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

Phase 3

Active, not recruiting

• Conditions: Chronic Lymphoid Leukemia
• Interventions: Biological: Ibrutinib; Biological: Obinutuzumab; Biological: Venetoclax

• Registration Number: NCT04608318
• Lead Sponsor: German CLL Study Group

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2020-10-23
• Study First Submitted QC: 2020-10-23
• Study First Posted: 2020-10-29
• Study Start: 2021-03-01
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-05
• Last Update Posted: 2024-03-06
• Primary Completion: 2027-03
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 897

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 ≥ 9 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 until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration for study screening (i.e. PCR only required when serology was positive).

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 or phenprocoumon, (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.

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
VI (Venetoclax + Ibrutinib)	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
VG (Obinutuzumab + Venetoclax)	Obinutuzumab	12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone
I (Ibrutinib)	Ibrutinib	Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first.
VI (Venetoclax + Ibrutinib)	Venetoclax	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
VG (Obinutuzumab + Venetoclax)	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

Primary Outcome Measures

Name	Time	Method
Investigator-assessed progression-free survival (PFS)	Up to 80 month	Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first

Secondary Outcome Measures

Name	Time	Method
Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI)	Up to 80 month	Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs
MRD levels in PB at different time points	Up to 80 month	MRD is defined as the number of CLL-cells that can be detected in peripheral blood (PB) or bone marrow (BM). MRD values will be categorized into negative (\<10-4) and positive (≥10-4)
Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM)	At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE	Undetectable MRD (uMRD) is defined as \<10-4 (=1 CLL-cell per 10,000 leukocytes analyzed).The uMRD rate is defined as the proportion of patients having achieved uMRD.
Overall response rate (ORR)	At final restaging (RE): 18 months after start of treatment	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.
CR/CRi rate	At final restaging (RE): 18 months after start of treatment	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 intention-to-treat population (ITT) population)

Trial Locations

Locations (180)

Klinikum rechts der Isar - Technische Universitaet Muenchen; 🇩🇪 München, Germany

Franciscus Vlietland; 🇳🇱 Schiedam, Netherlands

Hallands Sjukhus; 🇸🇪 Varberg, Sweden

Kantonsspital Baden; 🇨🇭 Baden, Switzerland

Inselspital Bern; 🇨🇭 Bern, Switzerland

Shamir Medical Center Assaf Harofeh; 🇮🇱 Be'er Ya'aqov, Israel

Hadassah Medical Center Ein Kerem University Hospital; 🇮🇱 Jerusalem, Israel

Meir Medical Center; 🇮🇱 Kfar-Saba, Israel

Rabin Medical Center Beilinson Hospital; 🇮🇱 Petach-Tikva, Israel

Chaim Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Galilee Medical Center; 🇮🇱 Nahariya, Israel

Akershus University Hospital; 🇳🇴 Lørenskog, Norway

Haukeland University Hospital; 🇳🇴 Bergen, Norway

Spital Thun; 🇨🇭 Thun, Switzerland

Soedra Aelvsborgs Sjukhus; 🇸🇪 Borås, Sweden

Beaumont Hospital; 🇮🇪 Dublin, Ireland

Onkologische Schwerpunktpraxis; 🇩🇪 Esslingen, Germany

LKH-Universtitätsklinikum Graz; 🇦🇹 Graz, Austria

Medizinische Universität Wien; 🇦🇹 Wien, Austria

Landeskrankenhaus - Universitätskliniken Innsbruck; 🇦🇹 Innsbruck, Austria

Universitair Ziekenhuis Leuven; 🇧🇪 Leuven, Belgium

Wiener Gesundheitsverbund Klinik Ottakring; 🇦🇹 Wien, Austria

Algemeen Ziekenhuis St. Jan; 🇧🇪 Brugge, Belgium

Hanusch Krankenhaus; 🇦🇹 Wien, Austria

Algemeen Ziekenhuis Delta; 🇧🇪 Roeselare, Belgium

Aalborg Universitetshospital; 🇩🇰 Aalborg, Denmark

Aarhus Universitetshospital; 🇩🇰 Aarhus, Denmark

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Regionshospitalet Holstebro; 🇩🇰 Holstebro, Denmark

Sydvestjysk Sygehus Esbjerg; 🇩🇰 Esbjerg, 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

Gemeinschaftspraxis für Hämatologie & Onkologie; 🇩🇪 Dortmund, Germany

Gemeinschaftspraxis Hämatologie Onkologie; 🇩🇪 Dresden, Germany

Universitätsklinik Carl Gustav Carus; 🇩🇪 Dresden, Germany

Universitätsklinikum Erlangen; 🇩🇪 Erlangen, Germany

St. Georg Klinikum Eisenach; 🇩🇪 Eisenach, Germany

Sana Krankenhaus Benrath; 🇩🇪 Düsseldorf, Germany

ISP Erlangen Onkologische Schwerpunktpraxis; 🇩🇪 Erlangen, Germany

Universitaetsklinikum Essen; 🇩🇪 Essen, Germany

Universitätsklinikum Freiburg; 🇩🇪 Freiburg, Germany

Centrum für Hämatologie und Onkologie Bethanien; 🇩🇪 Frankfurt, Germany

Uniklinikum Gießen und Marburg; 🇩🇪 Gießen, Germany

MVZ Onkologische Kooperation Harz; 🇩🇪 Goslar, Germany

Universitätsklinikum Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Onkologisches Ambulanzzentrum - MediProjekt; 🇩🇪 Hannover, Germany

