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JOURNAL ONKOLOGIE – STUDIE

A Phase-3-trial of Acalabrutinib, Obinutuzumab & Venetoclax Compared to Obinutuzumab and Venetoclax in Previously Untreated Patients With High Risk CLL

Rekrutierend

NCT-Nummer:
NCT05197192

Studienbeginn:
April 2022

Letztes Update:
25.03.2024

Wirkstoff:
Obinutuzumab, Venetoclax, Acalabrutinib

Indikation (Clinical Trials):
Leukemia, Leukemia, Lymphocytic, Chronic, B-Cell

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
German CLL Study Group

Collaborator:
AstraZeneca

Studienleiter

Barbara Eichhorst, MD, Prof.
Principal Investigator
Department I of Internal Medicine, University Hospital Cologne

Kontakt

Studienlocations
(3 von 30)

Alle anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Progression-free survival (PFS) (Time Frame - 50 months after FPI):
The study is designed to demonstrate that 14 cycles of treatment with GAVe followed by up to 10 cycles maintenance with acalabrutinib for patients with detectable MRD at cycle 14 day 14 prolong PFS as compared to 12 cycles of treatment with GVe in patients with high risk CLL (defined as hav-ing at least one of the following risk factors: 17p-deletion, TP53- mutation or complex karyotype).



Secondary outcome:

1. Minimal residual disease (MRD) levels (Time Frame - 50 months after FPI):
Minimal residual disease (MRD) levels in the peripheral blood (PB) and in the bone marrow (BM) at final restaging ((Staging 5) cycle 15 day 1 for patients in GVe study arm, cycle 14 day 14 for patients in GAVe study arm)

2. MRD in PB at cycle 27 day 1 (Time Frame - 50 months after FPI):
MRD in PB at cycle 27 day 1 for all patients (end of maintenance for patients in GAVe study arm, who had detectable MRD levels after 14 cycles of GAVe-treatment)

3. Overall response rate (Time Frame - 50 months after FPI):
Overall response rate (ORR; as per iwCLL guidelines) at cycle 15

4. Complete response rate (Time Frame - 50 months after FPI):
Complete response rate (CRR; as per iwCLL guidelines) at cycle 15

5. Overall Survival (OS) (Time Frame - 50 months after FPI):
Overall Survival (OS)

6. Event-free survival (EFS) (Time Frame - 50 months after FPI):
Event-free survival (EFS)

7. Duration of response (DOR) (Time Frame - 50 months after FPI):
Duration of response (DOR)

8. Time to next treatment (TTNT) (Time Frame - 50 months after FPI):
Time to next treatment (TTNT)

Studien-Arme

  • Experimental: GAVe-Arm
    Acalabrutinib plus Venetoclax plus Obinutuzumab plus (GAVe)
  • Experimental: GVe-Arm
    Obinutuzumab plus Venetoclax (GVe)

Geprüfte Regime

  • Obinutuzumab (Gazyva / Gazyvaro / ):
    Obinutuzumab i.v. infusion: Cycle 1 Day 1: Obinutuzumab 100 mg i.v. Cycle 1 Day 1 (or 2): Obinutuzumab 900 mg i.v. Cycle 1 Day 8: Obinutuzumab 1000 mg i.v. Cycle 1 Day 15: Obinutuzumab 1000 mg i.v. Cycles 2-6: Day 1: Obinutuzumab 1000 mg i.v.
  • Venetoclax (Venclexta / Venclyxto / ):
    Venetoclax p.o.: Cycle 1: Days 22-28: Venetoclax 20 mg (2 x 10 mg) Cycle 2: Days 1-7: Venetoclax 50 mg (1 x 50 mg) Cycle 2:Days 8-14: Venetoclax 100 mg (1 x 100 mg) Cycle 2:Days: 15-21: Venetoclax 200 mg (2 x 100 mg) Cycle 2:Days: 22-28: Venetoclax 400 mg (4 x 100 mg) Cycles 3-12: Days 1-28: Venetoclax 400 mg (4 x 100 mg)
  • Acalabrutinib (Calquence):
    Cycles 15-24: Days 1-28: 100 mg acalabrutinib twice daily p.o. approx. every 12 hrs (corresponding to a total daily dose of 200 mg).

Quelle: ClinicalTrials.gov


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