Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients with Previously Untreated Chronic Lymphocytic Leukaemia (CLL)

NCT ID: NCT04608318

Last Updated: 2024-12-31

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 897 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-01
• Study Completion Date: 2027-09-30

Brief Summary

The aim of this study is to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL.

Conditions

Chronic Lymphoid Leukemia

Keywords

CLL

Study Design

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

Study Groups

I (Ibrutinib)

Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: BIOLOGICAL

Cycles 1 - X: 420 mg daily, d1-28 p.o.

VG (Obinutuzumab + Venetoclax)

12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone

Group Type: EXPERIMENTAL

Venetoclax

Intervention Type: BIOLOGICAL

Arm VG

Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o.

Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o.

Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Arm VI

Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o.

Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Obinutuzumab

Intervention Type: BIOLOGICAL

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

VI (Venetoclax + Ibrutinib)

15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles

Group Type: EXPERIMENTAL

Ibrutinib

Intervention Type: BIOLOGICAL

Cycles 1 - X: 420 mg daily, d1-28 p.o.

Venetoclax

Intervention Type: BIOLOGICAL

Arm VG

Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o.

Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o.

Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Arm VI

Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o.

Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Interventions

Ibrutinib

Cycles 1 - X: 420 mg daily, d1-28 p.o.

Intervention Type: BIOLOGICAL

Venetoclax

Arm VG

Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o.

Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o.

Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Arm VI

Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o.

Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o.

Intervention Type: BIOLOGICAL

Obinutuzumab

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

Intervention Type: BIOLOGICAL

Other Intervention Names

Imbruvica; ABT-199, Venclyxto; GA101, Gazyvaro

Eligibility Criteria

Inclusion Criteria

1. Documented CLL requiring treatment according to iwCLL criteria.

2. Age at least 18 years.

3. Life expectancy ≥ 6 months.

4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.

5. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:

1. Absolute neutrophil count ≥ 1.0 × 109/L

2. Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L

3. Total haemoglobin ≥ 8 g/dL (without transfusion support, unless anaemia is due to CLL)

6. GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.

a. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.

7. 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.

8. Negative serological 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/every three months if persistently negative until 12 months after last treatment cycle), and for hepatitis C (anti-HCV-ab negative; in case of positive HCV anti-body test, negative HCV-PCR is required).

9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Exclusion Criteria

1. 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).

2. Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.

3. Patients with a history of PML.

4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition 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).

5. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treating physician or showing signs of progression after curative treatment.

6. Uncontrolled or active infection.

7. Patients with known infection with human immunodeficiency virus (HIV).

8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).

9. Anticoagulant therapy with warfarin, phenprocoumon or other vit-amin K antagonists (alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).

10. History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.

11. Known bleeding disorders

12. Child B / C liver cirrhosis

13. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.

14. Vaccination with live vaccines 28 days prior to registration for study screening.

15. Major surgery less than 30 days before start of study treatment.

16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.

17. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.

18. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).

19. Fertile men or women of childbearing potential unless:

1. surgically sterile or ≥ 2 years after the onset of menopause

2. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.

20. Legal incapacity.

21. Prisoners or subjects who are institutionalized by regulatory or court order.

22. Persons who are in dependence to the sponsor or an investigator.

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

Sponsors

Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)

UNKNOWN

Sponsor Role: collaborator

Nordic CLL Study Group (NCLLSG)

UNKNOWN

Sponsor Role: collaborator

Swiss Group for Clinical Cancer Research (SAKK)

UNKNOWN

Sponsor Role: collaborator

Cancer Trials Ireland

NETWORK

Sponsor Role: collaborator

Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)

UNKNOWN

Sponsor Role: collaborator

Grupo Español de Leucemia Linfocítica Crónica (GELLC)

OTHER_GOV

Sponsor Role: collaborator

The Israeli CLL Study Group (ICLLSG)

UNKNOWN

Sponsor Role: collaborator

Janssen Pharmaceutica N.V., Belgium

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: collaborator

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

German CLL Study Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Othman Al-Sawaf, Dr. med.