Evangelische Krankenhaus Hamm; 🇩🇪 Hamm, Germany

Onkologische Schwerpunktpraxis Heidelberg; 🇩🇪 Heidelberg, Germany

OncoResearch Lerchenfeld; 🇩🇪 Hamburg, Germany

Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

Marien Hospital Herne; 🇩🇪 Herne, Germany

Universitätskliniken des Saarlandes; 🇩🇪 Homburg, Germany

Universitätsklinikum Jena; 🇩🇪 Jena, Germany

Universitaetsklinikum Schleswig-Holstein Campus Kiel; 🇩🇪 Kiel, Germany

Westpfalz-Klinikum GmbH; 🇩🇪 Kaiserslautern, Germany

Praxis für Haematologie und Onkologie; 🇩🇪 Koblenz, Germany

Universitätsklinik Köln; 🇩🇪 Köln, Germany

MVZ Hämatologie Onkologie Koblenz; 🇩🇪 Koblenz, Germany

H.O.T Onkologie Praxis Landshut; 🇩🇪 Landshut, Germany

Universitätsklinikum Leipzig; 🇩🇪 Leipzig, Germany

Klinikum Lippe Lemgo; 🇩🇪 Lemgo, Germany

St Vincenz Krankenhaus; 🇩🇪 Limburg, Germany

Onkopraxis Probstheida; 🇩🇪 Leipzig, Germany

Universitätsklinikum Magdeburg; 🇩🇪 Magdeburg, Germany

Lübecker Onkologische Schwerpunktpraxis; 🇩🇪 Lübeck, Germany

Gemeinschaftspraxis Haematologie und Onkologie; 🇩🇪 Magdeburg, Germany

Kliniken Maria Hilf; 🇩🇪 Mönchengladbach, Germany

Mannheimer Onkologie Praxis; 🇩🇪 Mannheim, Germany

Stauferklinikum Schwäbisch Gmünd; 🇩🇪 Mutlangen, Germany

Praxis für Innere Medizin - Hämatologie und Onkologie; 🇩🇪 Marburg, Germany

Klinikum der Universitaet München - Grosshadern Campus; 🇩🇪 München, Germany

München Klinik Schwabing; 🇩🇪 München, Germany

Gemeinschaftspraxis für Hämatologie und Onkologie; 🇩🇪 Ravensburg, Germany

Klinikum Oldenburg; 🇩🇪 Oldenburg, Germany

Brüderkrankenhaus St. Josef Paderborn; 🇩🇪 Paderborn, Germany

Schwerpunktpraxis für Hämatologie & Onkologie - OncoPro GbR; 🇩🇪 Regensburg, Germany

Universitätsklinik Rostock; 🇩🇪 Rostock, Germany

OnkoSaar Praxis für Hämatologie und Onkologie; 🇩🇪 Saarbrücken, Germany

Barmherzigen Brüder Krankenhaus; 🇩🇪 Regensburg, Germany

Zentrum für abulante Hämatologie und Onkologie; 🇩🇪 Siegburg, Germany

Marienhospital Stuttgart; 🇩🇪 Stuttgart, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Robert-Bosch-Krankenhaus; 🇩🇪 Stuttgart, Germany

