CLL2-BZAG: Sequential Regimen of Bendamustine Followed by Obinutuzumab (GA101), Zanubrutinib (BGB-3111) and Venetoclax (ABT-199) in Patients With Relapsed/Refractory CLL
Study Details
Study Description
Brief 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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: BZAG Debulking: 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated Induction: 6 cycles (q 28d) of Obinutuzumab + Zanubrutinib + Venetoclax Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Zanubrutinib + Venetoclax Maintenance treatment will be continued until (whichever occurs first): 12 weeks (approx. 3 months) after confirmation of achievement of a CR/CRi and MRD negativity maintenance cycle 8 progression of CLL or start of a subsequent therapy unacceptable toxicity |
Drug: Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.
Other Names:
Biological: Obinutuzumab
Induction: Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg i.v.; Cycle 2 - 6: 1000 mg, d1 i.v.
Maintenance: Cycle 1 - 8: 1000 mg, d1 i.v.
Other Names:
Biological: Zanubrutinib
Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 160mg p.o.
Maintenance: Cycle 1 - 8: d1-84: 2 x 160mg p.o
Other Names:
Biological: Venetoclax
Induction: Cycles 1 + 2: --; Cycle 3: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg p.o.; Cycle 4 - 6: d1-28: 400 mg p.o.
Maintenance: Cycle 1 - 8: d1-84: 400 mg p.o.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by multi-color flow cytometry [At final restaging (RE): 12 weeks after the start of the last induction cycle]
MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%]. The MRD negativity rate is defined as the proportion of patients having achieved MRD negativity based on the full analysis set (FAS).
Secondary Outcome Measures
- Overall response rate (ORR) [At final restaging (RE): 12 weeks after the start of the last induction cycle]
Proportion of patients having achieved a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR) as best response.
- CR / CRi rate [At final restaging (RE): 12 weeks after the start of the last induction cycle]
Proportion of patients having achieved a CR or CRi as best response (= number of patients with best response CR or CRi divided by the number of the FAS)
- MRD in PB measured by 4-color flow cytometry at different times to guide the duration of maintenance therapy and for the assessment of the kinetics of response to the different treatment phases [From date of screening until the end of follow-up, up to 55 month]
MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4. MRD values will be categorized into negative (<10-4) and positive (≥10-4)
- Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular/special interest (AEPI/AESI) [Up to 55 months after first dose of study drug]
Type, frequency, severity and relationship to study treatment.of AEs, SAEs and AEPIs/AESIs
Eligibility Criteria
Criteria
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.
-
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
-
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 patient´s CLL (e.g. bone marrow infiltration), in this case, platelet count should be ≥ 10 × 109/L.
-
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
-
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
-
Age ≥ 18 years
-
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)
-
Life expectancy ≥ 6 months
-
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. Bruton´s 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 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)
-
Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathesis (e.g. von-Willebrandt´s 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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | RWTH Aachen | Aachen | Germany | 52074 | |
2 | Hamatologische/Onkologische Gemeinschaftspraxis | Augsburg | Germany | 86150 | |
3 | Universitätsklinik Bonn | Bonn | Germany | 53105 | |
4 | Gemeinschaftspraxis für Hämatologie & Onkologie (Gefos) | Dortmund | Germany | 44309 | |
5 | Universitaetsklinik Duesseldorf | Duesseldorf | Germany | 40001 | |
6 | Internistische Gemeinschaftspraxis | Erlangen | Germany | 91052 | |
7 | Onkologische Schwerpunktpraxis | Esslingen | Germany | 73728 | |
8 | Universitaetsklinikum Freiburg | Freiburg | Germany | 79106 | |
9 | Evangelische Krankenhaus Hamm | Hamm | Germany | 59063 | |
10 | Universitaetskliniken des Saarlandes | Homburg | Germany | 66424 | |
11 | Staedt Klinikum Karlsruhe | Karlsruhe | Germany | 76133 | |
12 | Universitaetsklinikum Schleswig-Holstein Campus Kiel | Kiel | Germany | 24105 | |
13 | Universitätsklinik Köln | Köln | Germany | 50937 | |
14 | Krankenhaus Muenchen-Schwabing | Munich | Germany | 80804 | |
15 | Klinikum Rechts der Isar - Technische Universitaet Muenchen | Munich | Germany | 81675 | |
16 | Stauferklinikum Schwaebisch-Gmuend | Mutlangen | Germany | 73557 | |
17 | KH Kliniken Maria Hilf | Mönchengladbach | Germany | 41063 | |
18 | Universitätsklinikum Münster | Münster | Germany | 48129 | |
19 | Studienzentrum Onkologie Ravensburg | Ravensburg | Germany | 88212 | |
20 | Universitätsklinik Ulm | Ulm | Germany | 89081 | |
21 | Hämatologisch Onkologische Schwerpunktpraxis | Würzburg | Germany | 97080 |
Sponsors and Collaborators
- German CLL Study Group
Investigators
- Principal Investigator: Paula Cramer, Dr. med., German CLL Study Group
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- CLL2-BZAG
- 2018-003270-27