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A Study Evaluating the Safety of Tocilizumab in Addition to Standard of Care Premedication Given Before Obinutuzumab + Chlorambucil in Participants With Untreated B-Cell Chronic Lymphocytic Leukemia (B-CLL) and Comorbidities

NCT02336048

Description:

This multicenter, double-blind, randomized, placebo-controlled study will evaluate the safety of a single infusion of tocilizumab versus placebo, administered in addition to standard premedications (antipyretic, antihistamine, and corticosteroid) prior to the first infusion of obinutuzumab administered in combination with oral chlorambucil to participants with previously untreated B-CLL who have comorbidities. All eligible participants will be treated with a total of 6 cycles of obinutuzumab + chlorambucil (cycle length = 28 days).

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety of Tocilizumab in Addition to Standard of Care Premedication Given Before Obinutuzumab + Chlorambucil in Participants With Untreated B-Cell Chronic Lymphocytic Leukemia (B-CLL) and Comorbidities
  • Official Title: A Multicenter, Double-Blind, Randomized, and Placebo-controlled Phase Ib Study Evaluating the Safety of Adding Tocilizumab to Standard Premedications Prior to Administration of Obinutuzumab in Combination With Chlorambucil in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia and Comorbidities

Clinical Trial IDs

  • ORG STUDY ID: BO29448
  • SECONDARY ID: 2014-004594-16
  • NCT ID: NCT02336048

Conditions

  • B-Cell Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
ChlorambucilPlacebo + Obinutuzumab + Chlorambucil
ObinutuzumabRO5072759, GA101, Gazya, GazyvaroPlacebo + Obinutuzumab + Chlorambucil
PlaceboPlacebo + Obinutuzumab + Chlorambucil
TocilizumabRO4877533, RoActemra, ActemraTocilizumab + Obinutuzumab + Chlorambucil

Purpose

This multicenter, double-blind, randomized, placebo-controlled study will evaluate the safety of a single infusion of tocilizumab versus placebo, administered in addition to standard premedications (antipyretic, antihistamine, and corticosteroid) prior to the first infusion of obinutuzumab administered in combination with oral chlorambucil to participants with previously untreated B-CLL who have comorbidities. All eligible participants will be treated with a total of 6 cycles of obinutuzumab + chlorambucil (cycle length = 28 days).

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
Placebo + Obinutuzumab + ChlorambucilActive ComparatorParticipants will receive placebo and standard premedications on Days 1 and 2 of Cycle 1 (cycle length= 28 days) along with obinutuzumab and chlorambucil administered for 6 cycles.
  • Chlorambucil
  • Obinutuzumab
  • Placebo
    Tocilizumab + Obinutuzumab + ChlorambucilExperimentalParticipants will receive tocilizumab and standard premedications on Days 1 and 2 of Cycle 1 (cycle length= 28 days) along with obinutuzumab and chlorambucil administered for 6 cycles.
    • Chlorambucil
    • Obinutuzumab
        • Tocilizumab

    Eligibility Criteria

    Inclusion Criteria:

    - Documented cluster of differentiation (CD) 20+ B-CLL according to NCI/IWCLL guideline

    - Total Cumulative Illness Rating Scale (CIRS) score greater than (>) 6 and/or creatinine clearance less than (<) 70 milliliters per minute (mL/min)

    - Previously untreated chronic lymphocytic leukemia (CLL) requiring treatment according to NCI/IWCLL guidelines who warrant treatment if they have any of the protocol-specified comorbidities

    - Life expectancy > 6 months

    - Adequate hematological function, unless abnormalities are caused by underlying CLL

    - Agreement to use highly effective contraceptive measures per protocol

    Exclusion Criteria:

    - Any previous CLL treatment

    - Documented transformation of CLL to aggressive non-Hodgkin's lymphoma (Richter's transformation)

    - Abnormal laboratory test values, unless abnormalities are caused by underlying CLL

    - History of progressive multifocal leukoencephalopathy

    - Previous treatment with tocilizumab for any indication

    - History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

    - Known hypersensitivity to any of the study drugs

    - History of prior malignancy unless the malignancy has been treated with a curative intent or is in remission without treatment for at least (>/=) 5 years prior to enrollment and with the exception of curatively-treated basal squamous cell carcinoma of the skin, low grade in situ carcinoma of the cervix, or low grade early stage localized prostate cancer treated surgically with curative intent and or ductal carcinoma in situ of the breast treated with lumpectomy alone

    - Treatment with glucocorticoids at any dose (except topical formulations) during the 2 weeks prior to the start of Cycle 1 Day 1. Regular treatment with glucocorticoids (> 5 days duration) is also prohibited during the 4-week screening period

    - Ongoing treatment with immunosuppressive medications or anti-tumor necrosis factor biologic therapies

    - Evidence of significant, uncontrolled concomitant diseases that could affect compliance with this protocol or interpretation of results, including significant cardiovascular or pulmonary disease

    - Known active or history of recurrent bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring treatment with intravenous (IV) antibiotics or hospitalization within 4 weeks prior to the start of Cycle 1 Day 1

    - Active tuberculosis (TB) requiring treatment within 3 years prior to baseline or latent TB diagnosed during screening that has not been appropriately treated

    - Vaccination with live or attenuated vaccines within 28 days prior to start of treatment

    - Major surgery (within 4 weeks prior to Cycle 1 Day 1), other than for diagnosis

    - Positive test results for chronic hepatitis B infection or positivity for hepatitis B core antibody

    - Positive test results for hepatitis C

    - Known history of human immuno-deficiency virus (HIV) seropositive status

    - Positive test results for human T-lymphotropic virus 1 (HTLV 1)

    - Pregnant or lactating women

    - Participation in another clinical study with drug intervention unless the last dose administered was greater than 5 half-lives of the study product prior to study start

    - Any participant actively taking anti-platelet medication or any participant who is fully anticoagulated with warfarin, low-molecular weight heparin or a novel oral anticoagulant including dabigatran, rivaroxiban, epixiban, and similar

    - Previous treatment with B-cell depleting agents

    - Any inherited bleeding disorder

    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    Time Frame:Baseline up to approximately 196 days
    Safety Issue:
    Description:

    Secondary Outcome Measures

    Measure:Percentage of Participants With Overall Response as Assessed by Investigator According to NCI/ International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
    Time Frame:84 days after last treatment (up to approximately 280 days)
    Safety Issue:
    Description:
    Measure:Percentage of Participants With Negative Results for Minimal Residual Disease (MRD) Measured According to NCI/IWCLL Guidelines
    Time Frame:84 days after last treatment (up to approximately 280 days)
    Safety Issue:
    Description:
    Measure:Area Under the Serum Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Obinutuzumab
    Time Frame:Cycle 1 Day 1 (C1D1), C1D2: Pre-dose (0 hours [hrs]), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Maximum Observed Serum Concentration (Cmax) of Obinutuzumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Terminal Half-Life (t1/2) of Obinutuzumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-last]) of Obinutuzumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Total Clearance (CL) of Obinutuzumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Volume of Distribution (Vd) of Obinutuzumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1, C6D1: pre-dose (0 hrs); additionally at 3 months after last treatment (9 months) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:AUC(0-inf) of Tocilizumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D1: immediately after tocilizumab infusion (1 hr); C1D3; C1D8, C1D15, C2D1: pre-dose (0 hrs) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Cmax of Tocilizumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D1: immediately after tocilizumab infusion (1 hr); C1D3; C1D8, C1D15, C2D1: pre-dose (0 hrs) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:t1/2 of Tocilizumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D1: immediately after tocilizumab infusion (1 hr); C1D3; C1D8, C1D15, C2D1: pre-dose (0 hrs) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:AUC(0-last) of Tocilizumab
    Time Frame:C1D1, C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D1: immediately after tocilizumab infusion (1 hr); C1D3; C1D8, C1D15, C2D1: pre-dose (0 hrs) (1 cycle=28 days)
    Safety Issue:
    Description:
    Measure:Change From Baseline in Interleukin (IL)-6 Level
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble IL-6 Receptor (sIL-6R)
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Ferritin
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: C-Reactive Protein (CRP)
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble Glycoprotein (gp) 130
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Serum Amyloid A (SAA)
    Time Frame:C1D1: pre-dose (0 hrs) (Baseline), immediately after tocilizumab and obinutuzumab infusion (1 hr, approximately 7 hrs); C1D2: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D8, C1D15, C2D1: pre-dose (0 hrs); C1D3
    Safety Issue:
    Description:1 cycle=28 days
    Measure:Percentage of Participants With Depletion in Absolute Lymphocyte Count (ALC)
    Time Frame:C1D1,C1D2,C1D8,C1D15: pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C1D3; C2D1: Pre-dose (0 hrs), immediately after obinutuzumab infusion (approximately 7 hrs); C3D1,C4D1,C5D1,C6D1: pre-dose (0 hrs) (1 cycle=28 days)
    Safety Issue:
    Description:

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Hoffmann-La Roche

    Trial Keywords

      Last Updated

      March 13, 2017