Role: PRINCIPAL_INVESTIGATOR

German CLL Study Group

Locations

LKH-Universtitätsklinikum Graz

Graz, , Austria

Landeskrankenhaus - Universitätskliniken Innsbruck

Innsbruck, , Austria

Medizinische Universität Wien

Vienna, , Austria

Hanusch Krankenhaus

Vienna, , Austria

Wiener Gesundheitsverbund Klinik Ottakring

Vienna, , Austria

Algemeen Ziekenhuis St. Jan

Bruges, , Belgium

Universitair Ziekenhuis Leuven

Leuven, , Belgium

Algemeen Ziekenhuis Delta

Roeselare, , Belgium

Aalborg Universitetshospital

Aalborg, , Denmark

Aarhus Universitetshospital

Aarhus, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Sydvestjysk Sygehus Esbjerg

Esbjerg, , Denmark

Regionshospitalet Holstebro

Holstebro, , Denmark

Odense Universitetshospital

Odense, , Denmark

Zealand University Hospital

Roskilde, , Denmark

Lillebaelt Vejle Sygehus

Vejle, , Denmark

Helsinki University Hospital

Helsinki, , Finland

Tampere University Hospital

Tampere, , Finland

Turku University Hospital

Turku, , Finland

Universitätsklinikum Augsburg

Augsburg, , Germany

Onkologische Schwerpunktpraxis Kurfürstendamm

Berlin, , Germany

Charite Universitaetsmedizin - Campus Benjamin Franklin

Berlin, , Germany

Helios Klinikum Berlin Buch

Berlin, , Germany

Charite Universitätsmedizin - Campus Virchow Klinikum

Berlin, , Germany

Ev. Diakoniekrankenhaus

Bremen, , Germany

Universitätsklinik Köln

Cologne, , Germany

Gemeinschaftspraxis für Hämatologie & Onkologie

Dortmund, , Germany

Gemeinschaftspraxis Hämatologie Onkologie

Dresden, , Germany

Universitätsklinik Carl Gustav Carus

Dresden, , Germany

Sana Krankenhaus Benrath

Düsseldorf, , Germany

St. Georg Klinikum Eisenach

Eisenach, , Germany

ISP Erlangen Onkologische Schwerpunktpraxis

Erlangen, , Germany

Universitätsklinikum Erlangen

Erlangen, , Germany

Universitaetsklinikum Essen

Essen, , Germany

Onkologische Schwerpunktpraxis

Esslingen am Neckar, , Germany

Centrum für Hämatologie und Onkologie Bethanien

Frankfurt, , Germany

Universitätsklinikum Freiburg

Freiburg im Breisgau, , Germany

Uniklinikum Gießen und Marburg

Giessen, , Germany

MVZ Onkologische Kooperation Harz

Goslar, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

OncoResearch Lerchenfeld

Hamburg, , Germany

Evangelische Krankenhaus Hamm

Hamm, , Germany

Onkologisches Ambulanzzentrum - MediProjekt

Hanover, , Germany

Onkologische Schwerpunktpraxis Heidelberg

Heidelberg, , Germany

Universitätsklinikum Heidelberg

Heidelberg, , Germany

Marien Hospital Herne

Herne, , Germany

Universitätskliniken des Saarlandes

Homburg, , Germany

Universitätsklinikum Jena

Jena, , Germany

Westpfalz-Klinikum GmbH

Kaiserslautern, , Germany

Universitaetsklinikum Schleswig-Holstein Campus Kiel

Kiel, , Germany

Praxis für Haematologie und Onkologie

Koblenz, , Germany

MVZ Hämatologie Onkologie Koblenz

Koblenz, , Germany

H.O.T Onkologie Praxis Landshut

Landshut, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

Onkopraxis Probstheida

Leipzig, , Germany

Klinikum Lippe Lemgo

Lemgo, , Germany

St Vincenz Krankenhaus

Limburg, , Germany

Lübecker Onkologische Schwerpunktpraxis

Lübeck, , Germany

Gemeinschaftspraxis Haematologie und Onkologie

Magdeburg, , Germany

Universitätsklinikum Magdeburg

Magdeburg, , Germany

Mannheimer Onkologie Praxis

Mannheim, , Germany

