Sequential Regimen of Bendamustin-Debulking Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients with Relapsed/refractory CLL

NCT03787264 | Completed Phase 2 DMC

• 1 other identifier: CLL2-BAAG
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 17

Brief Summary

CLL2-BAAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of debulking with bendamustine followed by induction and maintenance with GA101 (obinutuzumab), acalabrutinib (ACP-196) and venetoclax (ABT-199) in patients with relapsed/refractory CLL.

Conditions

Chronic Lymphoid Leukemia

Outcome Measures

Primary Outcomes (1)

• Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry

  MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed \[0.01%\], i.e. \< 10-4. 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: At screening, after debulking, 4-weekly during induction, at initial response assessment (after 6 induction cycles), at RE, every 12 weeks during maintenance and follow up.

  From date of screening until the end of follow-up, up to 40 month.

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

  up to 40 months after first dose of study drug

Study Arms (1)

BAAG

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 + Acalabrutinib + Venetoclax Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + 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: Acalabrutinib; Biological: Venetoclax

Interventions

Bendamustine DRUG

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

BAAG

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

BAAG

Acalabrutinib BIOLOGICAL

Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 100mg p.o. Maintenance: Cycle 1 - 8: d1-84: 2 x 100mg p.o.

Also known as: ACP-196, Calquence

BAAG

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

BAAG

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 iwCLL (international workshop on CLL) 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-BAAG trial:
• chemotherapy ≥ 28 days
• antibody treatment ≥ 14 days
• kinase inhibitors, BCL2-antagonists or immuno-modulatory agents ≥ 3 days
• corticosteroids may be applied until the start of the BAAG-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 in-tolerance 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 nega-tive and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every 4 weeks until one year after last dosage of GA101 (obinutuzumab)), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
• Age ≥ 18 years
• ECOG (Eastern Cooperative Oncology Group) performance status 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 proto-col requirements

You may not qualify if:

• (Suspicion of) transformation of CLL (i.e. Richter's trans-formation, 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. Bru-ton´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 CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system1 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), acalabrutinib (ACP-196) 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 preg-nancy 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 (17)

Universitätsklinik Köln

Cologne, 50937, Germany

Location

Gemeinschaftspraxis Hämatologie Onkologie

Dresden, 1307, Germany

Location

Gemeinschaftspraxis Mohm/Prange-Krex

Dresden, 1307, Germany

Location

Universitatsklinik Carl Gustav Carus

Dresden, 1307, Germany

Location

Helios Klinikum Erfurt

Erfurt, 99089, Germany

Location

Universitaetsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

Universitaetsklinikum Jena

Jena, 7747, Germany

Location

Praxis fuer Haematologie und Onkologie

Koblenz, 56068, Germany

Location

Gemeinschaftspraxis Haemato/ Onkologie Lebach

Lebach, 66822, Germany

Location

Klinikum Leverkusen GmbH

Leverkusen, 51375, Germany

Location

Krankenhaus Muenchen-Schwabing

Munich, 80804, Germany

Location

Ludwig-Maximilians-Universitaet Muenchen

München, 81377, Germany

Location

Praxis Dr. Uhlig

Naunhof, 4683, Germany

Location

Universitätsklinik Rostock

Rostock, 18057, Germany

Location

ZAHO-Rheinland

Siegburg, 53721, Germany

Location

Universitaetsklinik Tuebingen

Tübingen, 72076, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Related Publications (3)

• Furstenau M, Weiss J, Giza A, Franzen F, Robrecht S, Fink AM, Fischer K, Schneider C, Tausch E, Stilgenbauer S, Ritgen M, Schilhabel A, Bruggemann M, Eichhorst B, Hallek M, Cramer P. Circulating Tumor DNA-Based MRD Assessment in Patients with CLL Treated with Obinutuzumab, Acalabrutinib, and Venetoclax. Clin Cancer Res. 2022 Oct 3;28(19):4203-4211. doi: 10.1158/1078-0432.CCR-22-0433.

  PMID: 35594173 BACKGROUND

• Cramer P, Furstenau M, Robrecht S, Giza A, Zhang C, Fink AM, Fischer K, Langerbeins P, Al-Sawaf O, Tausch E, Schneider C, Schetelig J, Dreger P, Bottcher S, Kreuzer KA, Schilhabel A, Ritgen M, Bruggemann M, Kneba M, Stilgenbauer S, Eichhorst B, Hallek M. Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Lancet Haematol. 2022 Oct;9(10):e745-e755. doi: 10.1016/S2352-3026(22)00211-3. Epub 2022 Aug 18.

  PMID: 35988545 BACKGROUND

• Furstenau M, Giza A, Weiss J, Kleinert F, Robrecht S, Franzen F, Stumpf J, Langerbeins P, Al-Sawaf O, Simon F, Fink AM, Schneider C, Tausch E, Schetelig J, Dreger P, Bottcher S, Fischer K, Kreuzer KA, Ritgen M, Schilhabel A, Bruggemann M, Stilgenbauer S, Eichhorst B, Hallek M, Cramer P. Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial. Blood. 2024 Jul 18;144(3):272-282. doi: 10.1182/blood.2023022730.

  PMID: 38620072 BACKGROUND

Related Links

• Click here for more information about this study: CLL2-BAAG (German CLL Study Group)

MeSH Terms

Conditions

Leukemia, B-Cell

Interventions

Bendamustine Hydrochloride; obinutuzumab; acalabrutinib; 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: December 20, 2018
• First Posted: December 26, 2018
• Study Start: January 14, 2019
• Primary Completion: February 11, 2021
• Study Completion: September 26, 2023
• Last Updated: December 30, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

DE (17)