High Risk CLLPhase 2VISNCT05478512
Front-line VenObi Combination Followed by Ven or VenZan Combination in Patients With Residual Disease: a MRD Tailored Treatment for Young Patients With High-risk CLL
A Phase 2 study testing VenObi+Ven or VenObi+VenZan in people with High Risk CLL and Chronic Lymphocytic Leukemia, run by Gruppo Italiano Malattie EMatologiche dell'Adulto at 8 sites in Italy.
Trial summary
Multicentric phase 2 study for previously untreated high-risk CLL patients. Patients will receive 6 courses of the Venetoclax + Obinutuzumab combination. Patients with stable disease or a response (CR/PR) with uMRD in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- High Risk CLL, Chronic Lymphocytic Leukemia
- What is being tested?
- VenObi+Ven or VenObi+VenZan
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 8 sitesItaly
- Study dates
- 21 Jul 2023to Jul 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients older than 18 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.
- Active disease meeting at least 1 of the iwCLL 2018 criteria for treatment requirement.
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- 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.
Who cannot join
- 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
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- 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
- 5. 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:
- Congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification.
- Unstable angina or myocardial infarction with 6 months of enrollment.
- 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 1. 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.
- 2. 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.
- 6. 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
- 7. Females who are currently pregnant or breastfeeding.
- 8. Participation in a separate investigational therapeutic study unless authorized by the investigator.
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
Italy8 sites
Ematologia AOU Careggi
Florence
Ematologia IRST D.Amadori
Meldola
Ematologia AO di Perugia
Perugia
Ematologia Ospedale S.M. delle Croci
Ravenna
Ematologia Ospedale Infermi
Rimini
Ematologia Policlinico Gemelli
Roma
Ematologia Policlinico Umberto I
Roma
Ematologia AOUS - Policlinico S. M. alle Scotte
Siena
About this study
Official title: Front-line Venetoclax and Obinutuzumab Combination Followed by Venetoclax or Venetoclax and Zanubrutinib Combination in Patients With Residual Disease: a Minimal Residual Disease (MRD) Tailored Treatment for Young Patients With High-risk CLL
Multicentric phase 2 study for previously untreated high-risk CLL patients. Patients will receive 6 courses of the Venetoclax + Obinutuzumab combination.
- Patients with stable disease or a response (CR/PR) with uMRD in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then stop treatment.
- Patients with stable disease or a response (CR/PR) with evidence of residual disease in the PB and/or BM at cycle 9 will continue treatment with Venetoclax and Zanubrutinib combination until cycle 21. then, Patients with uMRD in the PB and BM at cycle 21 will stop treatment whereas patients with residual disease in the PB and/or BM at cycle 21 will discontinue Venetoclax and continue Zanubrutinib until disease progression.
Read the detailed description
This is a multicentric phase 2 study for previously untreated high-risk CLL patients.
- The study treatment will consist of 6 courses of the Venetoclax + Obinutuzumab combination.
- Patients with stable disease or a response (CR/PR) with undetectable MRD (uMRD) in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then stop treatment.
- Patients with stable disease or a response (CR/PR) with evidence of residual disease in the PB and/or BM at cycle 9 will continue treatment with Venetoclax and Zanubrutinib (VenZan) combination until cycle 21. c1. Patients with uMRD in the PB and BM at cycle 21 will stop treatment. c2. Patients with residual disease in the PB and/or BM at cycle 21 will discontinue Venetoclax and continue Zanubrutinib until disease progression.
In all patients with uMRD, MRD will be monitored during the follow-up. Patients with a response with uMRD in the PB and BM who subsequently develop an MRD positivity will not be treated. A new treatment will start at the time of clinical disease progression according to the iwCLL criteria.
- Conditions
- High Risk CLL, Chronic Lymphocytic Leukemia
- Being tested
- VenObi+Ven or VenObi+VenZan
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VenObi+Ven or VenObi+VenZanDrug
Patients will receive obinutuzumab 1000mg IV (cycle 1: day 1,8,15; Cycle2-6: day1) + venetoclax 400mg/d (preceded by a ramp-up phase) until cycle 9, day 28.
At cycle9:
- if uMRD = Venetoclax 400 mg/d orally until cycle 13.
