DCLLSG

CLL2-BZAG Trial

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
Protocol IDs EudraCT: 2018-003270-27
NCT04515238
Participating Countries Germany
Status Recruiting
Contact Medical Management: Dr. Paula Cramer

Dr. Paula Cramer
+49 221 478-88220 (Office)
paula.cramer@uk-koeln.de

Project Management: Berit Falkowski

Berit Falkowski
+49 221 478-96581
berit.falkowski@uk-koeln.de

Data Management: Olga Korf

Olga Korf
+49 221 478-96124
olga.korf@uk-koeln.de

Safety Management: Berit Falkowski

Berit Falkowski
+49 221 478-96581
berit.falkowski@uk-koeln.de

Contact for scientific queries Dr. Paula Cramer

Dr. Paula Cramer
+49 221 478-88220 (Office)
paula.cramer@uk-koeln.de

Dr. Moritz Fürstenau

Dr. Moritz Fürstenau
+49 221 478-96121
moritz.fuerstenau@uk-koeln.de

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)
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
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
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