Clinical Trials/NCT02336048

NCT02336048

Terminated

Phase 1

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

Hoffmann-La Roche14 sites in 5 countries38 target enrollmentJune 26, 2015

ConditionsB-Cell Chronic Lymphocytic Leukemia

InterventionsChlorambucil Obinutuzumab Placebo Standard Premedication Tocilizumab

DrugsChlorambucil Obinutuzumab Placebo Tocilizumab

Overview

Phase: Phase 1
Intervention: Chlorambucil
Conditions: B-Cell Chronic Lymphocytic Leukemia
Sponsor: Hoffmann-La Roche
Enrollment: 38
Locations: 14
Primary Endpoint: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Status: Terminated
Last Updated: 5 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

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).

Registry

clinicaltrials.gov

Start Date

June 26, 2015

End Date

September 21, 2018

Last Updated

5 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Hoffmann-La Roche

Responsible Party

Sponsor

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
•Regular treatment with glucocorticoids (\> 5 days duration) is also prohibited during the 4-week screening period

Arms & Interventions

Placebo + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Chlorambucil

Placebo + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Obinutuzumab

Placebo + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Placebo

Placebo + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Standard Premedication

Tocilizumab + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Chlorambucil

Tocilizumab + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Obinutuzumab

Tocilizumab + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Standard Premedication

Tocilizumab + Obinutuzumab + Chlorambucil

Participants 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.

Intervention: Tocilizumab

Outcomes

Primary Outcomes

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time Frame: Baseline up to approximately 196 days

Secondary Outcomes

Percentage of Participants With Negative Results for Minimal Residual Disease (MRD) Measured According to NCI/IWCLL Guidelines(84 days after last treatment (up to approximately 280 days))
Percentage of Treatment Discontinuations due to IRR(Day 1 (within 24 hours of first obinutuzumab infusion))
Percentage of Participants With IRRS >= Grade 3 as assessed by the Investigator and Reviewed by the EAC(Day 1 (within 24 hours of first obinutuzumab infusion))
Percentage of Participants With Overall Response as Assessed by Investigator According to NCI/ International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines(84 days after last treatment (up to approximately 280 days))
Terminal Half-Life (t1/2) of Obinutuzumab(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))
Total Clearance (CL) of Obinutuzumab(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))
AUC(0-last) of Tocilizumab(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))
Percentage of Participants With Infusion-Related Reactions (IRRs) as Assessed by Investigator and Reviewed by Endpoint Adjudication Committee (EAC)(Day 1 (within 24 hours of first obinutuzumab infusion))
Percentage of Participants With IRRs by Severity According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v4.0)(Day 1 (within 24 hours of first obinutuzumab infusion))
Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab(Day 1 (within 24 hours of first obinutuzumab infusion))
Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble IL-6 Receptor (sIL-6R)(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)
Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Ferritin(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)
Area Under the Serum Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Obinutuzumab(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))
Maximum Observed Serum Concentration (Cmax) of Obinutuzumab(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))
Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-last]) of Obinutuzumab(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))
Volume of Distribution (Vd) of Obinutuzumab(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))
AUC(0-inf) of Tocilizumab(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))
Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Serum Amyloid A (SAA)(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)
Change From Baseline in Interleukin (IL)-6 Level(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)
Percentage of Participants With Depletion in Absolute Lymphocyte Count (ALC)(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))
Cmax of Tocilizumab(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))
t1/2 of Tocilizumab(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))
Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: C-Reactive Protein (CRP)(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)
Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble Glycoprotein (gp) 130(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)