvement.
- An individual organ/system impairment score of 4 as assessed by the CIRS definition lim-iting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be in-cluded in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e. pulmonary embolism) and consider the level of morbid-ity associated with a patient’s condition. Current life-threatening illness, medical condi-tion, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.
- Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis.
- Patients with a history of confirmed progressive multifocal leukoencephalopathy.
- 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 dis-cretion of the treating physician) or showing signs of progression after curative treatment.
- Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrollment.
- Patients with known infection with human immunodeficiency virus (HIV).
- Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
- Anticoagulant therapy with warfarin or phenoprocoumon, (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly in-formed about the potential risk of bleeding under treatment with acalabrutinib).
- This exclusion criterion applies only as long as acalabrutinib capsules are used for study medication (for tablets please refer to section 8.2.2): Requirement of treatment with a PPI (proton pump inhibitor). If treatment with an acid reducing agent is required, consider us-ing an antacid (e.g. calcium carbonate) or an H2-receptor antagonist (e.g. ranitidine or fa-motidine) instead.
- History of stroke or intracranial hemorrhage within 6 months prior to registration.
- Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
- Vaccination with live vaccines 28 days prior to registration.
- Major surgery less than 30 days before start of 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 treatment; further pregnancy testing will be performed regularly see chapter 2.3.1.5).
- Fertile men or women of childbearing potential unless: a. surgically sterile or ≥ 2 years after the onset of menopause. b. willing to use two methods of reliable contraception including one highly effective con-traceptive method (Pearl Index <1) and one additional effective (barrier) method dur-ing study treatment and for 18 months after the end of study treatment.
- Inability to swallow a large number of tablets.
- Legal incapacity.
- Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 13 Jun 2022 | 15 |
 Germany | Recruiting | 13 Jun 2022 | 187 |
 Portugal | Recruiting | 13 Jun 2022 | 30 |
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 |
|---|---|---|---|---|---|---|
OBINUTUZUMAB | Test | — | INTRAVENOUS | 1000 | 6 | SUB32751 |
VENETOCLAX | Test | — | ORAL | 400 | 12 | SUB176260 |
ACALABRUTINIB | Test | — | ORAL | 200 | 24 | SUB182073 |
ACALABRUTINIB | Test | — | ORAL | 200 | 24 | SUB182073 |
VENETOCLAX | Test | — | ORAL | 400 | 12 | SUB176260 |
VENETOCLAX | Test | — | ORAL | 400 | 12 | SUB176260 |