Clinical trial NCT02336048: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: B-Cell Chronic Lymphocytic Leukemia
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-01-12
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline up to approximately 196 days
Secondary outcomes:
measure: Percentage of Participants With Infusion-Related Reactions (IRRs) as Assessed by Investigator and Reviewed by Endpoint Adjudication Committee (EAC)
timeFrame: Day 1 (within 24 hours of first obinutuzumab infusion)
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)
timeFrame: Day 1 (within 24 hours of first obinutuzumab infusion)
measure: Percentage of Participants With IRRS >= Grade 3 as assessed by the Investigator and Reviewed by the EAC
timeFrame: Day 1 (within 24 hours of first obinutuzumab infusion)
measure: Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab
timeFrame: Day 1 (within 24 hours of first obinutuzumab infusion)
measure: Percentage of Treatment Discontinuations due to IRR
timeFrame: Day 1 (within 24 hours of first obinutuzumab infusion)
measure: Percentage of Participants With Overall Response as Assessed by Investigator According to NCI/ International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
timeFrame: 84 days after last treatment (up to approximately 280 days)
measure: Percentage of Participants With Negative Results for Minimal Residual Disease (MRD) Measured According to NCI/IWCLL Guidelines
timeFrame: 84 days after last treatment (up to approximately 280 days)
measure: Area Under the Serum Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Obinutuzumab
timeFrame: 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)
measure: Maximum Observed Serum Concentration (Cmax) of Obinutuzumab
timeFrame: 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)
measure: Terminal Half-Life (t1/2) of Obinutuzumab
timeFrame: 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)
measure: Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-last]) of Obinutuzumab
timeFrame: 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)
measure: Total Clearance (CL) of Obinutuzumab
timeFrame: 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)
measure: Volume of Distribution (Vd) of Obinutuzumab
timeFrame: 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)
measure: AUC(0-inf) of Tocilizumab
timeFrame: 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)
measure: Cmax of Tocilizumab
timeFrame: 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)
measure: t1/2 of Tocilizumab
timeFrame: 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)
measure: AUC(0-last) of Tocilizumab
timeFrame: 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)
measure: Change From Baseline in Interleukin (IL)-6 Level
timeFrame: 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
measure: Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble IL-6 Receptor (sIL-6R)
timeFrame: 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
measure: Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Ferritin
timeFrame: 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
measure: Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: C-Reactive Protein (CRP)
timeFrame: 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
measure: Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble Glycoprotein (gp) 130
timeFrame: 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
measure: Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Serum Amyloid A (SAA)
timeFrame: 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
measure: Percentage of Participants With Depletion in Absolute Lymphocyte Count (ALC)
timeFrame: 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)
Other outcomes:
Locations:
city: Haifa
country: Israel
facility: Carmel medical center
city: Kfar Saba
country: Israel
facility: Meir Medical Center; Heamatology Dept
city: Rehovot
country: Israel
facility: Kaplan Medical Center; Hematology Institute; Hematolgy Institute
city: Zfat
country: Israel
facility: Ziv Medical Center
city: Genova
country: Italy
facility: A.O. Universitaria S. Martino Di Genova; Ematologia 1
state: Liguria
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
state: Lombardia
city: Cagliari
country: Italy
facility: Ospedale Businco; Ematologia
state: Sardegna
city: Sant'Andrea Delle Fratte (PG)
country: Italy
facility: Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
state: Umbria
city: Riga
country: Latvia
facility: RECUH, Oncology Centre of Latvia; Clinic of Chemotherapy and Heamatology
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Servicio de Hematologia
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Hematología y Oncología
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre; Servicio de Hematologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Hematologia
city: London
country: United Kingdom
facility: Barts & London School of Med; Medical Oncology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: