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

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Terminated

CT.gov ID

NCT02336048

Collaborator

(none)

Enrollment

Locations

Arms

38.9

Actual Duration (Months)

2.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
B-Cell Chronic Lymphocytic Leukemia	Drug: Chlorambucil Drug: Obinutuzumab Drug: Placebo Other: Standard Premedication Drug: Tocilizumab	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

38 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 26, 2015

Actual Primary Completion Date :

Sep 21, 2018

Actual Study Completion Date :

Sep 21, 2018

Arms and Interventions

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

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

Other Names:

RO5072759, GA101, Gazya, Gazyvaro

Other: Standard Premedication

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

Outcome Measures

Primary Outcome Measures

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to approximately 196 days]

Secondary Outcome Measures

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 [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 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
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
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
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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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