Phase 3 Randomized Study of Obinutuzumab, Acalabrutinib, and Chlorambucil in Untreated Chronic Lymphocytic Leukemia
- Trial ID
- 2023-509348-84-00
- Protocol
- ACE-CL-007
- Sponsor
- Acerta Pharma B.V.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of **obinutuzumab** in combination with **chlorambucil** (Arm A) compared with **acalabrutinib** in combination with obinutuzumab (Arm B), based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per IWCLL 2008 criteria, in subjects with previously untreated **Chronic Lymphocytic Leukemia** (CLL). This evaluation is clinically relevant as it aims to determine the most effective treatment regimen for improving PFS in CLL patients, which is a critical endpoint in the management of this disease.
Secondary objectives include: - Evaluating the efficacy of Arm A versus acalabrutinib monotherapy based on IRC assessment of PFS per IWCLL 2008 criteria. - Comparing Arm A versus Arm B and Arm A versus Arm C in terms of IRC-assessed objective response rate (ORR) per IWCLL 2008 criteria. - Assessing time to next treatment (TTNT), defined as the time from randomization to the institution of non-protocol specified treatment for CLL. - Evaluating overall survival (OS).
Participants
The clinical trial involves a total of **323 participants** diagnosed with **Chronic Lymphocytic Leukemia** (CLL). The study population includes both men and women, with an age range of **18 years and older**, specifically targeting those **≥ 65 years** or younger individuals who meet specific health criteria. Participants were selected based on their diagnosis of CD20+ CLL and the presence of active disease requiring treatment as per IWCLL 2008 criteria. The trial includes individuals with an **ECOG performance status** of 0, 1, or 2, ensuring they are capable of receiving outpatient treatment and undergoing necessary evaluations. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to the study visit schedule and comply with protocol requirements. The trial population is inclusive of a vulnerable group, emphasizing the need for careful monitoring and adherence to ethical standards. Key inclusion criteria focus on specific laboratory parameters and the ability to provide informed consent, while exclusion criteria are not detailed in the provided data.
Plans and Procedures
The clinical trial is a **randomized**, multicenter, open-label, three-arm Phase 3 study designed to evaluate the efficacy of different treatment regimens in subjects with previously untreated **Chronic Lymphocytic Leukemia** (CLL). The trial involves three treatment arms: Arm A with obinutuzumab in combination with chlorambucil, Arm B with acalabrutinib in combination with obinutuzumab, and Arm C with acalabrutinib monotherapy. The primary objective is to compare the progression-free survival (PFS) between Arm A and Arm B, as assessed by an independent review committee (IRC) using the IWCLL 2008 criteria. Secondary endpoints include overall survival (OS) and safety assessments, such as the frequency and severity of adverse events.
The trial is expected to last until September 2025, with participant recruitment having commenced in June 2015. Participants will be involved in the study for a maximum treatment period of 120 to 168 weeks, depending on the treatment arm. The study includes several key visits: an initial screening visit to confirm eligibility based on specific inclusion criteria, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent.
Inclusion criteria require participants to be adults with a confirmed diagnosis of CD20+ CLL, meeting specific laboratory and clinical parameters. Exclusion criteria are not explicitly detailed in the provided data. The study is not classified as low intervention and adheres to the regulatory framework of a Phase 3 clinical trial. The investigational products include acalabrutinib, chlorambucil, and obinutuzumab, administered either orally or intravenously, depending on the treatment arm. The trial is conducted under the sponsorship of AstraZeneca AB and Roche Registration GmbH, with the investigational products repackaged and relabeled for clinical trial use.
Treatment
The clinical trial involves the administration of **acalabrutinib**, marketed as Calquence, in two pharmaceutical forms: film-coated tablets and hard capsules. Both forms contain 100 mg of acalabrutinib, a second-generation, selective, irreversible small molecule inhibitor of Bruton's tyrosine kinase (BtK). The film-coated tablets and hard capsules are administered orally, with a maximum daily dose of 100 mg and a total dose of 200 mg per day. The treatment period for acalabrutinib is up to 120 days. The clinical supply of acalabrutinib differs from the marketed product in packaging, being provided in HDPE bottles rather than blisters, and may include printed or unprinted capsules.
