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

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

Study Description
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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

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leucemia Drug: Bendamustine Drug: GA101 Drug: ABT-199 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 6, 2015
Actual Primary Completion Date : December 13, 2016
Estimated Study Completion Date : April 2020

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Bendamustine + GA101 + ABT-199
Bendamustine: 70mg/m² i.v. GA101: 1000 mg i.v. ABT-199: 20 - 400 mg p.o.
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. Rate of minimal residual disease (MRD) [ Time Frame: up to 40 months ]
    Rate of MRD responses in peripheral blood measured by immunophenotyping


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02401503


Locations
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Germany
German CLL Study Group
Cologne, Germany, 50935
Sponsors and Collaborators
German CLL Study Group
Hoffmann-La Roche
AbbVie
Investigators
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Principal Investigator: Paula Cramer, Dr. med. German CLL Study Group
More Information
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Additional Information:
Click here for more information about this study: CLL2-BAG (German CLL Study Group)  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: German CLL Study Group
ClinicalTrials.gov Identifier: NCT02401503     History of Changes
Other Study ID Numbers: CLL2-BAG
2014-000580-40 ( EudraCT Number )
First Posted: March 27, 2015    Key Record Dates
Last Update Posted: October 17, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by German CLL Study Group:
CLL
Additional relevant MeSH terms:
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Bendamustine Hydrochloride
Venetoclax
Obinutuzumab
Antineoplastic Agents, Alkylating
 Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological