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

Chronic Lymphoid Leukemia Clinical Trial

— CLL17  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04608318
• Other study ID #: CLL17
• Secondary ID: 2019-003854-99
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 1, 2021
• Est. completion date: March 2027

Study information

• Verified date: March 2024
• Source: German CLL Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 897
• Est. completion date: March 2027
• Est. primary completion date: March 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Lymphoid Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

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

Locations

Country	Name	City	State
Austria	LKH-Universtitätsklinikum Graz	Graz
Austria	Landeskrankenhaus - Universitätskliniken Innsbruck	Innsbruck
Austria	Hanusch Krankenhaus	Wien
Austria	Medizinische Universität Wien	Wien
Austria	Wiener Gesundheitsverbund Klinik Ottakring	Wien
Belgium	Algemeen Ziekenhuis St. Jan	Brugge
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	Algemeen Ziekenhuis Delta	Roeselare
Denmark	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
Finland	Helsinki University Hospital	Helsinki
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku
Germany	Universitätsklinikum Augsburg	Augsburg
Germany	Charite Universitaetsmedizin - Campus Benjamin Franklin	Berlin
Germany	Charite Universitätsmedizin - Campus Virchow Klinikum	Berlin
Germany	Helios Klinikum Berlin Buch	Berlin
Germany	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin
Germany	Ev. Diakoniekrankenhaus	Bremen
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
Germany	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Uniklinikum Gießen und Marburg	Gießen
Germany	MVZ Onkologische Kooperation Harz	Goslar
Germany	OncoResearch Lerchenfeld	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Evangelische Krankenhaus Hamm	Hamm
Germany	Onkologisches Ambulanzzentrum - MediProjekt	Hannover
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	MVZ Hämatologie Onkologie Koblenz	Koblenz
Germany	Praxis für Haematologie und Onkologie	Koblenz
Germany	Universitätsklinik Köln	Köln
Germany	H.O.T Onkologie Praxis Landshut	Landshut
Germany	Onkopraxis Probstheida	Leipzig
Germany	Universitätsklinikum Leipzig	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	Klinikum der Universitaet München - Grosshadern Campus	München
Germany	Klinikum rechts der Isar - Technische Universitaet Muenchen	München
Germany	München Klinik Schwabing	München
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie	Münster
Germany	Stauferklinikum Schwäbisch Gmünd	Mutlangen
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
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	St Vincents University Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	University Hospital Galway	Galway
Ireland	University Hospital Limerick	Limerick
Ireland	University Hospital Waterford	Waterford
Israel	Soroka University Medical Center	Be'er Sheva
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	Petach-Tikva
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Kaplan Medical Center	Rechovot
Israel	Tel Aviv Sourasky Medical Center	Tel-Aviv
Italy	Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele	Catania
Italy	Azienda Ospedaliero Universitaria di Ferrara	Ferrara
Italy	Ospedale dell'Angelo	Mestre
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico	Milano
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	Ospedale S. Maria della Misericordia	Perugia
Italy	Gmelli University Hospital	Roma
Italy	Umberto I - Policlinico di Roma - Sapienza Università	Roma
Italy	Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino	Torino
Netherlands	Nordwest Ziekenhuisgroep, Locatie Alkmaar	Alkmaar
Netherlands	Amsterdam Universitair Medische Centra	Amsterdam
Netherlands	OLVG Amsterdam	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	Jeroen Bosch Ziekenhuis	s-Hertogenbosch
Netherlands	Franciscus Vlietland	Schiedam
Netherlands	Ziekenhuis Rivierenland Tiel	Tiel
Netherlands	Diakonessenhuis	Utrecht
Netherlands	VieCuri Medish Centrum	Venlo
Netherlands	Isala Zwolle	Zwolle
Norway	Haukeland University Hospital	Bergen
Norway	Akershus University Hospital	Lørenskog
Norway	Oslo University Hospital	Oslo
Norway	St. Olavs Hospital Trondheim University Hospital	Trondheim
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Duran i Reynals	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Infanta Leonor	Madrid
Spain	Hospital Universitario La Princesa	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	Sevilla
Spain	Hospital Clinico Universitario Valencia	Valencia
Spain	Residencia Sanitaria La Fe - Valencia	Valencia
Spain	Hospital Clinico Universitario Lozano Blesa	Zaragoza
Sweden	Soedra Aelvsborgs Sjukhus	Borås
Sweden	Falu Lasarett	Falun
Sweden	Sahlgrenska University Hospital	Göteborg
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
Switzerland	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	Geneve
Switzerland	Kantonsspital Baselland	Liestal
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Spital Thurgau AG - Kantonsspital Münsterlingen	Münsterlingen
Switzerland	Kantonsspital Olten	Olten
Switzerland	Kantonsspital St. Gallen	St Gallen
Switzerland	Spital Thun	Thun
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	Stadtspital Triemli	Zürich
Switzerland	Universitätsspital Zuerich	Zürich

Sponsors (8)

Lead Sponsor	Collaborator
German CLL Study Group	Cancer Trials Ireland, Grupo Español de Leucemia Linfocítica Crónica (GELLC), Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), Nordic CLL Study Group (NCLLSG), Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON), Swiss Group for Clinical Cancer Research (SAKK), The Israeli CLL Study Group (ICLLSG)

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Investigator-assessed progression-free survival (PFS)	Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first	Up to 80 month
Secondary	Rates of undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM)	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.	At final restaging (RE): 18 months after start of treatment and additional BM assessment approx. 12 months after RE
Secondary	MRD levels in PB at different time points	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)	Up to 80 month
Secondary	Overall response rate (ORR)	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.	At final restaging (RE): 18 months after start of treatment
Secondary	CR/CRi rate	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)	At final restaging (RE): 18 months after start of treatment
Secondary	Incidence of safety parameters such as adverse events (AE) and adverse events of particular/special interest (AEPI/AESI)	Type, frequency, severity and relationship to study treatment.of AEs and AEPIs/AESIs	Up to 80 month

External Links

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