Sequential Regimen of Bendamustin-Debulking Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients with Relapsed/refractory CLL
NCT ID: NCT03787264
Last Updated: 2024-12-30
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE2
46 participants
INTERVENTIONAL
2019-01-14
2023-09-26
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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BAAG
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 + Acalabrutinib + Venetoclax
Maintenance: max. 8 cycles (q 84d) of Obinutuzumab + Acalabrutinib + 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
Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.
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.
Acalabrutinib
Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 100mg p.o.
Maintenance: Cycle 1 - 8: d1-84: 2 x 100mg p.o.
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.
Interventions
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Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.
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.
Acalabrutinib
Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 100mg p.o.
Maintenance: Cycle 1 - 8: d1-84: 2 x 100mg p.o.
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 Intervention Names
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Eligibility Criteria
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Inclusion 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-BAAG trial:
* chemotherapy ≥ 28 days
* antibody treatment ≥ 14 days
* kinase inhibitors, BCL2-antagonists or immuno-modulatory agents ≥ 3 days
* corticosteroids may be applied until the start of the BAAG-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 in-tolerance 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 patient´s 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 nega-tive 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 4 weeks until one year after last dosage of GA101 (obinutuzumab)), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
6. Age ≥ 18 years
7. ECOG (Eastern Cooperative Oncology Group) performance status 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 proto-col requirements
Exclusion Criteria
2. Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bru-ton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
3. Confirmed progressive multifocal leukoencephalopathy (PML)
4. Malignancies other than CLL currently requiring systemic therapies
5. Uncontrolled infection requiring systemic treatment
6. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system1 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)
7. 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.
8. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with phenprocoumon (marcumar) or other vitamin K-antagonists
9. 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).
10. Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), acalabrutinib (ACP-196) 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
11. Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing potential within 7 days before start of treatment)
12. 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.
13. Vaccination with a live vaccine ≤ 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regula-tory or court order
16. Persons who are in dependence to the sponsor or an investigator
18 Years
ALL
No
Sponsors
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German CLL Study Group
OTHER
Responsible Party
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Principal Investigators
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Paula Cramer, Dr. med.
Role: PRINCIPAL_INVESTIGATOR
German CLL Study Group
Locations
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Universitätsklinik Köln
Cologne, , Germany
Gemeinschaftspraxis Hämatologie Onkologie
Dresden, , Germany
Gemeinschaftspraxis Mohm/Prange-Krex
Dresden, , Germany
Universitatsklinik Carl Gustav Carus
Dresden, , Germany
Helios Klinikum Erfurt
Erfurt, , Germany
Universitaetsklinikum Heidelberg
Heidelberg, , Germany
Universitaetsklinikum Jena
Jena, , Germany
Praxis fuer Haematologie und Onkologie
Koblenz, , Germany
Gemeinschaftspraxis Haemato/ Onkologie Lebach
Lebach, , Germany
Klinikum Leverkusen GmbH
Leverkusen, , Germany
Krankenhaus Muenchen-Schwabing
Munich, , Germany
Ludwig-Maximilians-Universitaet Muenchen
München, , Germany
Praxis Dr. Uhlig
Naunhof, , Germany
Universitätsklinik Rostock
Rostock, , Germany
ZAHO-Rheinland
Siegburg, , Germany
Universitaetsklinik Tuebingen
Tübingen, , Germany
Universitätsklinikum Ulm
Ulm, , Germany
Countries
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References
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Furstenau M, Weiss J, Giza A, Franzen F, Robrecht S, Fink AM, Fischer K, Schneider C, Tausch E, Stilgenbauer S, Ritgen M, Schilhabel A, Bruggemann M, Eichhorst B, Hallek M, Cramer P. Circulating Tumor DNA-Based MRD Assessment in Patients with CLL Treated with Obinutuzumab, Acalabrutinib, and Venetoclax. Clin Cancer Res. 2022 Oct 3;28(19):4203-4211. doi: 10.1158/1078-0432.CCR-22-0433.
Cramer P, Furstenau M, Robrecht S, Giza A, Zhang C, Fink AM, Fischer K, Langerbeins P, Al-Sawaf O, Tausch E, Schneider C, Schetelig J, Dreger P, Bottcher S, Kreuzer KA, Schilhabel A, Ritgen M, Bruggemann M, Kneba M, Stilgenbauer S, Eichhorst B, Hallek M. Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Lancet Haematol. 2022 Oct;9(10):e745-e755. doi: 10.1016/S2352-3026(22)00211-3. Epub 2022 Aug 18.
Furstenau M, Giza A, Weiss J, Kleinert F, Robrecht S, Franzen F, Stumpf J, Langerbeins P, Al-Sawaf O, Simon F, Fink AM, Schneider C, Tausch E, Schetelig J, Dreger P, Bottcher S, Fischer K, Kreuzer KA, Ritgen M, Schilhabel A, Bruggemann M, Stilgenbauer S, Eichhorst B, Hallek M, Cramer P. Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial. Blood. 2024 Jul 18;144(3):272-282. doi: 10.1182/blood.2023022730.
Related Links
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Click here for more information about this study: CLL2-BAAG (German CLL Study Group)
Other Identifiers
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CLL2-BAAG
Identifier Type: -
Identifier Source: org_study_id