Sequential Regimen of Bendamustin-Debulking Followed by Obinutuzumab, Acalabrutinib and Venetoclax in Patients With Relapsed/Refractory CLL (CLL2-BAAG)
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ClinicalTrials.gov Identifier: NCT03787264 |
Recruitment Status :
Active, not recruiting
First Posted : December 26, 2018
Last Update Posted : November 9, 2022
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Condition or disease | Intervention/treatment | Phase |
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Chronic Lymphoid Leukemia | Drug: Bendamustine Biological: Obinutuzumab Biological: Acalabrutinib Biological: Venetoclax | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 46 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | 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) |
Actual Study Start Date : | January 14, 2019 |
Estimated Primary Completion Date : | December 2022 |
Estimated Study Completion Date : | August 2023 |

Arm | Intervention/treatment |
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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):
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Drug: Bendamustine
Debulking: Cycles 1-2: d1+2 - 70mg/m² i.v. 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: 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. 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:
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- 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 ]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).
- Overall response rate (ORR) [ Time Frame: 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 [ Time Frame: 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
- 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. ]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 interest (AEPI) [ Time Frame: up to 40 months after first dose of study drug ]Type, frequency, and severity of AEs, SAEs and AESIs and their relationship to study treatment.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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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)
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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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03787264

Principal Investigator: | Paula Cramer, Dr. med. | German CLL Study Group |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | German CLL Study Group |
ClinicalTrials.gov Identifier: | NCT03787264 |
Other Study ID Numbers: |
CLL2-BAAG |
First Posted: | December 26, 2018 Key Record Dates |
Last Update Posted: | November 9, 2022 |
Last Verified: | November 2022 |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Leukemia Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leukemia, B-Cell |
Venetoclax Bendamustine Hydrochloride Obinutuzumab Acalabrutinib Antineoplastic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Immunological |