Title | A phase 3 multicenter, randomized, prospective, open-label trial of standard chemoimmunotherapy (FCR/BR) versus rituximab plus venetoclax (RVe) versus obinutuzumab (GA101) plus venetoclax (GVe) versus obinutuzumab plus ibrutinib plus venetoclax (GIVe) in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation |
---|---|
Protocol IDs | EudraCT: 2015-004936-36 NCT02950051 |
Status | in follow up |
General inquiries | cll13@uk-koeln.de |
Contact | Medical Management: Dr. Moritz Fürstenau Dr. Moritz Fürstenau Dr. Emily Holmes Dr. Florian Drey Tanja Annolleck |
Contact for scientific queries | Prof. Dr. Barbara Eichhorst Prof. Dr. Barbara Eichhorst |
Design | Prospective, multicenter, randomized, 4-arm, open-label phase III trial |
Objective | Evaluation of the efficacy of 3 combination therapies versus standard chemoimmunotherapy (BR/FCR) in previously untreated, fit CLL patients without del(17p) or TP53 mutation |
Primary Endpoints | - Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at month (MO) 15 for the comparison of
GVe vs. standard chemoimmunotherapy (SCIT)
- Progression free survival (PFS) for the comparison of GIVe vs. SCIT |
Secondary Endpoints | - MRD levels in PB at MO 15 (all other comparisons except for GVe vs.
SCIT - MRD levels in PB at different time points (MO 2, 9 and 13; MRD at later time points might be evaluated according to the discretion of the treating physician at local laboratories) - MRD levels measured in bone marrow (BM) at final restaging (RE, 2 month after the end of last treatment cycle) • PFS (all other comparisons except for GIVe vs. SCIT • Overall response rate (ORR) [MO 3, 9, 13, 15] • (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final restaging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and MO 15] (with regard to best response achieved) - Event-free survival (EFS) - Overall survival (OS) - Duration of response in patients with: - complete response (CR) or CR with incomplete recovery of the bone marrow (CRi), - partial response (PR) - Time to next CLL treatment - Safety parameters: Type, frequency, and severity of - adverse events (AEs) and - adverse events of special interest (AESI) and their relationship to study treatment - Health-related quality of life and compliance by MARS and EORTC QLQC30 and QLQ-CLL16 questionnaires - Exploratory evaluations of potential associations between biomarkers and subject characteristics or outcome measures |
Target Population | - CLL requiring treatment according to iwCLL criteria - No del(17p) or TP53 mutation - No prior therapy - Creatinine clearance ≥70ml/min - Age ≥ 18 years |
Treatment | Standard chemoimmunotherapy (SCIT) 6 cycles, q28d FCR (Patients ≤ 65 years) Fludarabine i.v.: 25 mg/m², d1-3 + Cyclophosphamide i.v.: 250 mg/m², d1-3 + Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1 BR (Patients > 65 years) Bendamustine i.v.: 90mg/m², d1-2 + Rituximab i.v. (before chemotherapy): cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1 |
Rituximab + Venetoclax (RVe) 6 cycles (q28d) of RVe + 6 cycles (q28d) of Venetoclax (alone) Rituximab i.v.: cycle 1: 375 mg/m², d0; cycles 2-6: 500 mg/m², d1 Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 |
|
Obinutuzumab + Venetoclax (GVe) 6 cycles (q28d) of GVe + 6 cycles (q28d) of Venetoclax (alone) Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1 Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 |
|
Obinutuzumab + Ibrutinib + Venetoclax (GIVe) 6 cycles (q28d) of GIVe + 6 cycles (q28d) of Ibrutinib plus Venetoclax Obinutuzumab i.v. cycle 1: 100 mg, d1; 900 mg, d1(2); 1000 mg, d8+15, q28d cycles 2-6: 1000 mg, d1 Ibrutinib p.o. cycles 1-12: 420 mg, d1-28, q28d cycles 13-36: 420 mg, d1-28, q28d Administration of ibrutinib will be continued for a maximum of 36 months or until MRD negativity, start of new anti-CLL therapy or inacceptable toxicity, whatever occurs first. Venetoclax p.o. (ramp-up: dose escalation until final dose is reached) cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 |
|
Patients recruitedl | 926 patients |
Time schedule | Recruitment period:
13 Dec 2016 – 13 Oct 2019 End of study: Q4 2022 Clinical study report: Q4 2023 |
Protocol Version | 02 Aug 2016 Protocol (Version 1.1) 20 Feb 2017 Amendment 1 (Version 2.0) 12 July 2017 Amendment 2 (Version 3.0) 12 Dec 2018 Amendment 4 (Version 4.0) 19 Feb 2020 Amendment 5 (Version 5.1) |
Sponsor | University of Cologne |
Global Principal Investigator | PD Dr. med. Barbara Eichhorst, Department I of Internal Medicine, University Hospital of Cologne |
Coordinating Physician | Dr. Moritz Fürstenau, Department I of Internal Medicine, University Hospital of Cologne |
Documents (password protected) |
Protocol and other documents see Download Center |