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

• ClinicalTrials.gov Identifier: NCT02401503
• Recruitment Status: Active, not recruiting
• First Posted: March 27, 2015
• Last Update Posted: October 17, 2018
• Sponsor: German CLL Study Group
• Collaborators: Hoffmann-La Roche; AbbVie
• Information provided by (Responsible Party): German CLL Study Group

Tracking Information

• First Submitted Date: March 24, 2015
• First Posted Date: March 27, 2015
• Last Update Posted Date: October 17, 2018
• Actual Study Start Date: May 6, 2015
• Actual Primary Completion Date: December 13, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 26, 2015)

Overall response rate (ORR) [ Time Frame: 84 days after start of the last cycle of induction therapy ]

Proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT02401503 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: March 27, 2015)

• Adverse Events (AEs) and adverse events of special interest (AESI) [ Time Frame: up to 40 months after first dose of study drug ]
  Type, frequency and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment
• Rate of minimal residual disease (MRD) [ Time Frame: up to 40 months ]
  Rate of MRD responses in peripheral blood measured by immunophenotyping

Original Secondary Outcome Measures (submitted: March 26, 2015)

• Adverse Events (AEs) and adverse events of special interest (AESI) [ Time Frame: up to 40 months after first dose of study drug ]
  Type, frequency and sevirity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment
• Rate of minimal residual disease (MRD) [ Time Frame: up to 40 months ]
  Rate of MRD responses in peripheral blood measured by immunophenotyping

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sequential Regimen of Bendamustine-Debulking Followed by ABT-199 and GA101-Induction and -Maintenance in CLL (CLL2-BAG)
• Official Title: 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
• Brief Summary: 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
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Lymphocytic Leucemia

Intervention

• Drug: Bendamustine
  Debulking: Cycles 1-2, d1 & 2: 70mg/m² i.v.
• Drug: GA101
  Induction: Cycle 1: d1: 100mg, d1(or 2): 900mg, d8 & 15: 1000mg; Cycle 2-6: d1: 1000mg Maintenance: Cycles 1-8 (Duration 12 weeks): d1: 1000mg
  Other Name: Obinutuzumab
• Drug: ABT-199
  Induction: Cycle 2: d1-7: 20mg, d8-14: 50mg, d15-21: 100mg, d22-28: 200mg; Cycle 3-6: d1-28: 400mg Maintenance: Cycles 1-8 (Duration 12 weeks): d1-84: 400mg
  Other Name: Venetoclax, GDC-0199

Study Arms

Experimental: Bendamustine + GA101 + ABT-199

Bendamustine: 70mg/m² i.v. GA101: 1000 mg i.v. ABT-199: 20 - 400 mg p.o.

Interventions:

• Drug: Bendamustine
• Drug: GA101
• Drug: ABT-199

• Publications *: Cramer P, von Tresckow J, Bahlo J, Robrecht S, Langerbeins P, Al-Sawaf O, Engelke A, Fink AM, Fischer K, Tausch E, Seiler T, Fischer von Weikersthal L, Hebart H, Kreuzer KA, Böttcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Sep;19(9):1215-1228. doi: 10.1016/S1470-2045(18)30414-5. Epub 2018 Aug 13.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 23, 2015): 66
• Original Estimated Enrollment (submitted: March 26, 2015): 62
• Estimated Study Completion Date: April 2020
• Actual Primary Completion Date: December 13, 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT02401503
• Other Study ID Numbers: CLL2-BAG; 2014-000580-40 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: German CLL Study Group
• Study Sponsor: German CLL Study Group

Collaborators

• Hoffmann-La Roche
• AbbVie

Investigators

• Principal Investigator: Paula Cramer, Dr. med.; German CLL Study Group

• PRS Account: German CLL Study Group
• Verification Date: October 2018