Clinical trial NCT05197192: A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients With High Risk CLL
Official title: A Prospective, Open-label, Multicentre, Randomized, Phase-3-trial of Acalabrutinib, Obinutuzumab and Venetoclax (GAVE) Compared to Obinutuzumab and Venetoclax (GVE) in Previously Untreated Patients With High Risk (17P-deletion, TP53-mutation or Complex Karyotype) Chronic Lymphatic Leukemia (CLL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2022-01-19
Enrollment: 650
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This multicenter, prospective, open-label, randomized, superiority phase 3 study is designed to demonstrate that treatment with a triple combination of acalabrutinib, obinutuzumab and venetoclax (GAVe) prolong the progression-free survival (PFS) as compared to treatment with the combination of obinutuzumab and venetoclax (GVe) in pa-tients with high risk CLL (defined as having at least one of the follow-ing risk factors: 17p-deletion, TP53-mutation or complex karyotype).

Detailed description: CLL is the most frequent leukemia in industrialized countries. International guidelines agree on diagnosis and management of this disease. The clinical course of CLL is highly variable and can be predicted by clinical staging (according to Rai and Binet) as well as genetic, serum markers and risk models. This study is designed for a randomized comparison of two different, non-chemotherapeutic and fixed-duration modalities for patients with high risk chronic lymphocytic leukemia (CLL) and addresses a high medical need, since high risk-CLL represents a so far incurable, aggressive cancer. The high risk-group of CLL patients can be identified by molecular characteristics, allowing the inclusion of a clearly described group of patients: 17p-deletion, TP53-mutation and/or complex karyotype.TP53 defects are the strongest prognostic factors for non-response to chemotherapy. Patients harboring TP53 defects should be treated with chemotherapy-free regimens. Complex karyotype (CKT), defined as the presence of three or more chromosomal aberrations in two or more metaphases is associated with a poorer outcome in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). In CLL, CKT is one of several well established adverse prognostic factors, comparable to 17p-deletion, TP53-mutation or unmutated IGHV status. Depending on age and prior exposure to chemotherapy, 10-30% of patients with CLL exhibit CKT. A broad body of evidence has suggested a predictive prognostic value of CKT. Despite considerable advances with chemoimmunotherapy in the treatment of frontline as well as relapsed/refractory (r/r) CLL, outcome of patients with CKT remains poor. To date, a randomized comparison to optimize the treatment of patients with high risk disease defined as either the presence of TP53 aberrations or CKT, by novel agents has not been performed. Patients with high risk CLL (TP53-defects and/or CKT) have a poor outcome with chemoimmunotherapy and do not benefit to the same extent from approved regimen such as continuous treatment of ibrutinib or 12 months treatment with obinutuzumab plus venetoclax. Monotherapy with BTK-inhibitor is less effective in those patients as compared with patients without high risk disease. Venetoclax combined with the anti-CD20 monoclonal antibody obinutuzumab offers a highly effective fixed-duration treatment option with a manageable toxicity profile. The recent results of the CLL14 study define a new standard of a fixed 12-months treatment with obinutuzumab and venetoclax in previously untreated patients yielding a major benefit also for patients with high risk disease as compared to chemoimmunotherapy. However, high risk patients appear to progress earlier than low risk patients and the therapy is not clearly curative so far. Acalabrutinib is a second generation, selective BTK inhibitor which has shown promising overall response rates in patients with relapsed CLL or patients intolerant to ibrutinib. The development of acalabrutinib focussed on minimization of off-target activity. Results of a three-arm study investigating the combination of acalabrutinib plus obinutuzumab versus acalabrutinib alone versus chlorambucil plus obinutuzumab (NCT02475681) showed a substantial improvement of PFS for the combination arm and the monotherapy versus the standard chemoimmunotherapy regimen. The addition of a BTK-inhibitor, such as acalabrutinib to obinutuzumab and venetoclax has the potential to result in a better outcome, because synergistic effects have been reported between BTK inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors or for BCL-2 inhibitors and monoclonal antibodies. Synergistic effects, which are expected to reduce early progressions or insufficient responses, are in particular important for this high risk population. The triple combination of acalabrutinib, obinutuzumab (or rituximab) and venetoclax has been investigated in a phase 1 b- study and had a tolerable safety profile with minimal to no drug-drug interactions, results of a phase 2 trial studying the same combination showed that the triple combination was highly active with 78% undetectable MRD levels in the bone marrow . Currently, the GCLLSG conducts phase 2 studies, investigating a triple combination consisting of BTK- and Bcl2-inhibitors and monoclonal antibodies (CLL2GIVe: NCT02758665; CLL2BAAG: NCT03787264) and a large phase 3 trial with one experimental arm with a triple combination (CLL13, NCT02950051) but results are not yet published. Acalabrutinib, venetoclax and obinutuzumab is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) against the current standard of chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR) in patients without 17p-deletion or TP53-mutation. Acalabrutinib is indicated in Germany as monotherapy or in combination with obinutuzumab for the treatment of adult patients with treatment-naive chronic lymphocytic leukemia (CLL) and as monotherapy for the treatment of adult patients with relapsed chronic lymphocytic leukemia (CLL).

