Evaluation of Venetoclax and Obinutuzumab, with or without Zanubrutinib, in High-Risk Chronic Lymphocytic Leukemia in Young Patients
- Trial ID
- 2023-510431-11-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of front-line therapy with **venetoclax** and **obinutuzumab** (VenObi) in young patients with high-risk **Chronic Lymphocytic Leukemia** (CLL) characterized by an adverse biologic profile. This will be assessed by determining the rate of patients achieving undetectable minimal residual disease (uMRD) using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and bone marrow (BM) at the end of combination therapy (EOCT month 9). Additionally, the study aims to assess the benefit of adding **zanubrutinib** to venetoclax (VenZan) in patients with residual disease at the EOCT with VenObi (month 21), again focusing on the rate of patients achieving uMRD by ASO-PCR in PB and BM. These objectives are clinically relevant as achieving uMRD is associated with improved long-term outcomes in CLL.
Secondary objectives include: - Evaluating the benefit of front-line therapy with VenObi in terms of the rate of patients with uMRD by flow-cytometry at EOCT month 9. - Assessing the benefit of treatment with VenObi+Ven and VenObi+VenZan in terms of the rate of patients with uMRD, low-level MRD (L-MRD), and high-level MRD (H-MRD) by ASO-PCR and flow-cytometry. - Determining the rate of patients with uMRD according to baseline clinical and biologic characteristics of CLL. - Evaluating progression-free survival (PFS) and overall survival (OS). - Analyzing survival outcomes (OS and PFS) according to MRD levels, response, treatment after VenObi, and clinical and biologic characteristics of CLL. - Assessing the hematological improvement benefits of treatment with VenObi+Ven or VenObi+VenZan. - Evaluating the toxicity profile of the treatment.
Participants
The clinical trial involves participants diagnosed with **Chronic Lymphocytic Leukemia** (CLL), specifically targeting a younger demographic with an adverse biologic profile. The study population includes both male and female subjects aged over 18 years and up to 65 years. Participants are required to have a diagnosis of CLL meeting the iwCLL 2018 criteria, with no prior treatment history. The trial includes individuals with unmutated IGHV, TP53 mutation, or deletion 17p, as assessed by certified laboratories. Participants must have a total Cumulative Illness Rating Scale (CIRS) score of less than 6, a creatinine clearance greater than 30 ml/min, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Adequate hematologic, renal, and hepatic function is necessary, with specific laboratory parameters outlined for inclusion. The trial population was selected based on these criteria, ensuring the ability and willingness to comply with the study protocol. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy in patients with **Chronic Lymphocytic Leukemia** (CLL) who have an adverse biological profile. This is a phase II, multicenter study with a randomized, double-blind, controlled design. The trial aims to assess the benefit of front-line therapy with **venetoclax** and **obinutuzumab** (VenObi) and the addition of **zanubrutinib** to venetoclax (VenZan) in terms of achieving undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM). The estimated duration of the trial is from July 2023 to November 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and laboratory parameters. The trial includes multiple follow-up visits to monitor treatment response and safety, with key assessments at months 9, 15, 21, 27, 33, and 36. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. The expected length of participant involvement is approximately 36 months, with conditions for early termination including significant adverse events or disease progression.
Participants will be randomly assigned to receive either the VenObi or VenZan treatment regimen. The primary endpoints focus on the rate of uMRD by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) at the end of combination therapy and after the addition of zanubrutinib. Secondary endpoints include the rate of uMRD by flow cytometry, progression-free survival, overall survival, and the toxicity profile of the treatments. The trial will adhere to rigorous ethical standards, with informed consent obtained from all participants prior to enrollment.
Treatment
**Venetoclax** is administered in the form of a film-coated tablet. The maximum daily dose is 400 mg, with a total dose not exceeding 217.7 g over a treatment period of 21 days. The route of administration is oral. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.
**Zanubrutinib**, marketed as Brukinsa 80 mg hard capsules, is administered orally. The maximum daily dose is 320 mg, with a total dose of 241.92 g over a 27-day treatment period. The pharmaceutical form is a hard capsule, and participant compliance is monitored throughout the study.
**Chlorphenamine Maleate** is provided as an injection for intravenous administration. The maximum daily dose is 10 mg/ml, with a total dose of 90 mg/ml over a 9-day period. This treatment is used as an auxiliary medication in the study.
