A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients With High Risk CLL

NCT ID: NCT05197192

Last Updated: 2025-08-17

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 202 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-19
• Study Completion Date: 2028-05-31

Brief Summary

This multicenter, prospective, open-label, randomized, superiority phase 3 study is designed to demonstrate that treatment with a triple combination of acalabrutinib, obinutuzumab and venetoclax (GAVe) prolong the progression-free survival (PFS) as compared to treatment with the combination of obinutuzumab and venetoclax (GVe) in pa-tients with high risk CLL (defined as having at least one of the follow-ing risk factors: 17p-deletion, TP53-mutation, complex karyotype or an unmutated IGHV-gene status).

Detailed Description

CLL is the most frequent leukemia in industrialized countries. International guidelines agree on diagnosis and management of this disease. The clinical course of CLL is highly variable and can be predicted by clinical staging (according to Rai and Binet) as well as genetic, serum markers and risk models. This study is designed for a randomized comparison of two different, non-chemotherapeutic and fixed-duration modalities for patients with high risk chronic lymphocytic leukemia (CLL) and addresses a high medical need, since high risk-CLL represents a so far incurable, aggressive cancer. The high risk-group of CLL patients can be identified by molecular characteristics, allowing the inclusion of a clearly described group of patients: 17p-deletion, TP53-mutation and/or complex karyotype.TP53 defects are the strongest prognostic factors for non-response to chemotherapy. Patients harboring TP53 defects should be treated with chemotherapy-free regimens. Complex karyotype (CKT), defined as the presence of three or more chromosomal aberrations in two or more metaphases is associated with a poorer outcome in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). In CLL, CKT is one of several well established adverse prognostic factors, comparable to 17p-deletion, TP53-mutation or unmutated IGHV status. Depending on age and prior exposure to chemotherapy, 10-30% of patients with CLL exhibit CKT. A broad body of evidence has suggested a predictive prognostic value of CKT. Despite considerable advances with chemoimmunotherapy in the treatment of frontline as well as relapsed/refractory (r/r) CLL, outcome of patients with CKT remains poor. To date, a randomized comparison to optimize the treatment of patients with high risk disease defined as either the presence of TP53 aberrations or CKT, by novel agents has not been performed. Patients with high risk CLL (TP53-defects and/or CKT) have a poor outcome with chemoimmunotherapy and do not benefit to the same extent from approved regimen such as continuous treatment of ibrutinib or 12 months treatment with obinutuzumab plus venetoclax. Monotherapy with BTK-inhibitor is less effective in those patients as compared with patients without high risk disease. Venetoclax combined with the anti-CD20 monoclonal antibody obinutuzumab offers a highly effective fixed-duration treatment option with a manageable toxicity profile. The recent results of the CLL14 study define a new standard of a fixed 12-months treatment with obinutuzumab and venetoclax in previously untreated patients yielding a major benefit also for patients with high risk disease as compared to chemoimmunotherapy. However, high risk patients appear to progress earlier than low risk patients and the therapy is not clearly curative so far. Acalabrutinib is a second generation, selective BTK inhibitor which has shown promising overall response rates in patients with relapsed CLL or patients intolerant to ibrutinib. The development of acalabrutinib focussed on minimization of off-target activity. Results of a three-arm study investigating the combination of acalabrutinib plus obinutuzumab versus acalabrutinib alone versus chlorambucil plus obinutuzumab (NCT02475681) showed a substantial improvement of PFS for the combination arm and the monotherapy versus the standard chemoimmunotherapy regimen. The addition of a BTK-inhibitor, such as acalabrutinib to obinutuzumab and venetoclax has the potential to result in a better outcome, because synergistic effects have been reported between BTK inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors or for BCL-2 inhibitors and monoclonal antibodies. Synergistic effects, which are expected to reduce early progressions or insufficient responses, are in particular important for this high risk population. The triple combination of acalabrutinib, obinutuzumab (or rituximab) and venetoclax has been investigated in a phase 1 b- study and had a tolerable safety profile with minimal to no drug-drug interactions, results of a phase 2 trial studying the same combination showed that the triple combination was highly active with 78% undetectable MRD levels in the bone marrow . Currently, the GCLLSG conducts phase 2 studies, investigating a triple combination consisting of BTK- and Bcl2-inhibitors and monoclonal antibodies (CLL2GIVe: NCT02758665; CLL2BAAG: NCT03787264) and a large phase 3 trial with one experimental arm with a triple combination (CLL13, NCT02950051) but results are not yet published. Acalabrutinib, venetoclax and obinutuzumab is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) against the current standard of chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR) in patients without 17p-deletion or TP53-mutation. Acalabrutinib is indicated in Germany as monotherapy or in combination with obinutuzumab for the treatment of adult patients with treatment-naive chronic lymphocytic leukemia (CLL) and as monotherapy for the treatment of adult patients with relapsed chronic lymphocytic leukemia (CLL).

Conditions

Chronic Lymphocytic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GAVe-Arm

Acalabrutinib plus Venetoclax plus Obinutuzumab plus (GAVe)

Group Type: EXPERIMENTAL

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab i.v. infusion:

Cycle 1 Day 1: Obinutuzumab 100 mg i.v.

Cycle 1 Day 1 (or 2): Obinutuzumab 900 mg i.v.

Cycle 1 Day 8: Obinutuzumab 1000 mg i.v.

Cycle 1 Day 15: Obinutuzumab 1000 mg i.v.

Cycles 2-6: Day 1: Obinutuzumab 1000 mg i.v.

Venetoclax

Intervention Type: DRUG

Venetoclax p.o.:

Cycle 1: Days 22-28: Venetoclax 20 mg (2 x 10 mg)

Cycle 2: Days 1-7: Venetoclax 50 mg (1 x 50 mg)

Cycle 2:Days 8-14: Venetoclax 100 mg (1 x 100 mg)

Cycle 2:Days: 15-21: Venetoclax 200 mg (2 x 100 mg)

Cycle 2:Days: 22-28: Venetoclax 400 mg (4 x 100 mg)

Cycles 3-12: Days 1-28: Venetoclax 400 mg (4 x 100 mg)

Acalabrutinib

Intervention Type: DRUG

Cycles 15-24: Days 1-28:

100 mg acalabrutinib twice daily p.o. approx. every 12 hrs (corresponding to a total daily dose of 200 mg).

GVe-Arm

Obinutuzumab plus Venetoclax (GVe)

Group Type: EXPERIMENTAL

Obinutuzumab

Intervention Type: DRUG

Obinutuzumab i.v. infusion:

Cycle 1 Day 1: Obinutuzumab 100 mg i.v.

Cycle 1 Day 1 (or 2): Obinutuzumab 900 mg i.v.

Cycle 1 Day 8: Obinutuzumab 1000 mg i.v.

Cycle 1 Day 15: Obinutuzumab 1000 mg i.v.

Cycles 2-6: Day 1: Obinutuzumab 1000 mg i.v.

Venetoclax

Intervention Type: DRUG

Venetoclax p.o.:

Cycle 1: Days 22-28: Venetoclax 20 mg (2 x 10 mg)

Cycle 2: Days 1-7: Venetoclax 50 mg (1 x 50 mg)

Cycle 2:Days 8-14: Venetoclax 100 mg (1 x 100 mg)

Cycle 2:Days: 15-21: Venetoclax 200 mg (2 x 100 mg)

Cycle 2:Days: 22-28: Venetoclax 400 mg (4 x 100 mg)

Cycles 3-12: Days 1-28: Venetoclax 400 mg (4 x 100 mg)

Interventions

Obinutuzumab

Obinutuzumab i.v. infusion:

Cycle 1 Day 1: Obinutuzumab 100 mg i.v.

Cycle 1 Day 1 (or 2): Obinutuzumab 900 mg i.v.

Cycle 1 Day 8: Obinutuzumab 1000 mg i.v.

Cycle 1 Day 15: Obinutuzumab 1000 mg i.v.

Cycles 2-6: Day 1: Obinutuzumab 1000 mg i.v.

Intervention Type: DRUG

Venetoclax

Venetoclax p.o.:

Cycle 1: Days 22-28: Venetoclax 20 mg (2 x 10 mg)

Cycle 2: Days 1-7: Venetoclax 50 mg (1 x 50 mg)

Cycle 2:Days 8-14: Venetoclax 100 mg (1 x 100 mg)

Cycle 2:Days: 15-21: Venetoclax 200 mg (2 x 100 mg)

Cycle 2:Days: 22-28: Venetoclax 400 mg (4 x 100 mg)

Cycles 3-12: Days 1-28: Venetoclax 400 mg (4 x 100 mg)

Intervention Type: DRUG

Acalabrutinib

Cycles 15-24: Days 1-28:

100 mg acalabrutinib twice daily p.o. approx. every 12 hrs (corresponding to a total daily dose of 200 mg).

Intervention Type: DRUG

Other Intervention Names

Gazyva; Gazyvaro; Venclexta; Venclyxto; Calquence

Eligibility Criteria

Inclusion Criteria

• Documented CLL/SLL requiring treatment according to iwCLL criteria
• Age at least 18 years
• At least one of the following risk factors: 17p-deletion, TP53-mutation, complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases) or an unmutated IGHV gene status.
• Life expectancy ≥ six months
• Adequate bone marrow function indicated by a platelet count >30 x10^9/l
• Creatinine clearance ≥ 30ml/min
• Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
• Negative testing for hepatitis B (HbsAg negative 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 month until 12 months after last treatment cycle),or hepatitis C (negative testing for hepatitis C RNA within 6 wee
• ks prior to registration for study screening (i.e. PCR only required when serology was positive))
• ECOG (Eastern Cooperative Oncology Group Performance Status) status 0-2

Exclusion Criteria

• Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted)
• Absence of high risk disease (17p-deletion, TP53-mutation complex karyotype
• An individual organ/system impairment score of 4 as assessed by the CIRS definition (e.g. advanced cardiac disease (NYHA class 3 or 4) limiting the ability to receive the study treatment 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)
• Transformation of CLL (Richter transformation)
• Malignancies other than CLL currently requiring systemic therapies
• Uncontrolled or active infection of HIV/PML or any other active infection
• Anticoagulant therapy with warfarin or phenoprocoumon
• Pregnant women and nursing mothers

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

German CLL Study Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Barbara Eichhorst, MD, Prof.

Role: PRINCIPAL_INVESTIGATOR

Department I of Internal Medicine, University Hospital Cologne

Locations

Helios Klinikum Bad Saarow

Bad Saarow, , Germany

Site Status: RECRUITING

DRK Kliniken Berlin Köpenick

Berlin, , Germany

Site Status: RECRUITING

Ev. Diakoniekrankenhaus

Bremen, , Germany

Site Status: RECRUITING

Universitätsklinik Köln

Cologne, , Germany

Site Status: RECRUITING

St. Johannes Hospital

Dortmund, , Germany

Site Status: RECRUITING

Marien Hospital Düsseldorf

Düsseldorf, , Germany

Site Status: RECRUITING

St. Antonius-Hospital

Eschweiler, , Germany

Site Status: RECRUITING

Universitaetsklinikum Essen

Essen, , Germany

Site Status: RECRUITING

Katholisches Krankenhaus Hagen - St. Josefs Hospital

Hagen, , Germany

Site Status: RECRUITING

Universitaetskliniken des Saarlandes

Homburg, , Germany

Site Status: RECRUITING

Klinikum Idar-Oberstein SHG

Idar-Oberstein, , Germany

Site Status: RECRUITING

Staedtisches Klinikum Karlsruhe

Karlsruhe, , Germany

Site Status: RECRUITING

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, , Germany

Site Status: RECRUITING

Klinikum Landshut

Landshut, , Germany

Site Status: RECRUITING

Klinikum Lippe-Lemgo

Lemgo, , Germany

Site Status: RECRUITING

St Vincenz Krankenhaus

Limburg, , Germany

Site Status: RECRUITING

Universitaetsklinikum Magdeburg

Magdeburg, , Germany

Site Status: RECRUITING

Klinikum Hochsauerland - St. Walburga Krankenhaus

Meschede, , Germany

Site Status: RECRUITING

KH Kliniken Maria Hilf

Mönchengladbach, , Germany

Site Status: RECRUITING

Krankenhaus Muenchen-Schwabing

Munich, , Germany

Site Status: RECRUITING

Klinikum Rechts der Isar - Technische Universitaet Muenchen

Munich, , Germany

Site Status: RECRUITING

Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd

Mutlangen, , Germany

Site Status: RECRUITING

Klinikum Oldenburg

Oldenburg, , Germany

Site Status: RECRUITING

Brüderkrankenhaus St. Josef Paderborn

Paderborn, , Germany

Site Status: RECRUITING

Universitätsklinik Rostock

Rostock, , Germany

Site Status: RECRUITING

Caritas-Klinik St. Theresia

Saarbrücken, , Germany

Site Status: RECRUITING

Klinikum Sindelfingen-Böbingen

Sindelfingen, , Germany

Site Status: RECRUITING

Marienhospital Stuttgart

Stuttgart, , Germany

Site Status: RECRUITING

Universitaetsklinik Tuebingen

Tübingen, , Germany

Site Status: RECRUITING

Universitätsklinik Ulm

Ulm, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Barbara Eichhorst, MD, Prof.

Role: CONTACT

barbara.eichhorst@uk-koeln.de

+4922147888220

Anna Fink, MD

Role: CONTACT

anna-maria.fink@uk-koeln.de

+4922147888220

Facility Contacts

Daniel Schöndube

Role: primary

Christian Neumann

Role: primary

Ralf Ulrich Trappe

Role: primary

Barbara Eichhorst

Role: primary

Ralf Meyer

Role: primary

Stefanie Gröpper

Role: primary

Peter Staib

Role: primary

Julia von Tresckow

Role: primary

Doris Kraemer

Role: primary

Jörg Bittenbring

Role: primary

Johannes Schneider

Role: primary

Henriette Huber

Role: primary

Matthias Ritgen

Role: primary

Christian Bogner

Role: primary

Karin Heinisch

Role: primary

Thomas Neuhaus

Role: primary

Ana Maria Waldleben

Role: primary

Mohammad Wattad

Role: primary

Ulrich Graeven

Role: primary

Clemens Wendtner

Role: primary

Simon Heidegger

Role: primary

Holger Hebart

Role: primary

Andrea Renzelmann

Role: primary

Tobias Gaska

Role: primary

Sebastian Böttcher

Role: primary

Michael Clemens

Role: primary

Markus Ritter

Role: primary

Claudio Denzlinger

Role: primary

Stefan Wirths

Role: primary

Christof Schneider

Role: primary

Related Links

https://www.dcllsg.com/cll16/

Related Info

Other Identifiers

2023-506414-46-00

Identifier Type: CTIS

Identifier Source: secondary_id

CLL16

Identifier Type: -

Identifier Source: org_study_id