Clinical trial NCT04608318: Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients with Previously Untreated Chronic Lymphocytic Leukaemia (CLL)
Official title: A Phase 3 Multicentre, Randomized, Prospective, Open-label Trial of Ibrutinib Monotherapy Versus Fixed-duration Venetoclax Plus Obinutuzumab Versus Fixed-duration Ibrutinib Plus Venetoclax in Patients with Previously Untreated Chronic Lymphocytic Leukaemia (CLL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphoid Leukemia
Keywords: CLL
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
Collaborators: name: Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)
name: Nordic CLL Study Group (NCLLSG)
name: Swiss Group for Clinical Cancer Research (SAKK)
name: Cancer Trials Ireland
name: Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)
name: Grupo Español de Leucemia Linfocítica Crónica (GELLC)
name: The Israeli CLL Study Group (ICLLSG)
name: Janssen Pharmaceutica N.V., Belgium
name: AbbVie
name: Hoffmann-La Roche
First posted: 2020-10-29
Enrollment: 897
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Investigator-assessed progression-free survival (PFS)
timeFrame: Up to 80 month
Secondary outcomes:
measure: Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM)
timeFrame: At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE
measure: MRD levels in PB at different time points
timeFrame: Up to 80 month
measure: Overall response rate (ORR)
timeFrame: At final restaging (RE): 18 months after start of treatment
measure: CR/CRi rate
timeFrame: At final restaging (RE): 18 months after start of treatment
measure: Event-free survival
timeFrame: Up to 80 month
measure: Time to next treatment
timeFrame: Up to 80 month
measure: PFS2
timeFrame: Up to 80 month
measure: Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI)
timeFrame: Up to 80 month
measure: Safety parameter TLS
timeFrame: Up to 80 month
Other outcomes:
Locations:
city: Graz
country: Austria
facility: LKH-Universtitätsklinikum Graz
city: Innsbruck
country: Austria
facility: Landeskrankenhaus - Universitätskliniken Innsbruck
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Wien
country: Austria
facility: Hanusch Krankenhaus
city: Wien
country: Austria
facility: Wiener Gesundheitsverbund Klinik Ottakring
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis St. Jan
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Roeselare
country: Belgium
facility: Algemeen Ziekenhuis Delta
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Esbjerg
country: Denmark
facility: Sydvestjysk Sygehus Esbjerg
city: Holstebro
country: Denmark
facility: Regionshospitalet Holstebro
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Roskilde
country: Denmark
facility: Zealand University Hospital
city: Vejle
country: Denmark
facility: Lillebaelt Vejle Sygehus
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Berlin
country: Germany
facility: Onkologische Schwerpunktpraxis Kurfürstendamm
city: Berlin
country: Germany
facility: Charite Universitaetsmedizin - Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Helios Klinikum Berlin Buch
city: Berlin
country: Germany
facility: Charite Universitätsmedizin - Campus Virchow Klinikum
city: Bremen
country: Germany
facility: Ev. Diakoniekrankenhaus
city: Dortmund
country: Germany
facility: Gemeinschaftspraxis für Hämatologie & Onkologie
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Hämatologie Onkologie
city: Dresden
country: Germany
facility: Universitätsklinik Carl Gustav Carus
city: Düsseldorf
country: Germany
facility: Sana Krankenhaus Benrath
city: Eisenach
country: Germany
facility: St. Georg Klinikum Eisenach
city: Erlangen
country: Germany
facility: ISP Erlangen Onkologische Schwerpunktpraxis
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Esslingen
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Frankfurt
country: Germany
facility: Centrum für Hämatologie und Onkologie Bethanien
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Gießen
country: Germany
facility: Uniklinikum Gießen und Marburg
city: Goslar
country: Germany
facility: MVZ Onkologische Kooperation Harz
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hamburg
country: Germany
facility: OncoResearch Lerchenfeld
city: Hamm
country: Germany
facility: Evangelische Krankenhaus Hamm
city: Hannover
country: Germany
facility: Onkologisches Ambulanzzentrum - MediProjekt
city: Heidelberg
country: Germany
facility: Onkologische Schwerpunktpraxis Heidelberg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Herne
country: Germany
facility: Marien Hospital Herne
city: Homburg
country: Germany
facility: Universitätskliniken des Saarlandes
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein Campus Kiel
city: Koblenz
country: Germany
facility: Praxis für Haematologie und Onkologie
city: Koblenz
country: Germany
facility: MVZ Hämatologie Onkologie Koblenz
city: Köln
country: Germany
facility: Universitätsklinik Köln
city: Landshut
country: Germany
facility: H.O.T Onkologie Praxis Landshut
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Leipzig
country: Germany
facility: Onkopraxis Probstheida
city: Lemgo
country: Germany
facility: Klinikum Lippe Lemgo
city: Limburg
country: Germany
facility: St Vincenz Krankenhaus
city: Lübeck
country: Germany
facility: Lübecker Onkologische Schwerpunktpraxis
city: Magdeburg
country: Germany
facility: Gemeinschaftspraxis Haematologie und Onkologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mannheim
country: Germany
facility: Mannheimer Onkologie Praxis
city: Marburg
country: Germany
facility: Praxis für Innere Medizin - Hämatologie und Onkologie
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf
city: München
country: Germany
