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Chronic Lymphoid LeukemiaPhase 2CLL2-BZAGNCT04515238

Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101), Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL

A Phase 2 study testing Bendamustine, Obinutuzumab and Zanubrutinib in people with Chronic Lymphoid Leukemia, run by German CLL Study Group at 11 sites in Germany.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

CLL2-BZAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by obinutuzumab (GA101), zanubrutinib (BGB-3111) and venetoclax (ABT-199) in patients with relapsed/refractory CLL. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphoid Leukemia
What is being tested?
Bendamustine, Obinutuzumab and Zanubrutinib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
42 participants
Where
11 sitesGermany
Study dates
1 Oct 2020to Feb 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 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Relapsed/refractory CLL in need of treatment according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
  • In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BZAG trial:
  • chemotherapy ≥ 28 days
  • antibody treatment ≥ 14 days
  • kinase inhibitors, BCL2-antagonists or immunomodulatory agents ≥ 3 days
  • corticosteroids may be applied until the start of the BZAG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment Please note: Patients with a progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due to intolerance to ibrutinib are eligible for participation.
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  • Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
  • Adequate hematologic function as indicated by a neutrophil count ≥ 1.0 x 109/L, a hemoglobin value ≥8.0 g/dL and a platelet count ≥ 25 x 109/L, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration), in this case, platelet count should be ≥ 10 × 109/L.
  • Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional 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, patients positive for anti-HBc may be included if PCR for Hepatitis B Virus (HBV) DNA is negative and HBV-DNA PCR is performed every 4 weeks until one year after last dosage of GA101 (obinutuzumab) or until the last dose of zanubrutinib, whichever occurs later), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
  • Age ≥ 18 years
  • Eastern Cooperative Oncology Group Performance Status (ECOG) 0 - 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
  • Life expectancy ≥ 6 months
  • Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Who cannot join

  • (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
  • Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
  • Confirmed progressive multifocal leukoencephalopathy (PML)
  • Malignancies other than CLL currently requiring systemic therapies
  • Uncontrolled infection requiring systemic treatment
  • Any comorbidity or organ system impairment rated with a Cumulative Illness Rating Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that - in the investigator´s opinion - could compromise the patients safety or interfere with the absorption or metabolism of the study drugs (e.g, inability to swallow tablets or impaired resorption in the gastrointestinal tract)
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  • Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hemorrhage ≤ 6 months.
  • Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
  • Use of investigational agents ≤ 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in accordance with inclusion criterion number 1 (see above).
  • Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), zanubrutinib (BGB-3111) or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
  • 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 18 months after end of study treatment.
  • Vaccination with a live vaccine ≤ 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 locations and contacts

11 sites in 1 country.

11 sites in 1 country

Germany11 sites

  • Hamatologische/Onkologische Gemeinschaftspraxis

    Augsburg, 86150

  • Universitätsklinik Köln

    Cologne, 50937

  • Onkologische Schwerpunktpraxis

    Esslingen am Neckar, 73728

  • Evangelische Krankenhaus Hamm

    Hamm, 59063

  • Universitaetskliniken des Saarlandes

    Homburg, 66424

  • Universitaetsklinikum Schleswig-Holstein Campus Kiel

    Kiel, 24105

  • KH Kliniken Maria Hilf

    Mönchengladbach, 41063

  • Klinikum Rechts der Isar - Technische Universitaet Muenchen

    Munich, 81675

  • Stauferklinikum Schwaebisch-Gmuend

    Mutlangen, 73557

  • Universitätsklinik Ulm

    Ulm, 89081

  • Hämatologisch Onkologische Schwerpunktpraxis

    Würzburg, 97080

Other trials in Germany

About this study

Official title: A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101), Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL (CLL2-BZAG Protocol)

CLL2-BZAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by obinutuzumab (GA101), zanubrutinib (BGB-3111) and venetoclax (ABT-199) in patients with relapsed/refractory CLL.

Read the detailed description

In the CLL2-BZAG trial will be included a total of 40 patients with relapsed or refractory CLL in need of treatment. This trial will evaluate a debulking with two cycles bendamustine (only for patients with a high tumor load), followed by an induction and maintenance treatment with obinutuzumab, zanubrutinib and venetoclax in patients with relapsed/refractory CLL. Thus, this trial combines one established (chemotherapy) and three novel, synergistic (antibody, Bruton's tyrosine kinase(BTK)-inhibitor and Bcl-2 antagonist) principles of action in order to achieve deep and long lasting remissions with a short duration of treatment. Additionally, this trial has an extensive accompanying scientific program aiming at a better understanding of the kinetics of response and clonal evolution of CLL.

