Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05197192 |
| Other study ID # |
CLL16 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
April 19, 2022 |
| Est. completion date |
February 2027 |
Study information
| Verified date |
March 2024 |
| Source |
German CLL Study Group |
| Contact |
Barbara Eichhorst, MD, Prof. |
| Phone |
+4922147888220 |
| Email |
barbara.eichhorst[@]uk-koeln.de |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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).
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).
