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

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

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).

Study Overview

• Status: Terminated
• Conditions: B-Cell Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Chlorambucil; Drug: Obinutuzumab; Drug: Placebo; Other: Standard Premedication; Drug: Tocilizumab

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 3436212
    • Carmel Medical Center
  • Kfar Saba, Israel, 4428164
    • Meir Medical Center; Heamatology Dept
  • Rehovot, Israel, 7610001
    • Kaplan Medical Center; Hematology Institute; Hematolgy Institute
  • Zfat, Israel, 1311001
    • Ziv Medical Center
• Italy
  • Liguria
    • Genova, Liguria, Italy, 16132
      • A.O. Universitaria S. Martino Di Genova; Ematologia 1
  • Lombardia
    • Milano, Lombardia, Italy, 20162
      • Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
  • Sardegna
    • Cagliari, Sardegna, Italy, 09121
      • Ospedale Businco; Ematologia
  • Umbria
    • Sant'Andrea Delle Fratte (PG), Umbria, Italy, 06132
      • Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
• Latvia
  • Riga, Latvia, 1079
    • RECUH, Oncology Centre of Latvia; Clinic of Chemotherapy and Heamatology
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron; Servicio de Hematologia
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Madrid, Spain, 28041
    • Hospital Univ. 12 de Octubre; Servicio de Hematologia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio; Servicio de Hematologia
• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Barts & London School of Med; Medical Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: Chlorambucil; Chlorambucil at a dose of 0.5 milligrams per kilogram (mg/kg) will be administered orally per local prescribing information, on Days 1 and 15 of Cycles 1 to 6.; Drug: Obinutuzumab; Obinutuzumab at a dose of 100 milligrams (mg) as an intravenous (IV) infusion will be administered on Cycle 1 Day 1; 900 mg as IV infusion on Cycle 1 Day 2; 1000 mg as IV infusion on Cycle 1 Days 8 and 15; and 1000 mg as IV infusion on Day 1 of each subsequent cycle for up to 6 cycles.; Other Names: RO5072759, GA101, Gazya, Gazyvaro; Drug: Placebo; Placebo matching to tocilizumab will be administered as IV infusion on Cycle 1 Day 1 (prior to the first dose of obinutuzumab).; Other: Standard Premedication; Standard-of-care premedication consisting of antipyretic, antihistamine, and corticosteroid will be administered as per United States Package Insert/ Summary of Product Characteristics on Cycle 1 Days 1 and 2 (prior to the first and second dose of obinutuzumab, respectively).
Experimental: 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.	Drug: Chlorambucil; Chlorambucil at a dose of 0.5 milligrams per kilogram (mg/kg) will be administered orally per local prescribing information, on Days 1 and 15 of Cycles 1 to 6.; Drug: Obinutuzumab; Obinutuzumab at a dose of 100 milligrams (mg) as an intravenous (IV) infusion will be administered on Cycle 1 Day 1; 900 mg as IV infusion on Cycle 1 Day 2; 1000 mg as IV infusion on Cycle 1 Days 8 and 15; and 1000 mg as IV infusion on Day 1 of each subsequent cycle for up to 6 cycles.; Other Names: RO5072759, GA101, Gazya, Gazyvaro; Other: Standard Premedication; Standard-of-care premedication consisting of antipyretic, antihistamine, and corticosteroid will be administered as per United States Package Insert/ Summary of Product Characteristics on Cycle 1 Days 1 and 2 (prior to the first and second dose of obinutuzumab, respectively).; Drug: Tocilizumab; Tocilizumab at a dose of 8 mg/kg or adjusted dose (up to a maximum threshold of 20 mg/kg) will be administered as IV infusion on Cycle 1 Day 1 (prior to the first dose of obinutuzumab).; Other Names: RO4877533, RoActemra, Actemra

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab		Day 1 (within 24 hours of first obinutuzumab infusion)
Percentage of Treatment Discontinuations due to IRR		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)
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)
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)
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)
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)
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)
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)
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)
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)
Change From Baseline in Interleukin (IL)-6 Level	1 cycle=28 days	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 IL-6 Receptor (sIL-6R)	1 cycle=28 days	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	1 cycle=28 days	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: C-Reactive Protein (CRP)	1 cycle=28 days	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	1 cycle=28 days	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: Serum Amyloid A (SAA)	1 cycle=28 days	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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2015
• Primary Completion (Actual): September 21, 2018
• Study Completion (Actual): September 21, 2018

Study Registration Dates

• First Submitted: January 6, 2015
• First Submitted That Met QC Criteria: January 7, 2015
• First Posted (Estimate): January 12, 2015

Study Record Updates

• Last Update Posted (Actual): April 8, 2021
• Last Update Submitted That Met QC Criteria: April 6, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Obinutuzumab; Chlorambucil
• Other Study ID Numbers: BO29448; 2014-004594-16 (EudraCT Number)