facility: München Klinik Schwabing
city: München
country: Germany
facility: Klinikum der Universitaet München - Grosshadern Campus
city: München
country: Germany
facility: Klinikum rechts der Isar - Technische Universitaet Muenchen
city: Münster
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Ravensburg
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Regensburg
country: Germany
facility: Barmherzigen Brüder Krankenhaus
city: Regensburg
country: Germany
facility: Schwerpunktpraxis für Hämatologie & Onkologie - OncoPro GbR
city: Rostock
country: Germany
facility: Universitätsklinik Rostock
city: Saarbrücken
country: Germany
facility: OnkoSaar Praxis für Hämatologie und Onkologie
city: Siegburg
country: Germany
facility: Zentrum für abulante Hämatologie und Onkologie
city: Stuttgart
country: Germany
facility: Marienhospital Stuttgart
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Weiden
country: Germany
facility: MVZ Weiden GmbH
city: Würzburg
country: Germany
facility: Hämatologisch Onkologische Schwerpunktpraxis
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: St Vincents University Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: St. James's Hospital
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Limerick
country: Ireland
facility: University Hospital Limerick
city: Waterford
country: Ireland
facility: University Hospital Waterford
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Center
city: Be'er Ya'aqov
country: Israel
facility: Shamir Medical Center Assaf Harofeh
city: Haifa
country: Israel
facility: Bnai-Zion Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center Ein Kerem University Hospital
city: Kfar-Saba
country: Israel
facility: Meir Medical Center
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Petach-Tikva
country: Israel
facility: Rabin Medical Center Beilinson Hospital
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Rechovot
country: Israel
facility: Kaplan Medical Center
city: Tel-Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele
city: Ferrara
country: Italy
facility: Azienda Ospedaliero Universitaria di Ferrara
city: Mestre
country: Italy
facility: Ospedale dell'Angelo
city: Milano
country: Italy
facility: Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Perugia
country: Italy
facility: Ospedale S. Maria della Misericordia
city: Roma
country: Italy
facility: Umberto I - Policlinico di Roma - Sapienza Università
city: Roma
country: Italy
facility: Gmelli University Hospital
city: Torino
country: Italy
facility: Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino
city: Alkmaar
country: Netherlands
facility: Nordwest Ziekenhuisgroep, Locatie Alkmaar
city: Amsterdam
country: Netherlands
facility: OLVG Amsterdam
city: Amsterdam
country: Netherlands
facility: Amsterdam Universitair Medische Centra
city: Arnhem
country: Netherlands
facility: Rijnstate, Locatie Arnhem
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St Jansdal
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiderdorp
country: Netherlands
facility: Alrijne Ziekenhuis
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: s-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Schiedam
country: Netherlands
facility: Franciscus Vlietland
city: Tiel
country: Netherlands
facility: Ziekenhuis Rivierenland Tiel
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Venlo
country: Netherlands
facility: VieCuri Medish Centrum
city: Zwolle
country: Netherlands
facility: Isala Zwolle
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Lørenskog
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Trondheim
country: Norway
facility: St. Olavs Hospital Trondheim University Hospital
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: Hospital Costa del Sol
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Marques de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de Valme
city: Valencia
country: Spain
facility: Hospital Clinico Universitario Valencia
city: Valencia
country: Spain
facility: Residencia Sanitaria La Fe - Valencia
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa
city: Borås
country: Sweden
facility: Soedra Aelvsborgs Sjukhus
city: Falun
country: Sweden
facility: Falu Lasarett
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Halmstad
country: Sweden
facility: Hallands Sjukhus Halmstad
city: Linköping
country: Sweden
facility: Universitetssjukhuset Linköping
city: Luleå
country: Sweden
facility: Sunderby Hospital
city: Lund
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Solna
city: Umeå
country: Sweden
facility: Umeå University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Varberg
country: Sweden
facility: Hallands Sjukhus
city: Örebro
country: Sweden
facility: Örebro University Hospital
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Brig
country: Switzerland
facility: Spitalzentrum Oberwallis
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Fribourg
country: Switzerland
facility: HFR Fribourg Hôpital cantonal
city: Geneve
country: Switzerland
facility: Hôpitaux Universitaires Genève
city: Liestal
country: Switzerland
facility: Kantonsspital Baselland
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Münsterlingen
country: Switzerland
facility: Spital Thurgau AG - Kantonsspital Münsterlingen
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: St Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Thun
country: Switzerland
facility: Spital Thun
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: Stadtspital Triemli
city: Zürich
country: Switzerland
facility: Universitätsspital Zuerich
Study officials:
affiliation: German CLL Study Group
name: Othman Al-Sawaf, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References: