We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
ClinicalTrials.gov Menu

Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101), Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL (CLL2-BZAG)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04515238
Recruitment Status : Active, not recruiting
First Posted : August 17, 2020
Last Update Posted : November 9, 2022
Information provided by (Responsible Party):
German CLL Study Group

Brief 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.

Condition or disease Intervention/treatment Phase
Chronic Lymphoid Leukemia Drug: Bendamustine Biological: Obinutuzumab Biological: Zanubrutinib Biological: Venetoclax Phase 2

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 1, 2020
Estimated Primary Completion Date : April 2025
Estimated Study Completion Date : March 2027

Arm Intervention/treatment
Experimental: BZAG

Debulking: 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
Drug: Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.
Other Names:
  • Treanda
  • Bendeka

Biological: Obinutuzumab

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.

Other Names:
  • GA101
  • Gazyvaro

Biological: Zanubrutinib

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

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

Other Name: BGB-3111

Biological: Venetoclax

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.

Other Names:
  • ABT-199
  • Venclyxto

Primary Outcome Measures :
  1. 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 ]
    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).

Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: At final restaging (RE): 12 weeks after the start of the last induction cycle ]
    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.

  2. CR / CRi rate [ Time Frame: At final restaging (RE): 12 weeks after the start of the last induction cycle ]
    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)

  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 [ Time Frame: From date of screening until the end of follow-up, up to 55 month ]
    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)

  4. Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular/special interest (AEPI/AESI) [ Time Frame: Up to 55 months after first dose of study drug ]
    Type, frequency, severity and relationship to study treatment.of AEs, SAEs and AEPIs/AESIs

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 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.
  2. 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
  3. 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.
  4. 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
  5. 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
  6. Age ≥ 18 years
  7. 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)
  8. Life expectancy ≥ 6 months
  9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

  1. (Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
  2. 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)
  3. Confirmed progressive multifocal leukoencephalopathy (PML)
  4. Malignancies other than CLL currently requiring systemic therapies
  5. Uncontrolled infection requiring systemic treatment
  6. 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)
  7. 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.
  8. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
  9. 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).
  10. 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
  11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
  12. 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.
  13. Vaccination with a live vaccine ≤ 28 days prior to registration
  14. Legal incapacity
  15. Prisoners or subjects who are institutionalized by regulatory or court order
  16. Persons who are in dependence to the sponsor or an investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04515238

Layout table for location information
Hamatologische/Onkologische Gemeinschaftspraxis
Augsburg, Germany, 86150
Onkologische Schwerpunktpraxis
Esslingen, Germany, 73728
Evangelische Krankenhaus Hamm
Hamm, Germany, 59063
Universitaetskliniken des Saarlandes
Homburg, Germany, 66424
Universitaetsklinikum Schleswig-Holstein Campus Kiel
Kiel, Germany, 24105
Universitätsklinik Köln
Köln, Germany, 50937
Klinikum Rechts der Isar - Technische Universitaet Muenchen
Munich, Germany, 81675
Stauferklinikum Schwaebisch-Gmuend
Mutlangen, Germany, 73557
KH Kliniken Maria Hilf
Mönchengladbach, Germany, 41063
Universitätsklinik Ulm
Ulm, Germany, 89081
Hämatologisch Onkologische Schwerpunktpraxis
Würzburg, Germany, 97080
Sponsors and Collaborators
German CLL Study Group
Layout table for investigator information
Principal Investigator: Paula Cramer, Dr. med. German CLL Study Group
Additional Information:
Layout table for additonal information
Responsible Party: German CLL Study Group
ClinicalTrials.gov Identifier: NCT04515238    
Other Study ID Numbers: CLL2-BZAG
2018-003270-27 ( EudraCT Number )
First Posted: August 17, 2020    Key Record Dates
Last Update Posted: November 9, 2022
Last Verified: November 2022

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by German CLL Study Group:
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Bendamustine Hydrochloride
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Protein Kinase Inhibitors
Enzyme Inhibitors