**Lamivudine**, under the brand name Lamivudina Mylan 150 mg, is administered as a film-coated tablet. The maximum daily dose is 300 mg, with a total dose of 50.4 g over a 6-day treatment period. The route of administration is oral, and it serves as an auxiliary treatment in the trial.
**Obinutuzumab**, marketed as Gazyvaro 1,000 mg concentrate for solution for infusion, is administered via infusion. The maximum daily dose is 1000 mg, with a total dose of 9000 mg over a 9-day period. This protein-based treatment is used as an auxiliary medication in the study.
**Dexamethasone Phosphate** is provided as a solution for injection/infusion, administered intravenously. The maximum daily dose is 20 mg/ml, with a total dose of 180 mg/ml over a 9-day period. This chemical-based treatment is used as an auxiliary medication in the trial.
**Sulfamethoxazole and Trimethoprim**, marketed as Bactrim 160 mg + 800 mg, is administered as a tablet. The maximum daily dose is 960 mg, with a total dose of 484 g over a 504-day treatment period. The route of administration is oral, and it serves as an auxiliary treatment in the study.
**Allopurinol** is administered in tablet form, with a maximum daily dose of 300 mg and a total dose of 177.3 g over a 591-day period. The route of administration is oral, and it is used as an auxiliary treatment in the trial.
**Paracetamol** is provided in tablet form, with a maximum daily dose of 1 g and a total dose of 9 g over a 9-day period. The route of administration is oral, and it serves as an auxiliary treatment in the study.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints focus on evaluating the benefit of front-line therapy with **Venetoclax** and **Obinutuzumab** (VenObi) in terms of the rate of patients achieving undetectable minimal residual disease (uMRD) by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and bone marrow (BM) at the end of combination therapy (EOCT) at month 9. Additionally, the trial will assess the benefit of adding **Zanubrutinib** to **Venetoclax** (VenZan) for patients with residual disease at the EOCT with VenObi at month 21.
Secondary endpoints include evaluating the rate of patients with uMRD by flow-cytometry in PB and BM at EOCT month 9, and the rate of patients with uMRD, low-level MRD (L-MRD), and high-level MRD (H-MRD) at months 15, 21, 27, 33, and 36 using both ASO-PCR and flow-cytometry. The trial will also assess progression-free survival (PFS) and overall survival (OS) at 36 months, survival outcomes based on MRD levels, response, treatment type, and clinical and biological characteristics of chronic lymphocytic leukemia (CLL). Additional assessments include the impact of treatment on hemoglobin levels, granulocyte and platelet counts, immunoglobulin levels, and the toxicity profile in terms of adverse events (AE) and serious adverse events (SAE).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients older than18 years and 65 years or less.
- Diagnosis of CLL meeting the iwCLL 2018 criteria.
- Total CIRS <6, creatinine clearance >30 ml/min [Cockcroft-Gault]) and ECOG performance status of 0-1.
- No prior treatment.
- Patients with unmutated IGHV, and, or TP53 mutation assessed by an ERIC certified laboratory, and, or deletion 17p assessed by FISH analysis (Appendix N).
- Active disease meeting at least 1 of the iwCLL 2018 criteria for treatment requirement.
- Adequate hematologic parameters unless due to disease under study: • Absolute neutrophil count (ANC) =1.0 x 109/L unless neutropenia is clearly due to disease under study (per investigator discretion) • Platelet count = 75,000/mm3 - OR - Platelet count = 20,000/mm3 if thrombocytopenia is clearly due to disease under study (per investigator discretion) • Hemoglobin =9.0 g/dL unless anemia is clearly due to marrow involvement of CLL (per investigator discretion)
- Adequate renal and hepatic function, per laboratory reference range at Screening as follows: • AST/SGOT, ALT/SGPT =2.0 x ULN • Total bilirubin =1.5 x ULN unless considered secondary to Gilbert’s syndrome, in which case =3 x ULN
- QT-interval corrected according to Fridericia’s formula (QTcF) =450 milliseconds (ms).
- For females of childbearing potential, a negative serum pregnancy test within 7 days of study treatment.
- For female patients of childbearing potential, agreement to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) or remain abstinent (refrain from heterosexual intercourse) during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib AND 30 days after the last dose of venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later). For men with a female partner of childbearing potential or a pregnant female partner: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom during the treatment period and to continue its use for 90 days after the last dose of zanubrutinib, or venetoclax AND for 18 months after the last dose of obinutuzumab (whichever date is later).
- A signed informed consent document indicating that they understand the purpose of and the procedures required for the study, including biomarkers, and are willing to participate in the study.
