- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03787264
Sequential Regimen of Bendamustin-Debulking Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients With Relapsed/Refractory CLL (CLL2-BAAG)
A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 (Obinutuzumab), Acalabrutinib (ACP-196) and ABT-199 (Venetoclax) in Patients With Relapsed/Refractory CLL (CLL2-BAAG Protocol)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Dresden, Germany, 1307
- Gemeinschaftspraxis Hämatologie Onkologie
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Dresden, Germany, 1307
- Gemeinschaftspraxis Mohm/Prange-Krex
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Dresden, Germany, 1307
- Universitätsklinik Carl Gustav Carus
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Erfurt, Germany, 99089
- Helios Klinikum Erfurt
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Heidelberg, Germany, 69120
- Universitaetsklinikum Heidelberg
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Jena, Germany, 7747
- Universitaetsklinikum Jena
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Koblenz, Germany, 56068
- Praxis fuer Haematologie und Onkologie
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Köln, Germany, 50937
- Universitätsklinik Köln
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Lebach, Germany, 66822
- Gemeinschaftspraxis Haemato/ Onkologie Lebach
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Leverkusen, Germany, 51375
- Klinikum Leverkusen GmbH
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Munich, Germany, 80804
- Krankenhaus Muenchen-Schwabing
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München, Germany, 81377
- Ludwig-Maximilians-Universitaet Muenchen
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Naunhof, Germany, 4683
- Praxis Dr. Uhlig
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Rostock, Germany, 18057
- Universitätsklinik Rostock
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Siegburg, Germany, 53721
- ZAHO-Rheinland
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Tübingen, Germany, 72076
- Universitaetsklinik Tuebingen
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Ulm, Germany, 89081
- Universitätsklinikum Ulm
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
Relapsed/refractory CLL in need of treatment according to iwCLL (international workshop on CLL) 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.
- 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 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
- Age ≥ 18 years
- 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)
- Life expectancy ≥ 6 months
- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other proto-col requirements
Exclusion Criteria:
- (Suspicion of) transformation of CLL (i.e. Richter's trans-formation, 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. Bru-ton´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 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)
- 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), 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
- 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)
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 regula-tory or court order
- Persons who are in dependence to the sponsor or an investigator
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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):
|
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v.
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:
Induction: Cycle 1: --; Cycles 2 - 6: d1-28: 2 x 100mg p.o. Maintenance: Cycle 1 - 8: d1-84: 2 x 100mg p.o.
Other Names:
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:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry
Time Frame: At final restaging (RE): 12 weeks after the start of the last induction cycle
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MRD negativity is defined as less than one (1) CLL-cell among 10,000 leukocytes analyzed [0.01%], i.e. < 10-4.
The MRD negativity rate is defined as the proportion of patients having achieved MRD negativity based on the full analysis set (FAS).
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At final restaging (RE): 12 weeks after the start of the last induction cycle
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall response rate (ORR)
Time Frame: At final restaging (RE): 12 weeks after the start of the last induction cycle
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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.
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At final restaging (RE): 12 weeks after the start of the last induction cycle
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CR / CRi rate
Time Frame: At final restaging (RE): 12 weeks after the start of the last induction cycle
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Proportion of patients having achieved a CR or CRi as best response
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At final restaging (RE): 12 weeks after the start of the last induction cycle
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MRD in PB measured by 4-color flow cytometry at different times: At screening, after debulking, 4-weekly during induction, at initial response assessment (after 6 induction cycles), at RE, every 12 weeks during maintenance and follow up.
Time Frame: From date of screening until the end of follow-up, up to 40 month.
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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)
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From date of screening until the end of follow-up, up to 40 month.
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Safety: Adverse events (AE), serious adverse events (SAE) and adverse events of particular interest (AEPI)
Time Frame: up to 40 months after first dose of study drug
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Type, frequency, and severity of AEs, SAEs and AESIs and their relationship to study treatment.
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up to 40 months after first dose of study drug
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Paula Cramer, Dr. med., German CLL Study Group
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Immunoproliferative Disorders
- Disease Attributes
- Leukemia
- Leukemia, B-Cell
- Chronic Disease
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Antineoplastic Agents, Immunological
- Venetoclax
- Bendamustine Hydrochloride
- Obinutuzumab
- Acalabrutinib
Other Study ID Numbers
- CLL2-BAAG
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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