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

B-Cell Chronic Lymphocytic Leukemia Clinical Trial

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 Details — Status: Terminated

Administrative data

• NCT number: NCT02336048
• Other study ID #: BO29448
• Secondary ID: 2014-004594-16
• Status: Terminated
• Phase: Phase 1
• Start date: June 26, 2015
• Est. completion date: September 21, 2018

Study information

• Verified date: April 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 38
• Est. completion date: September 21, 2018
• Est. primary completion date: September 21, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• B-Cell Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

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.
• 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.
• 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).

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).

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Israel,  Italy,  Latvia,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)		Baseline up to approximately 196 days
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab		Day 1 (within 24 hours of first obinutuzumab infusion)
Secondary	Percentage of Treatment Discontinuations due to IRR		Day 1 (within 24 hours of first obinutuzumab infusion)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)