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

Sponsor

German CLL Study Group (Other)

Overall Status

Completed

CT.gov ID

NCT02689141

Collaborator

Gilead Sciences (Industry), Novartis Pharmaceuticals (Industry)

Enrollment

Location

Arm

48.1

Actual Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

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 :

Feb 4, 2016

Actual Primary Completion Date :

Jul 13, 2017

Actual Study Completion Date :

Feb 6, 2020

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Overall response rate (ORR) [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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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)
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
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
Negative serological testing for hepatitis B, negative testing for hepatitis-C RNA and negative HIV antibody 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 (e.g. due to anemia or severe constitutional symptoms)
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, pro-lymphocytic leukemia)
Known central nervous system (CNS) involvement
Patients with confirmed progressive multifocal leukoencephalopathy (PML)
Malignancies other than CLL currently requiring systemic therapy
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)
Use of investigational agents which might interfere with the study drug within 3 days prior to Registration
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
Requirement of treatment with strong CYP3A4-inhibitors/-inducers or anticoagulant with phenprocoumon (marcumar), warfarin, or other vitamin k antagonists
History of stroke or intracranial hemorrhage within 6 months prior to registration
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)
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.