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Sequential Regimen of Bendamustin-Debulking Followed by Ofatumumab and Ibrutinib in CLL Patients (CLL2-BIO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02689141
Recruitment Status : Completed
First Posted : February 23, 2016
Last Update Posted : June 11, 2020
Sponsor:
Collaborators:
Gilead Sciences
Novartis Pharmaceuticals
Information provided by (Responsible Party):
German CLL Study Group

Brief Summary:
A prospective, open-label, multicentre phase-II trial to evaluate the efficacy and safety of a sequential regimen of bendamustine followed by ofatumumab and ibrutinib followed by ibrutinib and ofatumumab maintenance in CLL patients.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Bendamustine Drug: Ofatumumab Drug: Ibrutinib Phase 2

Detailed Description:

In the CLL2-BIO trial an allcomer CLL population with indication for treatment will be included.

Patient will receive 2 cycles of debulking treatment with bendamustin unless contraindications are existing or debulking is not indicated. Afterwards 6 cycles of induction therapy with ofatumumab and ibrutinib will be applied, each with a duration of 28 days. Primary endpoint overall Response rate will be assessed at final restaging.

Patients benefitting from BIO treatment will enter the maintenance phase of the trial. Maintenance treatment will be continued if no unacceptable toxicity occurs until three months after negativity of minimal residual disease (MRD) is achieved in peripheral blood in patients with (clinical) complete response (CR) or (clinical) incomplete complete response (CRi) confirmed by 2 consecutive testings of MRD within 3 months, progression of CLL, start of a subsequent therapy or up to 8 cycles of maintenance (each cycle with a duration of 84 calendar days = 3 months), whichever occurs first.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Open-label, Multicentre Phase-II Trial to Evaluate Efficacy and Safety of a Sequential Regimen of Bendamustine Followed by Ofatumumab and Ibrutinib Followed by Ibrutinib and Ofatumumab Maintenance in CLL Patients
Actual Study Start Date : February 4, 2016
Actual Primary Completion Date : July 13, 2017
Actual Study Completion Date : February 6, 2020


Arm Intervention/treatment
Experimental: Bendamustine + Ofatumumab + Ibrutinib
Bendamustine: 70mg/m² i.v. Ofatumumab: 1000 mg i.v. Ibrutinib: 420 mg po
Drug: Bendamustine
Debulking: Cycles 1 - 2, d1 & 2: 70 mg/m2 i.v.

Drug: Ofatumumab

Induction:

Cycle 1: Day 1 300 mg i.v.; Day 8 1000 mg i.v.; Day 15 1000 mg i.v. Cycle 2-6: Day 1 1000 mg i.v.

Maintenance: After the induction ofatumumab iv 1000 mg every three months will be continued.

Cycle 1-8: Day 1 1000 mg i.v.


Drug: Ibrutinib
Induction: Cycle 2-6: d1-28: 420 mg p.o. Maintenance: After the induction ibrutinib p.o. 420 mg daily will be continued. Cycle 1-8: d1-84: 420 mg p.o.




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: 84 days after first dose of last induction cycle ]
    Proportion of patients responding according to international working Group on chronic lymphocytic leukemia criteria


Secondary Outcome Measures :
  1. Safety: Adverse events (AEs) and adverse events of special interest (AESI) [ Time Frame: up to 48 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. minimal residual disease (MRD) [ Time Frame: up to 48 months after first dose of study drug ]
    Rate of MRD responses in peripheral blood measured by immunophenotyping



Information from the National Library of Medicine

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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:

  1. Documented CLL requiring treatment (irrespective if first- or relapse treatment) according to International Working Group on CLL (iwCLL) criteria

    In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BIO trial:

    • chemotherapy within ≥ 28 days
    • antibody treatment within ≥ 14 days
    • kinase inhibitors, Bcl-2-antagonists or immunomodulatory agents within ≥ 3 days
    • corticosteroids may be applied until the start of the BIO-regimen, these have to be reduced to an equivalent of ≤ 20 mg prednisolone during treatment
  2. Adequate hematologic function as indicated by a platelet count ≥ 25 x 109/L, a neutrophil count ≥ 1,0 x 109/L and a hemoglobin value ≥ 8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
  3. Adequate renal function as indicated by a creatinine clearance ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hrs urine collection
  4. Adequate liver function as indicated by a 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
  5. Negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV antibody test within 6 weeks prior to registration
  6. Age ≥ 18 years
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
  8. Life expectancy ≥ 6 months
  9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

  1. Transformation of CLL (i.e. Richter's transformation, pro-lymphocytic leukemia)
  2. Known central nervous system (CNS) involvement
  3. Patients with confirmed progressive multifocal leukoencephalopathy (PML)
  4. Malignancies other than CLL currently requiring systemic therapy
  5. Uncontrolled infection requiring systemic treatment
  6. 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)
  7. Use of investigational agents which might interfere with the study drug within 3 days prior to Registration
  8. Known hypersensitivity to ofatumumab, ibrutinib or any of the excipients Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
  9. Requirement of treatment with strong CYP3A4-inhibitors/-inducers or anticoagulant with phenprocoumon (marcumar), warfarin, or other vitamin k antagonists
  10. History of stroke or intracranial hemorrhage within 6 months prior to registration
  11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment and monthly during debulking, induction and maintenance therapy)
  12. 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 12 months after end of study treatment.
  13. Vaccination with a live vaccine ≤ 28 days prior to registration
  14. Legal incapacity
  15. Prisoners or subjects who are institutionalized by regulatory or court order
  16. Persons who are in dependence to the sponsor or an investigator

Information from the National Library of Medicine

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): NCT02689141


Locations
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Germany
German CLL Study Group
Cologne, Germany, 50935
Sponsors and Collaborators
German CLL Study Group
Gilead Sciences
Novartis Pharmaceuticals
Investigators
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Principal Investigator: Paula Cramer, Dr.med. German CLL Study Group
Additional Information:
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: NCT02689141    
Other Study ID Numbers: CLL2-BIO
2014-000590-39 ( EudraCT Number )
First Posted: February 23, 2016    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by German CLL Study Group:
chronic lymphocytic leukemia CLL
untreated chronic lymphocytic leukemia
relapsed chronic lymphocytic leukemia
refractory chronic lymphocytic leukemia
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Bendamustine Hydrochloride
Ofatumumab
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents