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| Title | 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 |
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| Protocol IDs | EudraCT: 2018-003270-27 NCT04515238 |
| Participating Countries | Germany |
| Status | Recruiting |
| Contact | Medical Management: Dr. Paula Cramer Dr. Paula Cramer Berit Falkowski Berit Falkowski Laura Miesen Olga Korf Berit Falkowski |
| Contact for scientific queries | Dr. Paula Cramer Dr. Paula Cramer Dr. Moritz Fürstenau |
| Design | Prospective, multicenter, single-arm, open-label, phase-II trial |
| Primary Endpoint | Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry at final restaging (RE) at the end of induction treatment (12 weeks after the start of the last induction cycle)
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| Secondary Endpoints | – Overall response rate (ORR) at RE, including all patients achieving: · a complete response (CR), · CR with incomplete recovery of the bone marrow (CRi) · a partial response (PR). – CR/CRi rate at RE – Safety parameters: adverse events (AE), serious adverse events (SAE) and adverse events of particular/special interest (AEPI/AESI) – 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 – MRD in bone marrow measured by 4-color flow cytometry optionally in patients with (clin.) CR/CRi (or PR almost fulfilling CR criteria, e.g. with residual splenomegaly) 12 weeks after achievement of MRD negativity in PB – Best response rate (BRR) until 6 months after RE – ORR after debulking and after end of maintenance treatment – Progression-free survival (PFS) – Event-free survival (EFS) – Overall survival (OS) – Duration of response in patients with a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi) or a partial remission (PR) – Treatment-free survival (TFS) and time to next CLL treatment (TTNT) – Exploratory endpoints: Evaluation of relationship between various baseline markers and clinical outcome parameters |
| Target Population | – Relapsed/refractory CLL in need of treatment according to iwCLL criteria – In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regi-men must be stopped within the following time periods before start of the study treatment in the CLL2-BZAG trial: a. chemotherapy ≥ 28 days; b. antibody treatment ≥ 14 days c. kinase inhibitors, BCL2-antagonists or immuno-modulatory agents ≥ 3 days d. 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 – Creatinine clearance ≥30ml/minL – ECOG performance status 0 – 2 (ECOG 3 only permitted if related to CLL) – Age ≥ 18 years |
| Treatment | Debulking 2 debulking cycles (q 28d) of bendamustine will be administered unless the patient has a contraindication or a debulking is not clinically indicated Bendamustin i.v. Cycle 1 - 2: 70 mg/m², d1+2 |
| Induction 6 cycles, q 28d Obinutuzumab (GA101) i.v. Cycle 1: d1 - 100 mg, d1 (or d2) - 900 mg, d8 + d15 - 1000 mg Cycle 2 - 6: 1000 mg, d1 + Zanubrutinib (BGB-3111) p.o.. Cycle 1: -- Cycles 2 - 6: d1-28: 2 x 160mg + Venetoclax (ABT-199) p.o. Cycles 1 + 2: -- Cycle 3: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg Cycle 4 - 6: d1-28: 400 mg |
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| Maintenance max. 8 cycles, q 84d Obinutuzumab i.v. Cycle 1 - 8: 1000 mg, d1 + Zanubrutinib (BGB-3111) p.o. Cycle 1 - 8: d1-84: 2 x 160mg + Venetoclax p.o. Cycle 1 - 8: d1-84: 400 mg 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 |
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| Targeted Accrual | 40 patients |
| Time schedule | Recruitment period: Q3/2020 - Q4/2021 End of trial Q4/2025 Final study report: Q4/2026 |
| Protocol Version | 20 Aug 2019 Protocol (Version 1.0) |
| Sponsor | University of Cologne |
| Principal Investigator | Dr. med. Paula Cramer, Department I of Internal Medicine, Cologne University Hospital |
| Coordinating Physician | Dr. med. Moritz Fürstenau, Department I of Internal Medicine, Cologne University Hospital |
| Documents (publicly available) |
Synopsis (Version 1.2 | 20 Aug 2020) |
| Documents (password protected) |
Protocol and other documents see Download Center |