Untreated patients with blood cancer (chronic lymphocytic leukemia) are randomized into four treatment arms. One treatment arm is standard-of-care. The other treatment arms are experimental, combining inhibitors with monoclonal antibodies.

• Register: EUCTR
• Last refreshed on: 9 January 2023
• Main ID: EUCTR2015-004936-36-DK
• Date of registration: 18/10/2016
• Prospective Registration: No
• Primary sponsor: University of Cologne
• Public title: Untreated patients with blood cancer (chronic lymphocytic leukemia) are randomized into four treatment arms. One treatment arm is standard-of-care. The other treatment arms are experimental, combining inhibitors with monoclonal antibodies.
• Scientific title: A phase 3 multicenter, randomized, prospective, open-label trial of standard chemoimmunotherapy (FCR/BR) versus rituximab plus ve-netoclax (RVe) versus obinutuzumab (GA101) plus venetoclax (GVe) versus obinutuzumab plus ibrutinib plus venetoclax (GIVe) in fit pa-tients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation - CLL13
• Date of first enrolment: 14/10/2016
• Target sample size: 920
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-004936-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Denmark, Finland, Germany, Ireland, Israel, Netherlands, Sweden, Switzerland

Contacts

• Name: Information Desk
• Affiliation: German CLL Study Group

• Name: Information Desk
• Affiliation: German CLL Study Group

Key inclusion & exclusion criteria

Inclusion criteria:
1. Documented CLL requiring treatment according to iwCLL criteria.
2. Age at least 18 years.
3. Life expectancy = 6 months.
4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow proven by bone marrow biopsy)
6. Creatinine clearance =70ml/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault (for men: GFR ˜ ((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85).
For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min.
7. Adequate liver function as indicated by a total bilirubin= 2 x, AST/ALT = 2.5 x the institu-tional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
8. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; pa-tients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after the last treatment cycle), nega-tive testing for hepatitis C RNA within 6 weeks prior to registration.
9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 600
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 320

Exclusion criteria:
1. Any prior CLL-specific therapies (except corticosteroid treatment ad-ministered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
2. Transformation of CLL (Richter transformation).
3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis
4. Detected del(17p) or TP53 mutation.
5. Patients with a history of PML.
6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could comprise the patients safety or interfere with the absorption or me-tabolism of the study drugs (e.g, inability to swallow tablets or im-paired resorption in the gastrointestinal tract).
7. Urinary outflow obstruction.
8. Malignancies other than CLL currently requiring systemic therapies, not being treated in curative intention before (unless the malignant disease is in a stable remission due to the discretion of the treating physician) or showing signs of progression after curative treatment.
9. Uncontrolled or active infection.
10. Patients with known infection with human immunodeficiency virus (HIV).
11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibi-tors/inducers.
12. Anticoagulant therapy with warfarin or phenoprocoumon,
(rotation to alternative anticoagulation is allowed, but note that patients being treated with NOAKs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
13. History of stroke or intracranial hemorrhage within 6 months prior to registration.
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
15. Vaccination with live vaccines 28 days prior to registration.
16. Major surgery less than 30 days before start of treatment.
17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
19. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).
20. Fertile men or women of childbearing potential unless:
a. surgically sterile or = 2 years after the onset of menopause
b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end of study treatment.
21. Legal incapacity.
22. Prisoners or subjects who are institutionalized by regulatory or court order.
23. Persons who are in dependence to the sponsor or an investigator.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

fit patients with previously untreated CLL without del(17p) or TP53 mutation
MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864

Intervention(s)

Trade Name: Gazyvaro®
Product Name: Obinutuzumab/GA101
Product Code: RO5072759
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Obinutuzumab
CAS Number: 949142-50-1
Current Sponsor code: RO5072759
Other descriptive name: OBINUTUZUMAB
Concentration unit: mg milligram(s)
Concentration type: up to
Concentration number: 1000-

Product Name: Venetoclax
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Venetoclax
Current Sponsor code: RO5537382
Other descriptive name: ABT-199 (GDC-0199)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Product Name: Venetoclax
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Venetoclax
Current Sponsor code: RO5537382
Other descriptive name: ABT-199 (GDC-0199)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Product Name: Venetoclax
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Venetoclax
Current Sponsor code: RO5537382
Other descriptive name: ABT-199 (GDC-0199)
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Imbruvica®
Product Name: Ibrutinib
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Ibrutinib
CAS Number: 936563-96-1
Other descriptive name: IBRUTINIB
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 420-

Trade Name: Levact ®
Product Name: Bendamustine hydrochloride
Pharmaceutical Form: Concentrate and solvent for concentrate for solution for infusion
INN or Proposed INN: BENDAMUSTINE HYDROCHLORIDE
CAS Number: 3543-75-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.5-

Trade Name: MabThera®
Pharmaceutical Form: Concentrate for solution for inf

Primary Outcome(s)

Main Objective: The primary objective of the study is to evaluate the efficacy of obinutuzumab (GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR) [concerning MRD negativity measured by flow cytometry in peripheral blood (PB) at month 15] and obinutuzumab plus ibrutinib plus venetoclax (GIVe) versus standard chemoimmunotherapy (BR/FCR) [concerning progression free survival (PFS)] in previously untreated, fit CLL patients without del(17p) or TP53 mutation.

Secondary Objective: Measurement of MRD-Level
Secondary objectives of the study are the evaluation of the efficacy of rituximab plus venetoclax (RVe) versus standard chemoimmunotherapy (BR/FCR), GVe and GIVe [concerning MRD negativity measured by flow cytometry in PB at month 15 and PFS].

Primary end point(s): •Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at month (MO) 15 for the comparison [GVe versus standard chemoimmunotherapy (SCIT)].
•Progression free survival (PFS) for the comparison [GIVe versus SCIT]

Timepoint(s) of evaluation of this end point: Q3 2022
Q1 2024

Secondary Outcome(s)

Secondary end point(s): • MRD levels in PB at MO 15 (all other comparisons except for [GVe ver-sus 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 versus SCIT])
• Overall response rate (ORR) [MO 3, 9, 13, 15]
• (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final re-staging (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:
o complete response (CR) or CR with incomplete recovery of the bone marrow (CRi),
o partial response (PR)
• Time to next CLL treatment
• Safety parameters:
Type, frequency, and severity of
o adverse events (AEs) and
o adverse events of special interest (AESI)
and their relationship to study treatment
• Health-related quality of life by MARS and EORTC QLQ-C30 and QLQ-CLL16 questionnaires
• Exploratory evaluations of potential associations between biomarkers and subject characteristics or outcome measures

Timepoint(s) of evaluation of this end point: Q3 2022
Q1 2024

Secondary ID(s)

NCT02950051

2015-004936-36-SE

CLL13

Source(s) of Monetary Support

AbbVie Inc.

F. Hoffmann-La Roche Ltd

Janssen Pharmaceutica NV

Ethics review

Status: Approved
Approval date: 30/09/2016
Contact: