Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation (GAIA)

A Phase 3 Multicenter, Randomized, Prospective, Open-label Trial of Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus Venetoclax (GVe) Versus Obinutuzumab Plus Ibrutinib Plus Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Rituximab; Drug: Bendamustine; Drug: Venetoclax; Biological: Obinutuzumab; Drug: Ibrutinib

Detailed Description

Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without del17p or TP 53 mutation; physically fit patients are treated with fludarabine, cyclophosphamide and rituximab (FCR)1. Due to the high risk of severe neutropenias and infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged >65 years.

However, these conventional chemoimmunotherapies are associated with side effects caused by the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need for alternatives, especially chemotherapy-free regimens.

In first line treatment of elderly patients with CLL and coexisting conditions, the anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved response rates as well as PFS times in comparison to chlorambucil alone or combined with rituximab.

The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis syndrome as dose limiting toxicity in patients with relapsed and refractory CLL. 400 mg venetoclax was determined to be a safe and efficacious dose. Several patients treated with the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD negativity. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on 12th April 2016.

Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin lymphoma xenograft model, and additive activity in a CLL lymph node model. The combination appears tolerable in the firstline treatment of CLL patients with coexisting conditions whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be replaced by obinutuzumab in combination with venetoclax in this trial.

Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton´s Tyrosine Kinase (BTK), showed excellent responses and a safe toxicity profile9,10, even in combination with BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL by the FDA and EMA (April 29th 2016).

The combination of ibrutinib and venetoclax showed synergy in primary CLL cells.

Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the frontline treatment of physically fit patients in CLL can be replaced by combinations of these targeted drugs with anti-CD20-antibodies.

• Study Type: Interventional
• Enrollment (Actual): 926
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Medizinische Universitaet Wien
  • Wien, Austria, 1160
    • Wilhelminenspital
  • Wien, Austria, 1140
    • Hanusch Hospital
• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Brugge, Belgium, 8000
    • Algemeen Ziekenhuis St. Jan
  • Ieper, Belgium, 8900
    • Jan Yperman ziekenhuis
  • Leuven, Belgium, 3000
    • Uz Gasthuisberg
  • Roeselare, Belgium, 8800
    • AZ DELTA
• Denmark
  • Aalborg, Denmark, 9100
    • Aalborg University Hospital
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet/Copenhagen
  • Esbjerg, Denmark, 6700
    • Sydvestjysk Sygehus Esbjerg
  • Herlev, Denmark, 2730
    • University Hospital Herlev
  • Holstebro, Denmark, 7500
    • Regionshospitalet Holstebro
  • Odense, Denmark, 5000
    • Odense Universitets Hospital
  • Roskilde, Denmark, 4000
    • Sjællands Universitetshospital
  • Vejle, Denmark, 7100
    • Vejle Hospital
• Finland
  • Helsinki, Finland, 29
    • Helsinki University Hospital
  • Jyväskylä, Finland, 40620
    • Jyväskylä Central Hospital
  • Oulu, Finland, 90029
    • Oulu University Hospital
  • Tampere, Finland, 33520
    • Tampere University Hospital
  • Turku, Finland, 20521
    • Turku University Hospital
• Germany
  • Amberg, Germany, 92224
    • Gesundheitszentrum Klinikum St Marien
  • Berlin, Germany, 10707
    • Onkologische Schwerpunktpraxis Kurfürstendamm
  • Berlin, Germany, 13125
    • Helios-Klinikum Berlin
  • Bonn, Germany, 53113
    • ZAHO Bonn
  • Bremen, Germany, 28239
    • Ev. Diakonie-Krankenhaus gemeinnuetzige GmbH
  • Dortmund, Germany, 44137
    • St. -Johannes-Hospital Dortmund
  • Dortmund, Germany, 44379
    • Gefos Dortmund mbH
  • Dresden, Germany, 1307
    • BAG Dresden
  • Dresden, Germany, 1307
    • Universitaetsklinik Carl Gustav Carus
  • Düsseldorf, Germany, 40479
    • Marien Hospital Dusseldorf GMBH
  • Eisenach, Germany, 99817
    • St. Georg Klinikum Eisenach GmbH
  • Erfurt, Germany, 99089
    • Helios Klinikum Erfurt
  • Eschweiler, Germany, 52249
    • St. Antonius-Hospital
  • Essen, Germany, 45122
    • Universitaetsklinikum Essen
  • Frankfurt, Germany, 60389
    • Centrum fuer Haematologie und Onkologie Bethanien
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg
  • Goslar, Germany, 38642
    • MVZ Onkologische Kooperation Harz, Drs. Tessen/Hoyer/Zahn
  • Greifswald, Germany, 17475
    • Universitaetsmedizin Greifswald
  • Göttingen, Germany, 37073
    • Onkologische Schwerpunktpraxis Göttingen
  • Göttingen, Germany, 37076
    • Universitaetsmedizin Göttingen
  • Hamburg, Germany, 22081
    • OncoResearch Lerchenfeld GmbH
  • Hamburg, Germany, 20246
    • UKE Hamburg
  • Hamm, Germany, 59063
    • EVK Hamm
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Hannover, Germany, 30171
    • MediProjekt GBR
  • Heidelberg, Germany, 69120
    • Universitaetsklinikum Heidelberg
  • Herne, Germany, 44625
    • Marienhospital Herne
  • Hildesheim, Germany, 31135
    • Onkologische Schwerpunktpraxis Des. Freier/Sievers, Hildesheim
  • Jena, Germany, 7747
    • Universitaetsklinikum Jena
  • Kaiserslautern, Germany, 67655
    • Westpfalz-Klinikum GmbH
  • Karlsruhe, Germany, 76133
    • Städt. Klinikum Karlsruhe
  • Kassel, Germany, 34119
    • Dres. Siehl / Soeling, Fachaerzte fuer Haematologie und Internistische Onkologie, Kassel
  • Kiel, Germany, 24105
    • Universitaetsklinikum Schleswig-Holstein Campus Kiel
  • Koblenz, Germany, 56068
    • InVO-Institut fuer Versorgungsforschung in der Onkologie GbR