Universitätsklinik Tübingen; 🇩🇪 Tübingen, Germany

Mater Misericordiae University Hospital; 🇮🇪 Dublin, Ireland

MVZ Weiden GmbH; 🇩🇪 Weiden, Germany

Hämatologisch Onkologische Schwerpunktpraxis; 🇩🇪 Würzburg, Germany

Cork University Hospital; 🇮🇪 Cork, Ireland

St Vincents University Hospital; 🇮🇪 Dublin, Ireland

University Hospital Galway; 🇮🇪 Galway, Ireland

St. James's Hospital; 🇮🇪 Dublin, Ireland

University Hospital Limerick; 🇮🇪 Limerick, Ireland

University Hospital Waterford; 🇮🇪 Waterford, Ireland

Soroka University Medical Center; 🇮🇱 Be'er Sheva, Israel

Bnai-Zion Medical Center; 🇮🇱 Haifa, Israel

Kaplan Medical Center; 🇮🇱 Rechovot, Israel

Tel Aviv Sourasky Medical Center; 🇮🇱 Tel-Aviv, Israel

Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele; 🇮🇹 Catania, Italy

Azienda Ospedaliero Universitaria di Ferrara; 🇮🇹 Ferrara, Italy

Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico; 🇮🇹 Milano, Italy

ASST Grande Ospedale Metropolitano Niguarda; 🇮🇹 Milano, Italy

Ospedale dell'Angelo; 🇮🇹 Mestre, Italy

IRCCS Ospedale San Raffaele; 🇮🇹 Milano, Italy

Ospedale S. Maria della Misericordia; 🇮🇹 Perugia, Italy

Umberto I - Policlinico di Roma - Sapienza Università; 🇮🇹 Roma, Italy

Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino; 🇮🇹 Torino, Italy

Gmelli University Hospital; 🇮🇹 Roma, Italy

Nordwest Ziekenhuisgroep, Locatie Alkmaar; 🇳🇱 Alkmaar, Netherlands

OLVG Amsterdam; 🇳🇱 Amsterdam, Netherlands

Amsterdam Universitair Medische Centra; 🇳🇱 Amsterdam, Netherlands

Amphia Ziekenhuis; 🇳🇱 Breda, Netherlands

Rijnstate, Locatie Arnhem; 🇳🇱 Arnhem, 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

Maasstad Ziekenhuis; 🇳🇱 Rotterdam, Netherlands

Jeroen Bosch Ziekenhuis; 🇳🇱 s-Hertogenbosch, Netherlands

Canisius-Wilhelmina Ziekenhuis; 🇳🇱 Nijmegen, Netherlands

Diakonessenhuis; 🇳🇱 Utrecht, Netherlands

Ziekenhuis Rivierenland Tiel; 🇳🇱 Tiel, Netherlands

Isala Zwolle; 🇳🇱 Zwolle, Netherlands

VieCuri Medish Centrum; 🇳🇱 Venlo, Netherlands

Oslo University Hospital; 🇳🇴 Oslo, Norway

St. Olavs Hospital Trondheim University Hospital; 🇳🇴 Trondheim, Norway

Hospital Germans Trias i Pujol; 🇪🇸 Badalona, Spain

Hospital Clinic de Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario La Princesa; 🇪🇸 Madrid, Spain

Vall d'Hebron University Hospital; 🇪🇸 Barcelona, Spain

Hospital Duran i Reynals; 🇪🇸 Barcelona, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

Hospital Costa del Sol; 🇪🇸 Málaga, Spain

Hospital Clinico Universitario de Salamanca; 🇪🇸 Salamanca, Spain

Hospital Marques de Valdecilla; 🇪🇸 Santander, Spain

Hospital Universitario Virgen de Valme; 🇪🇸 Sevilla, Spain

Hospital Clinico Universitario Valencia; 🇪🇸 Valencia, Spain

Hospital Clinico Universitario Lozano Blesa; 🇪🇸 Zaragoza, Spain

Falu Lasarett; 🇸🇪 Falun, Sweden

Residencia Sanitaria La Fe - Valencia; 🇪🇸 Valencia, Spain

Hallands Sjukhus Halmstad; 🇸🇪 Halmstad, Sweden

Sahlgrenska University Hospital; 🇸🇪 Göteborg, Sweden

Sunderby Hospital; 🇸🇪 Luleå, Sweden

Karolinska University Hospital Solna; 🇸🇪 Stockholm, Sweden

Universitetssjukhuset Linköping; 🇸🇪 Linköping, Sweden

Skåne University Hospital; 🇸🇪 Lund, Sweden

Uppsala University Hospital; 🇸🇪 Uppsala, Sweden

Umeå University Hospital; 🇸🇪 Umeå, Sweden

Örebro University Hospital; 🇸🇪 Örebro, Sweden

Kantonsspital Aarau; 🇨🇭 Aarau, Switzerland

Universitätsspital Basel; 🇨🇭 Basel, Switzerland

HFR Fribourg Hôpital cantonal; 🇨🇭 Fribourg, Switzerland

Ospedale Regionale Bellinzona e Valli; 🇨🇭 Bellinzona, Switzerland

Spitalzentrum Oberwallis; 🇨🇭 Brig, Switzerland

Kantonsspital Graubünden; 🇨🇭 Chur, Switzerland

Hôpitaux Universitaires Genève; 🇨🇭 Geneve, Switzerland

Kantonsspital Baselland; 🇨🇭 Liestal, Switzerland

Luzerner Kantonsspital; 🇨🇭 Luzern, Switzerland

Kantonsspital Olten; 🇨🇭 Olten, Switzerland

Kantonsspital St. Gallen; 🇨🇭 St Gallen, Switzerland

Spital Thurgau AG - Kantonsspital Münsterlingen; 🇨🇭 Münsterlingen, Switzerland

Kantonsspital Winterthur; 🇨🇭 Winterthur, Switzerland

Stadtspital Triemli; 🇨🇭 Zürich, Switzerland

Universitätsspital Zuerich; 🇨🇭 Zürich, Switzerland

Hospital Universitario Infanta Leonor; 🇪🇸 Madrid, Spain