Being tested
Bendamustine, Obinutuzumab, Zanubrutinib, Venetoclax
Keywords
CLL
Medical subject headings
Leukemia, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BendamustineDrug

    Also called Treanda, Bendeka

    Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.

  • ObinutuzumabBiological

    Also called GA101, Gazyvaro

    Induction: Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg i.v.; Cycle 2 - 6: 1000 mg, d1 i.v.

    Maintenance: Cycle 1 - 8: 1000 mg, d1 i.v.

  • ZanubrutinibBiological

    Also called BGB-3111

    Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 160mg p.o.

    Maintenance: Cycle 1 - 8: d1-84: 2 x 160mg p.o

  • VenetoclaxBiological

    Also called ABT-199, Venclyxto

    Induction: Cycles 1 + 2: --; Cycle 3: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg p.o.; Cycle 4 - 6: d1-28: 400 mg p.o.

    Maintenance: Cycle 1 - 8: d1-84: 400 mg p.o.

Study groups in NCT04515238
Study groupRoleWhat they receive
BZAGExperimentalDebulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated Induction: 6 cycles (q 28d) of Obinutuzumab + Zanubrutinib + Venetoclax Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Zanubrutinib + Venetoclax Maintenance treatment will be continued until (whichever occurs first): * 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity * maintenance cycle 8 * progression of CLL or start of a subsequent therapy unacceptable toxicity
Receives: Drug: Bendamustine; Biological: Obinutuzumab; Biological: Zanubrutinib; Biological: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by multi-color flow cytometry

    MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%]. The MRD negativity rate is defined as the proportion of patients having achieved MRD negativity based on the full analysis set (FAS).

    Measured: At final restaging (RE): 12 weeks after the start of the last induction cycle

Secondary outcomes (4)

  1. Overall response rate (ORR)

    Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR) as best response.

    Measured: At final restaging (RE): 12 weeks after the start of the last induction cycle

  2. CR / CRi rate

    Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the FAS)

    Measured: At final restaging (RE): 12 weeks after the start of the last induction cycle

  3. MRD in PB measured by 4-color flow cytometry at different times to guide the duration of maintenance therapy and for the assessment of the kinetics of response to the different treatment phases

    MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. MRD values will be categorized into negative (<10-4) and positive (≥10-4)

    Measured: From date of screening until the end of follow-up, up to 55 month

  4. Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular/special interest (AEPI/AESI)

    Type, frequency, severity and relationship to study treatment.of AEs, SAEs and AEPIs/AESIs

    Measured: Up to 55 months after first dose of study drug

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2020
  2. Study start1 Oct 2020
  3. Primary completionFeb 2027 (estimated)
  4. Study completionFeb 2027 (estimated)

Resources

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
42 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04515238
Sponsor's protocol ID
CLL2-BZAG
Other IDs
2022-502201-16-00, 2018-003270-27, 2018
Acronym
CLL2-BZAG
Status last verified
Aug 2026
First submitted
13 Aug 2020
Last updated
20 Aug 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Furstenau M, Robrecht S, Schneider C, Tausch E, Giza A, Ritgen M, Bittenbring J, Hebart H, Schottker B, Illert AL, Graeven U, Stoltefuss A, Heinrich B, Eckert R, Fink A, Stumpf J, Fischer K, Al-Sawaf O, Simon F, Kleinert F, Weiss J, Kreuzer KA, Schilhabel A, Bruggemann M, Langerbeins P, Stilgenbauer S, Eichhorst B, Hallek M, Cramer P. MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial. Blood. 2025 Mar 20;145(12):1282-1292. doi: 10.1182/blood.2024026685.

    PubMed 39883943

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Bendamustine, Obinutuzumab and Zanubrutinib in people with Chronic Lymphoid Leukemia, run by German CLL Study Group at 11 sites in Germany.

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 14 inclusion and 18 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 20 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Germany. 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?

Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by multi-color flow cytometry (time frame: At final restaging (RE): 12 weeks after the start of the last induction cycle). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04515238, which also lists 1 linked publication.

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 20 Aug 2026.

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