DCLLSG

CLL13 Trial

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

Project Management: Dr. Emily Holmes

Dr. Emily Holmes
+49 221 478-96118
emily.van-der-poel-holmes@uk-koeln.de

Data Management: Dr. Florian Drey

Dr. Florian Drey
+49 221 478-96583
florian.drey@uk-koeln.de

Safety Management: Tanja Annolleck

Tanja Annolleck
+49 221 478-96579
tanja.annolleck@uk-koeln.de

Contact for scientific queries Prof. Dr. Barbara Eichhorst

Prof. Dr. Barbara Eichhorst
+49 221 478-88155 (Office)
barbara.eichhorst@uk-koeln.de

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