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

Chronic Lymphocytic Leukemia Clinical Trial

— GAIA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02950051
• Other study ID #: CLL13
• Secondary ID: 2015-004936-36
• Status: Completed
• Phase: Phase 3
• Start date: December 13, 2016
• Est. completion date: February 29, 2024

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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 926
• Est. completion date: February 29, 2024
• Est. primary completion date: February 29, 2024
• 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 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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Fludarabine
Fludarabine i.v.: cycles 1-6: 25 mg/m², d1-3, q28d
• Cyclophosphamide
Cyclophosphamide i.v.: cycles 1-6: 250 mg/m², d1-3, q28d

Biological:
• Rituximab
Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1; q28d

Drug:
• Bendamustine
Bendamustine i.v.: cycles 1-6: 90mg/m², d1-2, q28d
• 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

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

Drug:
• Ibrutinib
Ibrutinib p.o. cycles 1-12: 420 mg, d1-28, q28d cycles 13-36: 420 mg, d1-28, q28d

Locations

Country	Name	City	State
Austria	Hanusch Hospital	Wien
Austria	Medizinische Universitaet Wien	Wien
Austria	Wilhelminenspital	Wien
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	Algemeen Ziekenhuis St. Jan	Brugge
Belgium	Jan Yperman Ziekenhuis	Ieper
Belgium	UZ Gasthuisberg	Leuven
Belgium	AZ Delta	Roeselare
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet/Copenhagen	Copenhagen
Denmark	Sydvestjysk Sygehus Esbjerg	Esbjerg
Denmark	University Hospital Herlev	Herlev
Denmark	Regionshospitalet Holstebro	Holstebro
Denmark	Odense Universitets Hospital	Odense
Denmark	Sjællands Universitetshospital	Roskilde
Denmark	Vejle Hospital	Vejle
Finland	Helsinki University Hospital	Helsinki
Finland	Jyväskylä Central Hospital	Jyväskylä
Finland	Oulu University Hospital	Oulu
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku
Germany	Gesundheitszentrum Klinikum St Marien	Amberg
Germany	Helios-Klinikum Berlin	Berlin
Germany	Onkologische Schwerpunktpraxis Kurfürstendamm	Berlin
Germany	ZAHO Bonn	Bonn
Germany	Ev. Diakonie-Krankenhaus gemeinnuetzige GmbH	Bremen
Germany	Gefos Dortmund mbH	Dortmund
Germany	St. -Johannes-Hospital Dortmund	Dortmund
Germany	BAG Dresden	Dresden
Germany	Universitaetsklinik Carl Gustav Carus	Dresden
Germany	Marien Hospital Düsseldorf GmbH	Düsseldorf
Germany	St. Georg Klinikum Eisenach GmbH	Eisenach
Germany	Helios Klinikum Erfurt	Erfurt
Germany	St. Antonius-Hospital	Eschweiler
Germany	Universitaetsklinikum Essen	Essen
Germany	Centrum fuer Haematologie und Onkologie Bethanien	Frankfurt
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	MVZ Onkologische Kooperation Harz, Drs. Tessen/Hoyer/Zahn	Goslar
Germany	Onkologische Schwerpunktpraxis Göttingen	Göttingen
Germany	Universitaetsmedizin Göttingen	Göttingen
Germany	Universitaetsmedizin Greifswald	Greifswald
Germany	OncoResearch Lerchenfeld GmbH	Hamburg
Germany	UKE Hamburg	Hamburg
Germany	EVK Hamm	Hamm
Germany	MediProjekt GBR	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitaetsklinikum Heidelberg	Heidelberg
Germany	Marienhospital Herne	Herne
Germany	Onkologische Schwerpunktpraxis Des. Freier/Sievers, Hildesheim	Hildesheim
Germany	Universitaetsklinikum Jena	Jena
Germany	Westpfalz-Klinikum GmbH	Kaiserslautern
Germany	Städt. Klinikum Karlsruhe	Karlsruhe
Germany	Dres. Siehl / Soeling, Fachaerzte fuer Haematologie und Internistische Onkologie, Kassel	Kassel
Germany	Universitaetsklinikum Schleswig-Holstein Campus Kiel	Kiel
Germany	InVO-Institut fuer Versorgungsforschung in der Onkologie GbR	Koblenz
Germany	University Hospital of Cologne	Köln
Germany	Tagesklinik Landshut, Dr. Vehling-Kaiser	Landshut
Germany	Gemeinschaftspraxis Haemato/ Onkologie Lebach	Lebach
Germany	Onkologische Schwerpunktpraxis Dr. Mueller, Leer	Leer
Germany	Klinikum Lippe GmbH	Lemgo
Germany	Gemeinschaftspraxis Haematologie und Onkologie	Magdeburg
Germany	Universitaetsklinikum Magdeburg	Magdeburg
Germany	Universitaetsklinik Mainz	Mainz
Germany	Mannheimer Onkologie Praxis	Mannheim
Germany	Institut fuer Versorgungsforschung Dr. med. M. Maasberger/ M. Schmitz/ Dr. med. M. T. Keller	Mayen
Germany	Kliniken Maria Hilf GmbH	Mönchengladbach
Germany	Klinikum rechts der Isar	München
Germany	Klinikum Schwabing	München
Germany	Ludwig-Maximilians-Universitaet Muenchen	München
Germany	MVZ MOP Elisenhof	München
Germany	Stauferklinikum Schwaebisch-Gmuend	Mutlangen
Germany	Haematologische/Onkologische Praxis Neunkirchen	Neunkirchen
Germany	Studiengesellschaft Onkologie Rhein Ruhr	Oberhausen
Germany	Gemeinschaftspraxis Dres. Ballo/Boeck	Offenbach
Germany	Klinik fuer Haematologie und Onkologie	Paderborn
Germany	Studienzentrum Onkologie Ravensburg	Ravensburg
Germany	Krankenhaus der Barmherzigen Brüder	Regensburg
Germany	OncoPro GbR	Regensburg
Germany	Universitätsmedizin Rostock	Rostock
Germany	Praxis für Hämatologie und Onkologie Dres. Jacobs/Daus/Schmits	Saarbrücken
Germany	Leopoldina-Krankenhaus	Schweinfurt
Germany	ZAHO-Rheinland	Siegburg
Germany	Marienhospital Stuttgart	Stuttgart
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Germany	Universitaetsklinikum Tuebingen	Tübingen
Germany	Universitaetsklinikum Ulm	Ulm
Germany	MVZ Weiden GmbH	Weiden
Germany	Haematologisch-Onkologische Schwerpunktpraxis Dres. Perker/Sandherr, Weilheim	Weilheim
Germany	Helios Klinikum Wuppertal	Wuppertal
Germany	Gemeinschaftspraxis Dr. Schlag/Dr. Schoettker	Würzburg
Germany	Universitaetsklinik Wuerzburg	Würzburg
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	Mater Misericordiae Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	University Hospital Galway	Galway
Ireland	University Hospital Waterford	Waterford
Israel	Bnai-Zion Medical. Il-Haifa	Haifa
Israel	Hadassah Ein Kerem	Jerusalem
Israel	Meir Medicail Center	Kfar-Saba
Israel	Rabin medical Center	Petach-Tikva
Israel	Kaplan Medical Center	Rechovot
Israel	Souraski Tel-Aviv Medical Center	Tel-Aviv
Netherlands	MC Alkmaar	Alkmaar
Netherlands	Meander Medisch Centrum, Amersfoort	Amersfoort
Netherlands	NL-Amsterdam-AMC	Amsterdam
Netherlands	VUmc, Amsterdam	Amsterdam
Netherlands	Ziekenhuis Rijnstate	Arnhem
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	IJsselland Ziekenhuis	Capelle aan den Ijssel
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	Deventer ziekenhuizen	Deventer
Netherlands	Albert Schweitzer Ziekenhuis, Dordrecht	Dordrecht
Netherlands	Gelderse Vallei	Ede
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	UMCG	Groningen
Netherlands	Ziekenhuisgroep Twente Hengelo	Hengelo
Netherlands	Tergooi Ziekenhuis	Hilversum
Netherlands	Spaarne Ziekenhuis	Hoofddorp
Netherlands	Medisch Centrum Leeuwarden Zuid	Leeuwarden
Netherlands	Leids Universitair Medisch Centrum	Leiden
Netherlands	Maastricht university medial Center	Maastricht
Netherlands	St. Antonius Ziekehuis	Nieuwegein
Netherlands	Canisius-Wilhelmina ZH	Nijmegen
Netherlands	Radboud UMC	Nijmegen
Netherlands	Maasstadziekenhuis	Rotterdam
Netherlands	Jeroen Bosch Ziekenhuis	s-Hertogenbosch
Netherlands	Antonius Ziekenhuis Sneek	Sneek
Netherlands	ZorgSaam Zeeuws Vlaanderen	Terneuzen
Netherlands	St. Elisabeth ZH	Tilburg
Netherlands	UMCU	Utrecht
Netherlands	VieCuri loc. Venlo	Venlo
Netherlands	Zaans Medisch Centrum	Zaandam
Netherlands	Isala	Zwolle
Sweden	Soedra Aelvsborgs Sjukhus	Borås
Sweden	Falu lasarett	Falun
Sweden	Hallands hospital - Halmstad	Halmstad
Sweden	Universitetsjukhuset i Linkoeping	Linköping
Sweden	Sunderby Hospital	Luleå
Sweden	Skane University Hospital Lund	Lund
Sweden	Universitetssjukhuset i Oerebro	Örebro
Sweden	Akademiska Sjukhuset	Uppsala
Sweden	Hallands hospital - Varberg	Varberg
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Kantonsspital Baden	Baden
Switzerland	Universitaetsspital Basel	Basel
Switzerland	IOSI, Ospedale Regionale Bellinzona e Valli	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Kantonsspital Graubunden	Chur
Switzerland	Universitaire de Geneve	Genève
Switzerland	KSBL Liestal	Liestal
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Spital Thurgau AG	Münsterlingen
Switzerland	Kantonsspital Olten	Olten
Switzerland	Kantonsspital St. Gallen	St Gallen
Switzerland	KS Winterthur	Winterthur
Switzerland	Stadtspital Triemli	Zürich
Switzerland	Universitaetsspital Zuerich	Zürich

Sponsors (9)

Lead Sponsor	Collaborator
German CLL Study Group	AbbVie, Cancer Trials Ireland, Hoffmann-La Roche, Israeli CLL Study Group, Janssen-Cilag Ltd., Nordic CLL Study Group (NCLLSG), Stichting Hemato-Oncologie voor Volwassenen Nederland, Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

Austria,  Belgium,  Denmark,  Finland,  Germany,  Ireland,  Israel,  Netherlands,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	MRD levels in PB		Month 2, 9, 13 and later time points according to the discretion of the treating physician at local laboratories
Secondary	MRD levels in bone marrow (BM)		at final restaging (RE): 2 month after the end of the last treatment cycle
Secondary	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)
Secondary	Overall response rate (ORR)		Month 3, 9, 13 and 15
Secondary	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

External Links

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