Praxis für Innere Medizin - Hämatologie und Onkologie

Marburg, , Germany

Kliniken Maria Hilf

Mönchengladbach, , Germany

Stauferklinikum Schwäbisch Gmünd

Mutlangen, , Germany

München Klinik Schwabing

München, , Germany

Klinikum der Universitaet München - Grosshadern Campus

München, , Germany

Klinikum rechts der Isar - Technische Universitaet Muenchen

München, , Germany

Gemeinschaftspraxis für Hämatologie und Onkologie

Münster, , Germany

Klinikum Oldenburg

Oldenburg, , Germany

Brüderkrankenhaus St. Josef Paderborn

Paderborn, , Germany

Gemeinschaftspraxis für Hämatologie und Onkologie

Ravensburg, , Germany

Barmherzigen Brüder Krankenhaus

Regensburg, , Germany

Schwerpunktpraxis für Hämatologie & Onkologie - OncoPro GbR

Regensburg, , Germany

Universitätsklinik Rostock

Rostock, , Germany

OnkoSaar Praxis für Hämatologie und Onkologie

Saarbrücken, , Germany

Zentrum für abulante Hämatologie und Onkologie

Siegburg, , Germany

Marienhospital Stuttgart

Stuttgart, , Germany

Robert-Bosch-Krankenhaus

Stuttgart, , Germany

Universitätsklinik Tübingen

Tübingen, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

MVZ Weiden GmbH

Weiden, , Germany

Hämatologisch Onkologische Schwerpunktpraxis

Würzburg, , Germany

Cork University Hospital

Cork, , Ireland

St Vincents University Hospital

Dublin, , Ireland

Mater Misericordiae University Hospital

Dublin, , Ireland

St. James's Hospital

Dublin, , Ireland

Beaumont Hospital

Dublin, , Ireland

University Hospital Galway

Galway, , Ireland

University Hospital Limerick

Limerick, , Ireland

University Hospital Waterford

Waterford, , Ireland

Soroka University Medical Center

Beersheba, , Israel

Shamir Medical Center Assaf Harofeh

Be’er Ya‘aqov, , Israel

Bnai-Zion Medical Center

Haifa, , Israel

Hadassah Medical Center Ein Kerem University Hospital

Jerusalem, , Israel

Meir Medical Center

Kfar Saba, , Israel

Galilee Medical Center

Nahariya, , Israel

Rabin Medical Center Beilinson Hospital

Petah Tikva, , Israel

Chaim Sheba Medical Center

Ramat Gan, , Israel

Kaplan Medical Center

Rehovot, , Israel

Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele

Catania, , Italy

Azienda Ospedaliero Universitaria di Ferrara

Ferrara, , Italy

Ospedale dell'Angelo

Mestre, , Italy

Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico

Milan, , Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

IRCCS Ospedale San Raffaele

Milan, , Italy

Ospedale S. Maria della Misericordia

Perugia, , Italy

Umberto I - Policlinico di Roma - Sapienza Università

Roma, , Italy

Gmelli University Hospital

Roma, , Italy

Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino

Torino, , Italy

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Nordwest Ziekenhuisgroep, Locatie Alkmaar

Alkmaar, , Netherlands

OLVG Amsterdam

Amsterdam, , Netherlands

Amsterdam Universitair Medische Centra

Amsterdam, , Netherlands

Rijnstate, Locatie Arnhem

Arnhem, , Netherlands

Amphia Ziekenhuis

Breda, , Netherlands

Reinier de Graaf Ziekenhuis

Delft, , Netherlands

Slingeland ziekenhuis

Doetinchem, , Netherlands

Albert Schweitzer Ziekenhuis

Dordrecht, , Netherlands

Ziekenhuis Gelderse Vallei

Ede, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

Ziekenhuis St Jansdal

Harderwijk, , Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Alrijne Ziekenhuis

Leiderdorp, , Netherlands

St. Antonius Ziekenhuis

Nieuwegein, , Netherlands

Canisius-Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

Maasstad Ziekenhuis

Rotterdam, , Netherlands

Franciscus Vlietland

Schiedam, , Netherlands

Ziekenhuis Rivierenland Tiel

Tiel, , Netherlands

Diakonessenhuis

Utrecht, , Netherlands

VieCuri Medish Centrum

Venlo, , Netherlands

Isala Zwolle

Zwolle, , Netherlands

Haukeland University Hospital

Bergen, , Norway

Akershus University Hospital

Lørenskog, , Norway

Oslo University Hospital

Oslo, , Norway

St. Olavs Hospital Trondheim University Hospital

Trondheim, , Norway

Hospital Germans Trias i Pujol

Badalona, , Spain

Vall d'Hebron University Hospital

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital Duran i Reynals

Barcelona, , Spain

Hospital Universitario La Princesa

Madrid, , Spain

Hospital Universitario Infanta Leonor

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Costa del Sol

Málaga, , Spain

Hospital Universitario Central de Asturias

Oviedo, , Spain

Hospital Clinico Universitario de Salamanca

Salamanca, , Spain

Hospital Marques de Valdecilla

Santander, , Spain

Hospital Universitario Virgen de Valme

Seville, , Spain

Hospital Clinico Universitario Valencia

Valencia, , Spain

Residencia Sanitaria La Fe - Valencia

Valencia, , Spain

Hospital Clinico Universitario Lozano Blesa

Zaragoza, , Spain

Soedra Aelvsborgs Sjukhus

Borås, , Sweden

Falu Lasarett

Falun, , Sweden

Sahlgrenska University Hospital

Gothenburg, , Sweden

Hallands Sjukhus Halmstad

Halmstad, , Sweden

Universitetssjukhuset Linköping

Linköping, , Sweden

Sunderby Hospital

Luleå, , Sweden

Skåne University Hospital

Lund, , Sweden

Örebro University Hospital

Örebro, , Sweden

Karolinska University Hospital Solna

Stockholm, , Sweden

Umeå University Hospital

Umeå, , Sweden

Uppsala University Hospital

Uppsala, , Sweden

Hallands Sjukhus

Varberg, , Sweden

Kantonsspital Aarau

Aarau, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

Universitätsspital Basel

Basel, , Switzerland

Ospedale Regionale Bellinzona e Valli

Bellinzona, , Switzerland

Inselspital Bern

Bern, , Switzerland

Spitalzentrum Oberwallis

Brig, , Switzerland

Kantonsspital Graubünden

Chur, , Switzerland

HFR Fribourg Hôpital cantonal

Fribourg, , Switzerland

Hôpitaux Universitaires Genève

Geneva, , Switzerland

Kantonsspital Baselland

Liestal, , Switzerland

Luzerner Kantonsspital

Lucerne, , Switzerland

Spital Thurgau AG - Kantonsspital Münsterlingen

Münsterlingen, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

Spital Thun

Thun, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Stadtspital Triemli

Zurich, , Switzerland

Universitätsspital Zuerich

Zurich, , Switzerland

Countries

Austria; Belgium; Denmark; Finland; Germany; Ireland; Israel; Italy; Netherlands; Norway; Spain; Sweden; Switzerland

Related Links

https://www.dcllsg.com/cll17/

Click here for more information about this study: CLL17 (German CLL Study Group)

Other Identifiers

2022-500439-35-00

Identifier Type: CTIS

Identifier Source: secondary_id

2019-003854-99

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CLL17

Identifier Type: -

Identifier Source: org_study_id