**Chlorambucil**, marketed as Chlorambucil 2 mg tablets, is used as a comparator treatment in the study. It is a chemical substance administered orally in the form of film-coated tablets. The maximum daily dose is 0.5 mg/kg, with a total dose of 0.5 mg per day. The treatment period for chlorambucil extends up to 168 days. For the purposes of the clinical trial, chlorambucil is repackaged and relabeled.
**Obinutuzumab**, marketed as Gazyvaro, is provided as a 1,000 mg concentrate for solution for infusion. It is a protein of biological/biotechnological origin, administered intravenously. The maximum daily and total dose is 1,000 mg, with a treatment period of up to 168 days. Obinutuzumab is repackaged and relabeled for clinical trial purposes and holds an orphan drug designation.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of obinutuzumab in combination with chlorambucil, acalabrutinib in combination with obinutuzumab, and acalabrutinib monotherapy in subjects with previously untreated chronic lymphocytic leukemia.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of **Progression-Free Survival (PFS)**, as determined by an Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria. The primary analysis will involve a comparison of PFS between Arm A, which involves the combination of obinutuzumab and chlorambucil, and Arm B, which involves the combination of acalabrutinib and obinutuzumab. Secondary efficacy endpoints include a comparison of IRC-assessed PFS between Arm A and Arm C, which involves acalabrutinib monotherapy, as well as overall survival (OS) comparisons between Arm A versus Arm B and Arm A versus Arm C.
Inclusion and Exclusion Criteria
Inclusion Criteria
- "• Men and women ≥ 65 years of age, or > 18 and < 65 years of age provided that they meet at least one of the following criteria: o Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation. o A score higher than 6 on the Cumulative Illness Rating Scale-Geriatric (CIRS-G). • ECOG performance status of 0, 1, or 2. • Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008) • Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL). o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 x 10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded. o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. o Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: - Unintentional weight loss ≥ 10% within the previous 6 months before Screening. - Significant fatigue (ie, ECOG performance status 2; inability to work or perform usual activities). - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection. - Night sweats for > 1 month before Screening without evidence of infection. • Meet the following laboratory parameters: o Absolute neutrophil count ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment. o Platelet count ≥ 50,000 cells/μL (50 x 10^9/L), or ≥ 30,000 cells/μL (30 x 10^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN). o Total bilirubin ≤ 1.5 x ULN. o Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min. • Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations. • Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. • Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Are willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information."
- Men and women ≥ 65 years of age, or > 18 and < 65 years of age provided that they meet at least one of the following criteria: o Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation. o A score higher than 6 on the Cumulative Illness Rating Scale-Geriatric (CIRS-G). • ECOG performance status of 0, 1, or 2. • Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008) • Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: o Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/μL). o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of < 30 x 10^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded. o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. o Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: - Unintentional weight loss ≥ 10% within the previous 6 months before Screening. - Significant fatigue (ie, ECOG performance status 2; inability to work or perform usual activities). - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection. - Night sweats for > 1 month before Screening without evidence of infection. • Meet the following laboratory parameters: o Absolute neutrophil count ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment. o Platelet count ≥ 50,000 cells/μL (50 x 10^9/L), or ≥ 30,000 cells/μL (30 x 10^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN). o Total bilirubin ≤ 1.5 x ULN. o Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min. • Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations. • Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. • Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Are willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.
Exclusion Criteria
- "• Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed). • Known central nervous system (CNS) lymphoma or leukemia. • Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome. • Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization. • Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (> 20mg daily of prednisone daily or equivalent). • Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count (WBC) lowering are excluded"
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Jun 2015 | 13 |
 France | Not Recruiting | 01 Jun 2015 | 7 |
 Germany | Not Recruiting | 01 Jun 2015 | 7 |
 Hungary | Not Recruiting | 01 Jun 2015 | 58 |
 Italy | Not Recruiting | 01 Jun 2015 | 31 |
 Lithuania | Not Recruiting | 01 Jun 2015 | 17 |
 Poland | Not Recruiting | 01 Jun 2015 | 59 |
 Spain | Not Recruiting | 01 Jun 2015 | 13 |
 Sweden | Not Recruiting | 01 Jun 2015 | 7 |
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 |
|---|---|---|---|---|---|---|
Calquence 100 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 100 | 120 | PRD8485701 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1000 | 168 | PRD1753415 |
Chlorambucil 2 mg tablets | Comparator | TABLETS | ORAL USE | 0.5 | 168 | PRD980411 |
Calquence 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 100 | 120 | PRD10242587 |