- if residual disease in the BM or PB = Venetoclax 400 mg/d + Zanubrutinib 160 mg orally twice daily until cycle 21. then, at cycle 21:
- if uMRD = stop treatment
- if residual disease in the BM or PB = zanubrutinib 160 mg orally twice daily until disease progression
| Study group | Role | What they receive |
|---|---|---|
| VenObi+Ven or VenObi+VenZan | Experimental | Patients will receive VenObi combination followed by Venetoclax single agent or Venetoclax+zanubrutinib, according to MRD. Receives: Drug: VenObi+Ven or VenObi+VenZan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Front-line VenObi efficacy in terms of MRD negativity
Evaluation of front-line treatment (VenObi) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease at the end of combination therapy
Measured: at month 9
VenZan efficacy in terms of MRD negativity
Evaluation of treatment (VenZan) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease in patients with residual disease at the end of combination therapy with VenObi
Measured: at month 21
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jul 2022
- Study start21 Jul 2023
- Primary completionMay 2026 (estimated)
- Study completionJul 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for High Risk CLLStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 78 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Gruppo Italiano Malattie EMatologiche dell'Adulto
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05478512
- Sponsor's protocol ID
- CLL2222
- Acronym
- VIS
- Status last verified
- Mar 2026
- First submitted
- 26 Jul 2022
- Last updated
- 17 Mar 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Front-line Venetoclax and Obinutuzumab Combination Followed by Venetoclax or Venetoclax and Zanubrutinib Combination in Patients With Residual Disease: a Minimal Residual Disease (MRD) Tailored Treatment for Young Patients With High-risk CLL
- ClinicalTrials.gov ID
- NCT05478512
- Acronym / sponsor ID
- VIS / CLL2222
- Conditions
- High Risk CLL, Chronic Lymphocytic Leukemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 78 participants (estimated)
- Lead sponsor
- Gruppo Italiano Malattie EMatologiche dell'AdultoUniversity, hospital or other
- Study start
- 21 Jul 2023 (actual)
- Primary completion
- May 2026 (estimated)
- Study completion
- Jul 2027 (estimated)
- First posted
- 28 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multicentric phase 2 study for previously untreated high-risk CLL patients. Patients will receive 6 courses of the Venetoclax + Obinutuzumab combination.
- Patients with stable disease or a response (CR/PR) with uMRD in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then stop treatment.
- Patients with stable disease or a response (CR/PR) with evidence of residual disease in the PB and/or BM at cycle 9 will continue treatment with Venetoclax and Zanubrutinib combination until cycle 21. then, Patients with uMRD in the PB and BM at cycle 21 will stop treatment whereas patients with residual disease in the PB and/or BM at cycle 21 will discontinue Venetoclax and continue Zanubrutinib until disease progression.
Detailed description
This is a multicentric phase 2 study for previously untreated high-risk CLL patients.
- The study treatment will consist of 6 courses of the Venetoclax + Obinutuzumab combination.
- Patients with stable disease or a response (CR/PR) with undetectable MRD (uMRD) in the PB and BM at cycle 9 will continue treatment with Venetoclax single agent until cycle 13 and then stop treatment.
- Patients with stable disease or a response (CR/PR) with evidence of residual disease in the PB and/or BM at cycle 9 will continue treatment with Venetoclax and Zanubrutinib (VenZan) combination until cycle 21. c1. Patients with uMRD in the PB and BM at cycle 21 will stop treatment. c2. Patients with residual disease in the PB and/or BM at cycle 21 will discontinue Venetoclax and continue Zanubrutinib until disease progression.
In all patients with uMRD, MRD will be monitored during the follow-up. Patients with a response with uMRD in the PB and BM who subsequently develop an MRD positivity will not be treated. A new treatment will start at the time of clinical disease progression according to the iwCLL criteria.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| VenObi+Ven or VenObi+VenZan | Experimental | Drug: VenObi+Ven or VenObi+VenZanPatients will receive VenObi combination followed by Venetoclax single agent or Venetoclax+zanubrutinib, according to MRD. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Patients older than 18 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.
Key exclusion criteria (38 listed)
- 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
- Malignancies surgically treated with curative intent and with no known active disease present for ≥ 3 years before randomization
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VenObi+Ven or VenObi+VenZanPatients will receive obinutuzumab 1000mg IV (cycle 1: day 1,8,15; Cycle2-6: day1) + venetoclax 400mg/d (preceded by a ramp-up phase) until cycle 9, day 28. At cycle9: * if uMRD = Venetoclax 400 mg/d orally until cycle 13. * if residual disease in the BM or PB = Venetoclax 400 mg/d + Zanubrutinib 160 mg orally twice daily until cycle 21. then, at cycle 21: * if uMRD = stop treatment * if residual disease in the BM or PB = zanubrutinib 160 mg orally twice daily until disease progression | Drug | VenObi+Ven or VenObi+VenZan |
Primary outcome
Front-line VenObi efficacy in terms of MRD negativity
Time frame: at month 9
Evaluation of front-line treatment (VenObi) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease at the end of combination therapy
VenZan efficacy in terms of MRD negativity
Time frame: at month 21
Evaluation of treatment (VenZan) efficacy in terms of percentage of patients who achieve Undetectable Minimal Residual Disease in patients with residual disease at the end of combination therapy with VenObi
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Mar 2026.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing VenObi+Ven or VenObi+VenZan in people with High Risk CLL and Chronic Lymphocytic Leukemia, run by Gruppo Italiano Malattie EMatologiche dell'Adulto at 8 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 17 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Front-line VenObi efficacy in terms of MRD negativity (time frame: at month 9). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Mar 2026.