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

NCT04515238 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: CLL2-BZAG2022-502201-16-002018-003270-27
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 11

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.

Conditions

Chronic Lymphoid Leukemia

Keywords

CLL

Outcome Measures

Primary Outcomes (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).

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

Secondary Outcomes (4)

• Overall response rate (ORR)

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

• CR / CRi rate

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

• 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

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

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

  Up to 55 months after first dose of study drug

Study Arms (1)

BZAG

EXPERIMENTAL

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; Biological: Obinutuzumab; Biological: Zanubrutinib; Biological: Venetoclax

Interventions

Bendamustine DRUG

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

Also known as: Treanda, Bendeka

BZAG

Obinutuzumab BIOLOGICAL

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.

Also known as: GA101, Gazyvaro

BZAG

Zanubrutinib BIOLOGICAL

Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 160mg p.o. Maintenance: Cycle 1 - 8: d1-84: 2 x 160mg p.o

Also known as: BGB-3111

BZAG

Venetoclax BIOLOGICAL

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.

Also known as: ABT-199, Venclyxto

BZAG

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• (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)
• 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
• 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

Sponsors & Collaborators

• German CLL Study Group: lead

Study Sites (11)

Hamatologische/Onkologische Gemeinschaftspraxis

Augsburg, 86150, Germany

Location

Universitätsklinik Köln

Cologne, 50937, Germany

Location

Onkologische Schwerpunktpraxis

Esslingen am Neckar, 73728, Germany

Location

Evangelische Krankenhaus Hamm

Hamm, 59063, Germany

Location

Universitaetskliniken des Saarlandes

Homburg, 66424, Germany

Location

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, 24105, Germany

Location

KH Kliniken Maria Hilf

Mönchengladbach, 41063, Germany

Location

Klinikum Rechts der Isar - Technische Universitaet Muenchen

Munich, 81675, Germany

Location

Stauferklinikum Schwaebisch-Gmuend

Mutlangen, 73557, Germany

Location

Universitätsklinik Ulm

Ulm, 89081, Germany

Location

Hämatologisch Onkologische Schwerpunktpraxis

Würzburg, 97080, Germany

Location

Related Publications (1)

• 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.

  PMID: 39883943 DERIVED

Related Links

• Click here for more information about this study: CLL2-BZAG (German CLL Study Group)
• 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. PMID: 39883943.

MeSH Terms

Conditions

Leukemia, B-Cell

Interventions

Bendamustine Hydrochloride; obinutuzumab; zanubrutinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Paula Cramer, Dr. med.

  German CLL Study Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 13, 2020
• First Posted: August 17, 2020
• Study Start: October 1, 2020
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: June 10, 2025

Record last verified: 2025-06

Locations

DE (11)