- Ability and willingness to comply with the requirements of the study protocol.
Exclusion Criteria
- Any significant concurrent, uncontrolled medical condition or organ system dysfunction and laboratory abnormality or psychiatric disease, which, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk or prevent the subject from signing the informed consent form.
- Known active histological transformation from CLL to an aggressive lymphoma (i.e., Richter’s transformation or pro-lymphocytic leukemia).
- Known central nervous system involvement.
- Active malignancy or systemic therapy for another malignancy within 3 years Except: • Malignancies surgically treated with curative intent and with no known active disease present for = 3 years before randomization • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease • Adequately treated cervical carcinoma in situ without evidence of disease • Surgically/adequately treated low grade, early stage localized prostate cancer without evidence of disease
- Co-morbidities: • Uncontrolled autoimmune hemolytic anemia or thrombocytopenia • Any uncontrolled illness that, in the opinion of the investigator, would preclude administration of study therapy. • History of stroke or intracranial hemorrhage within 180 days before first dose of study drug. • History of severe bleeding disorder or history of spontaneous bleeding requiring blood transfusion or other medical intervention due to thrombocytopenia or inherited or acquired bleeding disorders due to deficiency or functional abnormality of any coagulation proteins. • History of significant cardiovascular disease, defined as: a. Congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification. b. Unstable angina or myocardial infarction with 6 months of enrollment. c. Serious cardiac arrhythmia or clinically significant ECG abnormality: corrected QT wave (QTcF) > 480 msec based on the Fridericia's formula or other ECG abnormalities including second-degree atrioventricular block type II, third-degree atrioventricular block. Participants who have a pacemaker will be allowed on study despite ECG abnormalities or the inability to calculate the QTc. • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1, Day 1. • History of tuberculosis within the last five years or recent exposure to tuberculosis equal to or less than 6 months. • History of progressive multifocal leukoencephalopathy (PML). • History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection: I. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to take appropriate anti-viral prophylaxis as indicated and undergo monthly DNA testing. II. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. • Inadequate renal function: CrCl < 30 mL/min. • Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis. • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products. • Known intolerance or hypersensitivity to any of the components of the therapeutic regimen. • Receipt of live-virus vaccines within 28 days prior to the initiation of study treatment or need for live-virus vaccines at any time during study treatment. • Prior major surgical procedure within 4 weeks of study, or anticipation of need for a major surgical procedure during the course of the study. • Known condition or other clinical situation that would affect oral absorption. • Psychiatric illness/social situations that would interfere with study compliance. • Inability to swallow a large number of tablets.
- Concomitant medications and drug interactions: • Patients who are on treatment with the following agents within 7 days prior to treatment: Strong CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin Strong CYP3A inducers such as rifampin, carbamazepine and strong inhibitors or inducers of CYP2C8, CYP2C9 and CYP2C19. The same applied for moderate inhibitors or inducers of CYP3A Requires warfarin, marcumar, or phenprocoumon (due to potential drug-drug interactions that may potentially increase the exposure of warfarin or phenprocoumon) • Prior anti-CD20 monoclonal antibody therapy for non-malignant indication
- Females who are currently pregnant or breastfeeding.
- Participation in a separate investigational therapeutic study unless authorized by PI
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 21 Jul 2023 | 78 |
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 |
|---|---|---|---|---|---|---|
PARACETAMOL | Other | — | ORAL | 1 | 9 | SUB09611MIG |
CHLORPHENAMINE MALEATE | Other | — | INTRAVENOUS | 10 | 9 | SUB01243MIG |
VENETOCLAX | Test | — | ORAL | 50 | 7 | SUB176260 |
ALLOPURINOL | Other | — | ORAL | 300 | 591 | SUB05338MIG |
Bactrim 160 mg + 800 mg compresse | Other | COMPRESSE | ORAL USE | 960 | 504 | PRD8429959 |
VENETOCLAX | Test | — | ORAL | 400 | 21 | SUB176260 |
BRUKINSA 80 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 320 | 27 | PRD9341336 |
Lamivudina Mylan 150 mg compresse rivestite con film | Other | COMPRESSE RIVESTITE CON FILM | ORAL | 300 | 6 | PRD2543453 |
DEXAMETHASONE PHOSPHATE | Other | — | INTRAVENOUS | 20 | 9 | SUB01612MIG |
VENETOCLAX | Test | — | ORAL | 20 | 7 | SUB176260 |