Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation
Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation
The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline
 treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by
 combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab,
 Obinutuzumab), which may induce extremely long lasting remissions.
Chemoimmunotherapy is the standard of care in first-line treatment of CLL patients without
 del17p or TP 53 mutation; physically fit patients are treated with fludarabine,
 cyclophosphamide and rituximab (FCR)1. Due to the high risk of severe neutropenias and
 infections with FCR, bendamustine and rituximab (BR) must be considered in patients aged >65
 years.

 However, these conventional chemoimmunotherapies are associated with side effects caused by
 the rather unspecific mode of action of the chemotherapy. Therefore, there is an urgent need
 for alternatives, especially chemotherapy-free regimens.

 In first line treatment of elderly patients with CLL and coexisting conditions, the
 anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial the
 combination of obinutuzumab with chlorambucil proved to be safe and lead to markedly improved
 response rates as well as PFS times in comparison to chlorambucil alone or combined with
 rituximab.

 The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity with tumor lysis
 syndrome as dose limiting toxicity in patients with relapsed and refractory CLL. 400 mg
 venetoclax was determined to be a safe and efficacious dose. Several patients treated with
 the combination of venetoclax and rituximab in relapsed refractory CLL even achieved MRD
 negativity. The FDA approved Venetoclax for the treatment of relapsed CLL with 17p/TP53 on
 12th April 2016.

 Therefore, venetoclax plus CD20-antibody based combinations have the potential to induce
 higher rates of MRD negativity in frontline therapy of CLL and concomitantly induce lower
 rates of toxicities so that chemotherapy might be replaced. Furthermore, venetoclax and
 obinutuzumab demonstrated synergistic activity in a preclinical study of a murine Non-Hodgkin
 lymphoma xenograft model, and additive activity in a CLL lymph node model. The combination
 appears tolerable in the firstline treatment of CLL patients with coexisting conditions
 whilst the toxicity profile of both drugs compares favorably to those of the chemotherapies
 currently used in the treatment of CLL. Consequently, it should be tested if rituximab can be
 replaced by obinutuzumab in combination with venetoclax in this trial.

 Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton´s Tyrosine Kinase
 (BTK), showed excellent responses and a safe toxicity profile9,10, even in combination with
 BR. Ibrutinib is approved for treatment of relapsed CLL as well as frontline therapy of CLL
 by the FDA and EMA (April 29th 2016).

 The combination of ibrutinib and venetoclax showed synergy in primary CLL cells.

 Consequently, the aim of the current trial is to evaluate if chemoimmunotherapy in the
 frontline treatment of physically fit patients in CLL can be replaced by combinations of
 these targeted drugs with anti-CD20-antibodies.
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
 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

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

 Exclusion Criteria:

 1. Any prior CLL-specific therapies (except corticosteroid treatment administere due to
 necessary immediate intervention; within the last 10 days before start of study
 treatment, only dose equivalents of 20 mg prednisolone are permitted).

 2. Transformation of CLL (Richter transformation)

 3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more
 concurrent treatments 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 metabolism of
 the study drugs (e.g, inability to swallow tablets or impaired 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 inhibitors/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:

 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

 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