  • Köln, Germany, 50937
    • University Hospital of Cologne
  • Landshut, Germany, 84028
    • Tagesklinik Landshut, Dr. Vehling-Kaiser
  • Lebach, Germany, 66822
    • Gemeinschaftspraxis Haemato/ Onkologie Lebach
  • Leer, Germany, 26788
    • Onkologische Schwerpunktpraxis Dr. Mueller, Leer
  • Lemgo, Germany, 32657
    • Klinikum Lippe GmbH
  • Magdeburg, Germany, 39104
    • Gemeinschaftspraxis Haematologie und Onkologie
  • Magdeburg, Germany, 39120
    • Universitaetsklinikum Magdeburg
  • Mainz, Germany, 55131
    • Universitaetsklinik Mainz
  • Mannheim, Germany, 68161
    • Mannheimer Onkologie Praxis
  • Mayen, Germany, 56727
    • Institut fuer Versorgungsforschung Dr. med. M. Maasberger/ M. Schmitz/ Dr. med. M. T. Keller
  • Mutlangen, Germany, 73557
    • Stauferklinikum Schwaebisch-Gmuend
  • Mönchengladbach, Germany, 41063
    • Kliniken Maria Hilf GmbH
  • München, Germany, 80804
    • Klinikum Schwabing
  • München, Germany, 81657
    • Klinikum rechts der Isar
  • München, Germany, 80335
    • MVZ MOP Elisenhof
  • München, Germany, 81377
    • Ludwig-Maximilians-Universitaet Muenchen
  • Neunkirchen, Germany, 66538
    • Haematologische/Onkologische Praxis Neunkirchen
  • Oberhausen, Germany, 46145
    • Studiengesellschaft Onkologie Rhein Ruhr
  • Offenbach, Germany, 63065
    • Gemeinschaftspraxis Dres. Ballo/Boeck
  • Paderborn, Germany, 33098
    • Klinik fuer Haematologie und Onkologie
  • Ravensburg, Germany, 88212
    • Studienzentrum Onkologie Ravensburg
  • Regensburg, Germany, 93049
    • Krankenhaus der Barmherzigen Brüder
  • Regensburg, Germany, 93053
    • OncoPro GbR
  • Rostock, Germany, 18057
    • Universitatsmedizin Rostock
  • Saarbrücken, Germany, 66113
    • Praxis für Hämatologie und Onkologie Dres. Jacobs/Daus/Schmits
  • Schweinfurt, Germany, 97422
    • Leopoldina-Krankenhaus
  • Siegburg, Germany, 53721
    • ZAHO-Rheinland
  • Stuttgart, Germany, 70376
    • Robert-Bosch-Krankenhaus
  • Stuttgart, Germany, 70199
    • Marienhospital Stuttgart
  • Tübingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
  • Ulm, Germany, 89081
    • Universitaetsklinikum Ulm
  • Weiden, Germany, 92637
    • MVZ Weiden GmbH
  • Weilheim, Germany, 82362
    • Haematologisch-Onkologische Schwerpunktpraxis Dres. Perker/Sandherr, Weilheim
  • Wuppertal, Germany, 42283
    • Helios Klinikum Wuppertal
  • Würzburg, Germany, 97080
    • Gemeinschaftspraxis Dr. Schlag/Dr. Schoettker
  • Würzburg, Germany, 97080
    • Universitaetsklinik Wuerzburg
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin, Ireland, Dublin 9
    • Beaumont Hospital
  • Dublin, Ireland, Dublin 7
    • Mater Misericordiae Hospital
  • Dublin, Ireland, Dublin 8
    • St. James's Hospital
  • Galway, Ireland
    • University Hospital Galway
  • Waterford, Ireland
    • University Hospital Waterford
• Israel
  • Haifa, Israel, 31048
    • Bnai-Zion Medical. Il-Haifa
  • Jerusalem, Israel, 91120
    • Hadassah Ein Kerem
  • Kfar-Saba, Israel, 4428164
    • Meir Medicail Center
  • Petach-Tikva, Israel, 4941492
    • Rabin Medical Center
  • Rechovot, Israel, 76100
    • Kaplan Medical Center
  • Tel-Aviv, Israel, 6423906
    • Souraski Tel-Aviv Medical Center
• Netherlands
  • Alkmaar, Netherlands, 1814HB
    • MC Alkmaar
  • Amersfoort, Netherlands, 3813TZ
    • Meander Medisch Centrum, Amersfoort
  • Amsterdam, Netherlands, 1081HV
    • VUmc, Amsterdam
  • Amsterdam, Netherlands, 1105AZ
    • NL-Amsterdam-AMC
  • Arnhem, Netherlands, 6815AD
    • Ziekenhuis Rijnstate
  • Breda, Netherlands, 4818CK
