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
Phase 1
Terminated
- Conditions
- B-Cell Chronic Lymphocytic Leukemia
- Interventions
- Registration Number
- NCT02336048
- Lead Sponsor
- Hoffmann-La Roche
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 38
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + Obinutuzumab + Chlorambucil Placebo 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. Placebo + Obinutuzumab + Chlorambucil Standard Premedication 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. Tocilizumab + Obinutuzumab + Chlorambucil Standard Premedication 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. Placebo + Obinutuzumab + Chlorambucil Obinutuzumab 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. Placebo + Obinutuzumab + Chlorambucil 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. Tocilizumab + Obinutuzumab + Chlorambucil 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. Tocilizumab + Obinutuzumab + Chlorambucil Obinutuzumab 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. Tocilizumab + Obinutuzumab + Chlorambucil Tocilizumab 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline up to approximately 196 days
- Secondary Outcome Measures
Name Time Method 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 1 cycle=28 days
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 1 cycle=28 days
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 1 cycle=28 days
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 1 cycle=28 days
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 1 cycle=28 days
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 1 cycle=28 days
Trial Locations
- Locations (14)
Hospital Universitari Vall d'Hebron; Servicio de Hematologia
🇪🇸Barcelona, Spain
Hospital ClÃnic i Provincial; Servicio de HematologÃa y OncologÃa
🇪🇸Barcelona, Spain
Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
🇮🇹Sant'Andrea Delle Fratte (PG), Umbria, Italy
Ospedale Businco; Ematologia
🇮🇹Cagliari, Sardegna, Italy
Hospital Universitario Virgen del Rocio; Servicio de Hematologia
🇪🇸Sevilla, Spain
Barts & London School of Med; Medical Oncology
🇬🇧London, United Kingdom
Kaplan Medical Center; Hematology Institute; Hematolgy Institute
🇮🇱Rehovot, Israel
Carmel medical center
🇮🇱Haifa, Israel
A.O. Universitaria S. Martino Di Genova; Ematologia 1
🇮🇹Genova, Liguria, Italy
Ziv Medical Center
🇮🇱Zfat, Israel
Meir Medical Center; Heamatology Dept
🇮🇱Kfar Saba, Israel
RECUH, Oncology Centre of Latvia; Clinic of Chemotherapy and Heamatology
🇱🇻Riga, Latvia
Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
🇮🇹Milano, Lombardia, Italy
Hospital Univ. 12 de Octubre; Servicio de Hematologia
🇪🇸Madrid, Spain