Eine prospektive, randomisierte, unverblindete, multizentrische Phase-III-Studie zum Vergleich der Wirksamkeit und Sicherheit von Ibrutinib Monotherapie gegen eine zeitlich begrenzte Therapie mit Venetoclax plus Obinutuzumab oder Ibrutinib plus Venetoclax bei Patienten mit bislang unbehandelter chronisch lymphatischer Leukämie (CLL) - CLL17

Biological: Ibrutinib;Biological: Venetoclax;Biological: Obinutuzumab

Gender: All
Maximum age: N/A
Minimum age: 18 Years

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 independent of growth factor or transfusion support
within 2 weeks of screening initiation as follows, unless cytopenia is due to CLL:

1. Absolute neutrophil count = 1.0 ? 109/L

2. Platelet counts = 30 ? 109/L; in cases of thrombocytopenia clearly due to CLL
(per the discretion of the investigator), platelet count should be = 10 ? 109/L

3. Total haemoglobin = 9 g/dL (without transfusion support, unless anaemia is due to
CLL)

6. GFR >30ml/min directly measured with 24hr urine collection, 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) or an equally accurate method.

a. 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 30 ml/min may be eligible if a repeat estimate after adequate hydration is >
30 ml/min.

7. Adequate liver function as indicated by a total bilirubin = 2 x, AST/ ALT = 2.5 x the
institutional 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;
patients 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 last treatment cycle),
negative testing for hepatitis C RNA within 6 weeks prior to registration for study
screening (i.e. PCR only required when serology was positive).

9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.

Exclusion criteria:

1. Any prior CLL-specific therapies (except corticosteroid treatment administered 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). When Richter transformation is
suspected, PET-CT and/or biopsy should be performed to rule out transformation.

3. Patients with a history of PML.

4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition
limiting the ability to receive the study treatment or any other life-threatening
illness, medical condition or organ system dysfunction that, in the investigator?s
opinion, could compromise the patients' safety or interfere with the absorption or
metabolism of the study drugs (e.g. inability to swallow tablets or impaired
resorption in the gastrointestinal tract).

5. Malignancies other than CLL currently requiring systemic therapies, not being treated
with curative intent 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.

6. Uncontrolled or active infection.

7. Patients with known infection with human immunodeficiency virus (HIV).

8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to
7 days prior to study treatment start).

9. Anticoagulant therapy with warfarin or phenprocoumon, (alternative anticoagulation is
allowed (e.g. DOACs), but patients must be properly informed about the potential risk
of bleeding under treatment with ibrutinib).

10. History of stroke or intracranial hemorrhage within 6 months prior to registration for
study screening.

11. Known bleeding disorders

12. Child B / C liver cirrhosis

13. Use of investigational agents which might interfere with the study drug within 28 days
prior to registration for study screening.

14. Vaccination with live vaccines 28 days prior to registration for study screening.

15. Major surgery less than 30 days before start of study treatment.

16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies, known sensitivity or allergy to murine products.

17. Known hypersensitivity to any active substance or to any of the excipients of one of
the drugs used in the trial.

18. Pregnant women and nursing mothers (a negative pregnancy test is required for all
women of childbearing potential within 7 days before start of study treatment; further
pregnancy testing will be performed monthly).

19. Fertile men or women of childbearing potential unless:

1. surgically sterile or = 2 years after the onset of menopause

2. 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.

20. Legal incapacity.

21. Prisoners or subjects who are institutionalized by regulatory or court order.

22. Persons who are in dependence to the sponsor or an investigator.