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

NCT02689141 | Completed Phase 2

• 2 other identifiers: CLL2-BIO2014-000590-39
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Lymphocytic Leukemia

Keywords

chronic lymphocytic leukemia CLL; untreated chronic lymphocytic leukemia; relapsed chronic lymphocytic leukemia; refractory chronic lymphocytic leukemia

Outcome Measures

Primary Outcomes (1)

• Overall response rate (ORR)

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

  84 days after first dose of last induction cycle

Secondary Outcomes (2)

• Safety: Adverse events (AEs) and adverse events of special interest (AESI)

  up to 48 months after first dose of study drug

• minimal residual disease (MRD)

  up to 48 months after first dose of study drug

Study Arms (1)

Bendamustine + Ofatumumab + Ibrutinib

EXPERIMENTAL

Bendamustine: 70mg/m² i.v. Ofatumumab: 1000 mg i.v. Ibrutinib: 420 mg po

Drug: Bendamustine; Drug: Ofatumumab; Drug: Ibrutinib

Interventions

Bendamustine DRUG

Debulking: Cycles 1 - 2, d1 \& 2: 70 mg/m2 i.v.

Bendamustine + Ofatumumab + Ibrutinib

Ofatumumab DRUG

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.

Bendamustine + Ofatumumab + Ibrutinib

Ibrutinib DRUG

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.

Bendamustine + Ofatumumab + Ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• Vaccination with a live vaccine ≤ 28 days prior to registration

Sponsors & Collaborators

• German CLL Study Group: lead
• Gilead Sciences: collaborator
• Novartis Pharmaceuticals: collaborator

Study Sites (1)

German CLL Study Group

Cologne, 50935, Germany

Location

Related Publications (3)

• Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Furstenau M, Kutsch N, Simon F, Goede V, Hoechstetter M, Niemann CU, da Cunha-Bang C, Kater A, Dubois J, Gregor M, Staber PB, Tausch E, Schneider C, Stilgenbauer S, Eichhorst B, Fischer K, Hallek M. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024 Jun 20;143(25):2588-2598. doi: 10.1182/blood.2023022564.

  PMID: 38620092 DERIVED

• Cramer P, Tausch E, von Tresckow J, Giza A, Robrecht S, Schneider C, Furstenau M, Langerbeins P, Al-Sawaf O, Pelzer BW, Fink AM, Fischer K, Wendtner CM, Eichhorst B, Kneba M, Stilgenbauer S, Hallek M. Durable remissions following combined targeted therapy in patients with CLL harboring TP53 deletions and/or mutations. Blood. 2021 Nov 11;138(19):1805-1816. doi: 10.1182/blood.2020010484.

  PMID: 34086865 DERIVED

• Cramer P, Tresckow JV, Robrecht S, Bahlo J, Furstenau M, Langerbeins P, Pflug N, Al-Sawaf O, Heinz WJ, Vehling-Kaiser U, Durig J, Tausch E, Hensel M, Sasse S, Fink AM, Fischer K, Kreuzer KA, Bottcher S, Ritgen M, Kneba M, Wendtner CM, Stilgenbauer S, Eichhorst B, Hallek M. Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial. Haematologica. 2021 Feb 1;106(2):543-554. doi: 10.3324/haematol.2019.223693.

  PMID: 32107341 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell

Interventions

Bendamustine Hydrochloride; ofatumumab; ibrutinib

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Paula Cramer, Dr.med.

  German CLL Study Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2016
• First Posted: February 23, 2016
• Study Start: February 4, 2016
• Primary Completion: July 13, 2017
• Study Completion: February 6, 2020
• Last Updated: June 11, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)