Sequential Regimen of Bendamustine-Debulking Followed by ABT-199 and GA101-Induction and -Maintenance in CLL (CLL2-BAG)

A Prospective, Open-label, Multicenter Phase-II Trial to Evaluate the Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by GA101 and ABT-199 Followed by ABT-199 and GA101 Maintenance in CLL Patients

The CLL2-BAG-trial is a prospective, open-label, multicenter phase-II trial to evaluate the efficacy and safety of a sequential regimen of a debulking with Bendamustine followed by an induction with GA101 (obinutuzumab) and ABT-199 (venetoclax, GDC-0199) followed by ABT-199 and GA101-maintenance in CLL patients

In the CLL2-BAG-trial, a total of 62 patients of an allcomer CLL population (irrespective of physical fitness, previous therapies and prognostic factors) with an indication for treatment will be included. Patient will receive 2 cycles of debulking treatment with Bendamustine unless contraindications (e.g. refractoriness) are present or a debulking is not indicated due to a low tumor load. Afterwards, 6 cycles of induction treatment with GA101 (obinutuzumab, 3 doses in the first cycle and monthly in cycles 2-6) and ABT-199 (venetoclax, continuously starting in cycle 2 with a low dose escalation) will be applied. The primary endpoint overall response rate will be assessed at final restaging (2 months after end of induction treatment). Patients benefitting from treatment receive further therapy with GA101 (3 monthly) and ABT-199 (continuously) in a maintenance phase for up to 24 months. Maintenance treatment will be stopped in case of achievement of a complete remission and confirmation of MRD (minimal residual disease) negativity in peripheral blood or if unacceptable toxicity or progression occurs.

Since the results of the primary endpoint analysis of the CLL2-BAG trial were very promising and this trial is one of the first studies evaluating the combination of venetoclax and obinutuzumab, it is scientifically very important to follow these first patients treated with this combination as long as possible. Therefore, with amendment 4 and 5, an extended follow-up for all patients willing to continue their study participation was implemented as well as the possibility of a re-treatment with venetoclax and obinutuzumab (but without a prior bendamustine debulking) in case of a progression.

Inclusion Criteria:

• documented chronic lymphocytic leukemia (CLL) requiring treatment according to International Working Group on CLL (iwCLL) criteria
• adequate renal function: a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
• adequate hematologic function: platelets ≥ 25.000/µl, neutrophils ≥ 1.000/µl and hemoglobin ≥8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
• adequate liver function: total bilirubin ≤2x, aspartate aminotransferase (AST) / alanin aminotransferase (ALT) ≤2.5x the institutional upper Limit of normal (ULN) value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome
• negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
• age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2, ECOG 3 is only permitted if related to CLL
• life expectancy ≥ 6 months
• ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

• transformation of CLL (i.e. Richter's transformation, prolymphocytic leukemia)
• known central nervous system (CNS) involvement
• confirmed progressive multifocal leukoencephalopathy (PML)
• malignancies other than CLL currently requiring systemic therapies
• uncontrolled infection requiring systemic treatment
• any comorbidity or organ system impairment rated with a cumulative illness rating scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system 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)
• requirement of therapy with strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors/inducers or anticoagulant with warfarin, phenprocoumon (marcumar) or other vitamin K-antagonists
• use of investigational agents within 28 days prior to registration
• known hypersensitivity to GA101 (obinutuzumab), ABT-199 (venetoclax, GDC-0199) or any of the excipients
• pregnant women and nursing mothers
• fertile men or women of childbearing potential unless surgically sterile or ≥ 2 years after the onset of menopause, or willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment
• vaccination with a live vaccine ≤28 days prior to registration
• legal incapacity
• prisoners or subjects who are institutionalized by regulatory or court order
• persons who are in dependence to the sponsor or an investigator

Inclusion/Exclusion criteria for extended follow-up and re-treatment

• Patients must have participated in the CLL2-BAG trial and must have benefitted from study treatment
• Only patients with a confirmed progression of CLL who are in need of treatment according to iwCLL 2008 criteria are eligible for retreatment with venetoclax and obinutuzumab
• Patients who received any subsequent treatment for CLL outside the study are ineligible