Eligibility criteria: Inclusion Criteria:

* Documented CLL/SLL requiring treatment according to iwCLL criteria
* Age at least 18 years
* At least one of the following risk factors: 17p-deletion, TP53-mutation or complex karyotype (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases.).
* Life expectancy ≥ six months
* Adequate bone marrow function indicated by a platelet count \>30 x10\^9/l
* Creatinine clearance ≥ 30ml/min
* 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
* Negative 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),or hepatitis C (negative testing for hepatitis C RNA within 6 wee
* ks prior to registration for study screening (i.e. PCR only required when serology was positive))
* ECOG (Eastern Cooperative Oncology Group Performance Status) status 0-2

Exclusion Criteria:

* 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)
* Absence of high risk disease (17p-deletion, TP53-mutation complex karyotype
* An individual organ/system impairment score of 4 as assessed by the CIRS definition (e.g. advanced cardiac disease (NYHA class 3 or 4) 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)
* Transformation of CLL (Richter transformation)
* Malignancies other than CLL currently requiring systemic therapies
* Uncontrolled or active infection of HIV/PML or any other active infection
* Anticoagulant therapy with warfarin or phenoprocoumon
* Pregnant women and nursing mothers

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 50 months after FPI
Secondary outcomes:
measure: Minimal residual disease (MRD) levels
timeFrame: 50 months after FPI
measure: MRD in PB at cycle 27 day 1
timeFrame: 50 months after FPI
measure: Overall response rate
timeFrame: 50 months after FPI
measure: Complete response rate
timeFrame: 50 months after FPI
measure: Overall Survival (OS)
timeFrame: 50 months after FPI
measure: Event-free survival (EFS)
timeFrame: 50 months after FPI
measure: Duration of response (DOR)
timeFrame: 50 months after FPI
measure: Time to next treatment (TTNT)
timeFrame: 50 months after FPI
Other outcomes:
measure: Correlation between MRD in PB/BM and PFS/OS
timeFrame: 50 months after FPI
measure: MRD by methods other than flow cytometry (ddPCR)
timeFrame: 50 months after FPI
measure: Correlation between MRD in PB and BM
timeFrame: 50 months after FPI
measure: Longitudinal Analysis of European Organisation for Research and Treatment of Cancer(EORTC): Quality of Life Questionnaire (QLQ-C30) at defined timepoints
timeFrame: 50 months after FPI
Locations:
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Berlin
country: Germany
facility: DRK Kliniken Berlin Köpenick
city: Bremen
country: Germany
facility: Ev. Diakoniekrankenhaus
city: Dortmund
country: Germany
facility: St. Johannes Hospital
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Eschweiler
country: Germany
facility: St. Antonius-Hospital
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Hagen
country: Germany
facility: Katholisches Krankenhaus Hagen - St. Josefs Hospital
city: Homburg
country: Germany
facility: Universitaetskliniken des Saarlandes
city: Idar-Oberstein
country: Germany
facility: Klinikum Idar-Oberstein SHG
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein Campus Kiel
city: Köln
country: Germany
facility: Universitätsklinik Köln
city: Landshut
country: Germany
facility: Klinikum Landshut
city: Lemgo
country: Germany
facility: Klinikum Lippe-Lemgo
city: Limburg
country: Germany
facility: St Vincenz Krankenhaus
city: Magdeburg
country: Germany
facility: Universitaetsklinikum Magdeburg
city: Meschede
country: Germany
facility: Klinikum Hochsauerland - St. Walburga Krankenhaus
city: Munich
country: Germany
facility: Krankenhaus Muenchen-Schwabing
city: Munich
country: Germany
facility: Klinikum Rechts der Isar - Technische Universitaet Muenchen
city: Mutlangen
country: Germany
facility: Kliniken Ostalb, Stauferklinikum Schwäbisch Gmünd
city: Mönchengladbach
country: Germany
facility: KH Kliniken Maria Hilf
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Rostock
country: Germany
facility: Universitätsklinik Rostock
city: Saarbrucken
country: Germany
facility: Caritas-Klinik St. Theresia
city: Sindelfingen
country: Germany
facility: Klinikum Sindelfingen-Böbingen
city: Stuttgart
country: Germany
facility: Marienhospital Stuttgart
city: Tübingen
country: Germany
facility: Universitaetsklinik Tuebingen
city: Ulm
country: Germany
facility: Universitätsklinik Ulm
Study officials:
affiliation: Department I of Internal Medicine, University Hospital Cologne
name: Barbara Eichhorst, MD, Prof.
role: PRINCIPAL_INVESTIGATOR
References: