Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101) Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL

  • STATUS
    Recruiting
  • End date
    Sep 25, 2025
  • participants needed
    40
  • sponsor
    German CLL Study Group
Updated on 25 January 2021
platelet count
corticosteroids
lymphoid leukemia
anemia
chronic lymphocytic leukemia
gilbert's syndrome
venetoclax
neutrophil count
ibrutinib
bendamustine
btk inhibitor
hepatitis b core antibody
chronic lymphocytic leukemia refractory
obinutuzumab
constitutional symptoms
abt-199

Summary

CLL2-BZAG is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by obinutuzumab (GA101), zanubrutinib (BGB-3111) and venetoclax (ABT-199) in patients with relapsed/refractory CLL.

Description

In the CLL2-BZAG trial will be included a total of 40 patients with relapsed or refractory CLL in need of treatment. This trial will evaluate a debulking with two cycles bendamustine (only for patients with a high tumor load), followed by an induction and maintenance treatment with obinutuzumab, zanubrutinib and venetoclax in patients with relapsed/refractory CLL. Thus, this trial combines one established (chemotherapy) and three novel, synergistic (antibody, Bruton's tyrosine kinase(BTK)-inhibitor and Bcl-2 antagonist) principles of action in order to achieve deep and long lasting remissions with a short duration of treatment. Additionally, this trial has an extensive accompanying scientific program aiming at a better understanding of the kinetics of response and clonal evolution of CLL.

Details
Condition Chronic Lymphocytic Leukemia, Lymphocytic Leukemia, Chronic, leukemia chronic lymphocytic, chronic lymphocytic leukemia (cll), small lymphocytic lymphoma
Treatment Obinutuzumab, Bendamustine, venetoclax, Zanubrutinib
Clinical Study IdentifierNCT04515238
SponsorGerman CLL Study Group
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Relapsed/refractory CLL in need of treatment according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
In case of a recent previous treatment, patients must have recovered from
acute toxicities and treatment regimen must be stopped within the following
time periods before start of the study treatment in the CLL2-BZAG trial
chemotherapy 28 days
antibody treatment 14 days
kinase inhibitors, BCL2-antagonists or immunomodulatory agents 3 days
corticosteroids may be applied until the start of the BZAG-regimen, these have to be reduced to an equivalent of 20mg prednisolone per day during treatment Please note: Patients with a progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due to intolerance to ibrutinib are eligible for participation. 2. Adequate renal function, as indicated by a creatinine clearance 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection 3. Adequate hematologic function as indicated by a neutrophil count 1.0 x 109/L, a hemoglobin value 8.0 g/dL and a platelet count 25 x 109/L, unless directly attributable to the patients CLL (e.g. bone marrow infiltration), in this case, platelet count should be 10 109/L. 4. Adequate liver function as indicated by a total bilirubin 2x, AST/ALT 2.5x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome 5. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for Hepatitis B Virus (HBV) DNA is negative and HBV-DNA PCR is performed every 4 weeks until one year after last dosage of GA101 (obinutuzumab) or until the last dose of zanubrutinib, whichever occurs later), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration 6. Age 18 years 7. Eastern Cooperative Oncology Group Performance Status (ECOG) 0 - 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms) 8. Life expectancy 6 months 9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria

(Suspicion of) transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Brutons Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
Confirmed progressive multifocal leukoencephalopathy (PML)
Malignancies other than CLL currently requiring systemic therapies
Uncontrolled infection requiring systemic treatment
Any comorbidity or organ system impairment rated with a Cumulative Illness Rating Scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that
in the investigators 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)
Significantly increased risk of bleeding according to the investigators evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandts disease or hemophilia), major surgical procedure 4 weeks or stroke/intracranial hemorrhage 6 months
Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
Use of investigational agents 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in accordance with inclusion criterion number 1 (see above)
Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), zanubrutinib (BGB-3111) or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment)
Fertile men or women of childbearing potential unless
surgically sterile or 2 years after the onset of menopause, or
willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment
Vaccination with a live vaccine 28 days prior to registration
Legal incapacity
Prisoners or subjects who are institutionalized by regulatory or court order
Persons who are in dependence to the sponsor or an investigator
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