    • Amphia Ziekenhuis
  • Capelle aan den Ijssel, Netherlands, 2906ZC
    • IJsselland ziekenhuis
  • Delft, Netherlands, 2625AD
    • Reinier de Graaf Gasthuis
  • Deventer, Netherlands, 7400GC
    • Deventer ziekenhuizen
  • Dordrecht, Netherlands, 3318AT
    • Albert Schweitzer Ziekenhuis, Dordrecht
  • Ede, Netherlands, 6716RP
    • Gelderse Vallei
  • Eindhoven, Netherlands, 5631BM
    • Maxima Medisch Centrum
  • Enschede, Netherlands, 7511JX
    • Medisch Spectrum Twente
  • Gouda, Netherlands, 2803HH
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands, 9713GZ
    • UMCG
  • Hengelo, Netherlands, 7550AM
    • Ziekenhuisgroep Twente Hengelo
  • Hilversum, Netherlands, 1213XZ
    • Tergooi Ziekenhuis
  • Hoofddorp, Netherlands, 2134TM
    • Spaarne Ziekenhuis
  • Leeuwarden, Netherlands, 8934AD
    • Medisch Centrum Leeuwarden Zuid
  • Leiden, Netherlands, 2333RA
    • Leids Universitair Medisch Centrum
  • Maastricht, Netherlands, 6229HX
    • Maastricht university medial Center
  • Nieuwegein, Netherlands, 3435CM
    • St. Antonius Ziekehuis
  • Nijmegen, Netherlands, 6525GA
    • Radboud UMC
  • Nijmegen, Netherlands, 6532SZ
    • Canisius-Wilhelmina ZH
  • Rotterdam, Netherlands, 3079DZ
    • Maasstadziekenhuis
  • Sneek, Netherlands, 8601ZK
    • Antonius Ziekenhuis Sneek
  • Terneuzen, Netherlands, 4535PA
    • ZorgSaam Zeeuws Vlaanderen
  • Tilburg, Netherlands, 5022GC
    • St. Elisabeth ZH
  • Utrecht, Netherlands, 3584CX
    • UMCU
  • Venlo, Netherlands, 5912BL
    • VieCuri loc. Venlo
  • Zaandam, Netherlands, 1502DV
    • Zaans Medisch Centrum
  • Zwolle, Netherlands, 8025AB
    • Isala
  • s-Hertogenbosch, Netherlands, 5223GZ
    • Jeroen Bosch Ziekenhuis
• Sweden
  • Borås, Sweden, 50182
    • Soedra Aelvsborgs Sjukhus
  • Falun, Sweden, 79182
    • Falu Lasarett
  • Halmstad, Sweden, 30185
    • Hallands hospital - Halmstad
  • Linköping, Sweden, 58185
    • Universitetsjukhuset i Linkoeping
  • Luleå, Sweden, 97180
    • Sunderby Hospital
  • Lund, Sweden, 22185
    • Skane University Hospital Lund
  • Uppsala, Sweden, 75185
    • Akademiska Sjukhuset
  • Varberg, Sweden, 43237
    • Hallands hospital - Varberg
  • Örebro, Sweden, 70185
    • Universitetssjukhuset i Oerebro
• Switzerland
  • Aarau, Switzerland, 5000
    • Kantonsspital Aarau
  • Baden, Switzerland, 5404
    • Kantonsspital Baden
  • Basel, Switzerland, 4031
    • Universitaetsspital Basel
  • Bellinzona, Switzerland, 6500
    • IOSI, OSpedale Regionale Bellinzona e Valli
  • Bern, Switzerland, 3010
    • Inselspital Bern
  • Chur, Switzerland, 7000
    • Kantonsspital Graubünden
  • Genève, Switzerland, 1211
    • Universitaire de Geneve
  • Liestal, Switzerland, 4410
    • KSBL Liestal
  • Luzern, Switzerland, 6000
    • Luzerner Kantonsspital
  • Münsterlingen, Switzerland, 8596
    • Spital Thurgau AG
  • Olten, Switzerland, 4600
    • Kantonsspital Olten
  • St Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
  • Winterthur, Switzerland, 8401
    • KS Winterthur
  • Zürich, Switzerland, 8063
    • Stadtspital Triemli
  • Zürich, Switzerland, 8091
    • Universitaetsspital Zuerich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy)
6. Creatinine clearance ≥70ml/min directly measured with 24hr urine collection or 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). 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 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 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
9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2

Exclusion Criteria:

1. Any prior CLL-specific therapies (except corticosteroid treatment administere due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents of 20 mg prednisolone are permitted).
2. Transformation of CLL (Richter transformation)
3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more concurrent treatments being administered for hemolysis
4. Detected del(17p) or TP53 mutation
5. Patients with a history of PML
6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could comprise 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)
7. Urinary outflow obstruction
8. Malignancies other than CLL currently requiring systemic therapies, not being treated in curative intention 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
9. Uncontrolled or active infection
10. Patients with known infection with human immunodeficiency virus (HIV)
11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers
12. Anticoagulant therapy with warfarin or phenoprocoumon, (rotation to alternative anticoagulation is allowed, but note that patients being treated with NOAKs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib)
13. History of stroke or intracranial hemorrhage within 6 months prior to registration
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration
15. Vaccination with live vaccines 28 days prior to registration
16. Major surgery less than 30 days before start of treatment
17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products
18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial
19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly)

20. 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
21. Legal incapacity
22. Prisoners or subjects who are institutionalized by regulatory or court order
23. Persons who are in dependence to the sponsor or an investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard chemoimmunotherapy (SCIT); Patients up to age 65: 6 cycles (q28d) of Fludarabine + Cyclophosphamide + Rituximab (FCR) Patients older than 65 years: 6 cycles (q28d) of Bendamustine + Rituximab (BR)	Drug: Fludarabine; Fludarabine i.v.: cycles 1-6: 25 mg/m², d1-3, q28d; Other Names: Fludura; Drug: Cyclophosphamide; Cyclophosphamide i.v.: cycles 1-6: 250 mg/m², d1-3, q28d; Other Names: Endoxan; Biological: Rituximab; Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1; q28d; Other Names: Rituxan; MabThera; Drug: Bendamustine; Bendamustine i.v.: cycles 1-6: 90mg/m², d1-2, q28d; Other Names: Levact; Ribomustin
Experimental: Rituximab + Venetoclax (RVe); 6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone)	Biological: Rituximab; Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1; q28d; Other Names: Rituxan; MabThera; Drug: Venetoclax; Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28, q28d 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, q28d cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28, q28d; Other Names: Venclexta; Venclyxto
Experimental: Obinutuzumab + Venetoclax (GVe); 6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone)	Drug: Venetoclax; Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28, q28d 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, q28d cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28, q28d; Other Names: Venclexta; Venclyxto; Biological: Obinutuzumab; Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1, q28d; Other Names: Gazyva; Gazyvaro
Experimental: Obinutuzumab + Ibrutinib + Venetoclax (GIVe); 6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax. Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first.	Drug: Venetoclax; Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28, q28d 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, q28d cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28, q28d; Other Names: Venclexta; Venclyxto; Biological: Obinutuzumab; Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1, q28d; Other Names: Gazyva; Gazyvaro; Drug: Ibrutinib; Ibrutinib p.o. cycles 1-12: 420 mg, d1-28, q28d cycles 13-36: 420 mg, d1-28, q28d; Other Names: Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Miminimal residual disease (MRD) negativity rate in peripheral blood (PB)	Proportion of MRD negative patients at month15 based on the intention-to-treat population (ITT population), that is the number of MRD negative patients divided by the number of the ITT population. MRD negativity is defined as <1 CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. Primary outcome measure for the comparison of GVe vs. SCIT	Month 15
Progression free survival (PFS)	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. Primary outcome measure for the comparison GIVe vs. SCIT	anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD negativity rate in PB	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GVe vs. SCIT	Month 15
MRD levels in PB		Month 2, 9, 13 and later time points according to the discretion of the treating physician at local laboratories
MRD levels in bone marrow (BM)		at final restaging (RE): 2 month after the end of the last treatment cycle
PFS	Time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines [2008]), or death from any cause, whichever occurs first. Secondary outcome measure for all other comparisons with the exception of GIVe vs.SCIT	anticipated for January 2023 (after 213 events occured and 73 months after the first patient has been randomized)
Overall response rate (ORR)		Month 3, 9, 13 and 15
Rate of complete responses (CR) / complete responses with incomplete bone marrow recovery(CRi)	Complete response (CR) rate is defined by the proportion of patients having achieved a CR/CRi defined by the IWCLL guidelines as best response until and including the response assessment at Month 6, 9, 12 and 15 (= number of patients with best response CR/CRi divided by the ITT population).	Interim staging (IST: cycle 4 d1), cycle 9 d1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and Month 15, with regard to best response achieved

Collaborators and Investigators

• Sponsor: German CLL Study Group
• Collaborators: AbbVie; Hoffmann-La Roche; Swiss Group for Clinical Cancer Research; Stichting Hemato-Oncologie voor Volwassenen Nederland; Janssen-Cilag Ltd.; Cancer Trials Ireland; Nordic CLL Study Group (NCLLSG); Israeli CLL Study Group
• Investigators: Principal Investigator: Barbara Eichhorst, MD, Prof., Department I of Internal Medicine, University Hospital Cologne

Publications and helpful links

General Publications

• Furstenau M, Langerbeins P, De Silva N, Fink AM, Robrecht S, von Tresckow J, Simon F, Hohloch K, Droogendijk J, van der Klift M, van der Spek E, Illmer T, Schottker B, Fischer K, Wendtner CM, Tausch E, Stilgenbauer S, Niemann CU, Gregor M, Kater AP, Hallek M, Eichhorst B. COVID-19 among fit patients with CLL treated with venetoclax-based combinations. Leukemia. 2020 Aug;34(8):2225-2229. doi: 10.1038/s41375-020-0941-7. Epub 2020 Jun 29. No abstract available.

Helpful Links

• Click here for more information about this study: CLL13 (German CLL Study Group)

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2016
• Primary Completion (Actual): February 29, 2024
• Study Completion (Actual): February 29, 2024

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: October 27, 2016
• First Posted (Estimated): October 31, 2016

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: CLL
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Cyclophosphamide; Venetoclax; Bendamustine Hydrochloride; Rituximab; Fludarabine; Obinutuzumab; Ibrutinib
• Other Study ID Numbers: CLL13; 2015-004936-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO