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).
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
Drug | Synonyms | Arms |
---|
Chlorambucil | | Placebo + Obinutuzumab + Chlorambucil |
Obinutuzumab | RO5072759, GA101, Gazya, Gazyvaro | Placebo + Obinutuzumab + Chlorambucil |
Placebo | | Placebo + Obinutuzumab + Chlorambucil |
Tocilizumab | RO4877533, RoActemra, Actemra | Tocilizumab + 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).
Trial Arms
Name | Type | Description | Interventions |
---|
Placebo + Obinutuzumab + Chlorambucil | Active Comparator | 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. | - Chlorambucil
- Obinutuzumab
- Placebo
|
Tocilizumab + Obinutuzumab + Chlorambucil | Experimental | 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. | - 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 Infusion-Related Reactions (IRRs) as Assessed by Investigator and Reviewed by Endpoint Adjudication Committee (EAC) |
Time Frame: | Day 1 (within 24 hours of first obinutuzumab infusion) |
Safety Issue: | |
Description: | |
Measure: | 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) |
Time Frame: | Day 1 (within 24 hours of first obinutuzumab infusion) |
Safety Issue: | |
Description: | |
Measure: | Percentage of Participants With IRRS >= Grade 3 as assessed by the Investigator and Reviewed by the EAC |
Time Frame: | Day 1 (within 24 hours of first obinutuzumab infusion) |
Safety Issue: | |
Description: | |
Measure: | Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab |
Time Frame: | Day 1 (within 24 hours of first obinutuzumab infusion) |
Safety Issue: | |
Description: | |
Measure: | Percentage of Treatment Discontinuations due to IRR |
Time Frame: | Day 1 (within 24 hours of first obinutuzumab infusion) |
Safety Issue: | |
Description: | |
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: | Terminated |
Lead Sponsor: | Hoffmann-La Roche |
Last Updated
April 7, 2021