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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

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ClinicalTrials.gov Identifier: NCT02336048
Recruitment Status : Terminated (This study was terminated early because premedication with tocilizumab was unlikely to reduce the risk of IRR.)
First Posted : January 12, 2015
Last Update Posted : October 1, 2019
Sponsor:
Information provided by (Responsible Party):
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).

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

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Study Type : Interventional  (Clinical Trial)
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 : June 26, 2015
Actual Primary Completion Date : September 21, 2018
Actual Study Completion Date : September 21, 2018


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 Name: 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 Name: 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 Name: RO4877533, RoActemra, Actemra




Primary Outcome Measures :
  1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to approximately 196 days ]

Secondary Outcome Measures :
  1. Percentage of Participants With Infusion-Related Reactions (IRRs) as Assessed by Investigator and Reviewed by Endpoint Adjudication Committee (EAC) [ Time Frame: Day 1 (within 24 hours of first obinutuzumab infusion) ]
  2. 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) [ Time Frame: Day 1 (within 24 hours of first obinutuzumab infusion) ]
  3. Percentage of Participants With IRRS >= Grade 3 as assessed by the Investigator and Reviewed by the EAC [ Time Frame: Day 1 (within 24 hours of first obinutuzumab infusion) ]
  4. Number of Interruptions or Administration rate modifications of the First Infusion of Obinutuzumab [ Time Frame: Day 1 (within 24 hours of first obinutuzumab infusion) ]
  5. Percentage of Treatment Discontinuations due to IRR [ Time Frame: Day 1 (within 24 hours of first obinutuzumab infusion) ]
  6. Percentage of Participants With Overall Response as Assessed by Investigator According to NCI/ International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines [ Time Frame: 84 days after last treatment (up to approximately 280 days) ]
  7. Percentage of Participants With Negative Results for Minimal Residual Disease (MRD) Measured According to NCI/IWCLL Guidelines [ Time Frame: 84 days after last treatment (up to approximately 280 days) ]
  8. Area Under the Serum Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Obinutuzumab [ Time Frame: 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) ]
  9. Maximum Observed Serum Concentration (Cmax) of Obinutuzumab [ Time Frame: 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) ]
  10. Terminal Half-Life (t1/2) of Obinutuzumab [ Time Frame: 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) ]
  11. Area Under the Serum Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUC[0-last]) of Obinutuzumab [ Time Frame: 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) ]
  12. Total Clearance (CL) of Obinutuzumab [ Time Frame: 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) ]
  13. Volume of Distribution (Vd) of Obinutuzumab [ Time Frame: 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) ]
  14. AUC(0-inf) of Tocilizumab [ Time Frame: 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) ]
  15. Cmax of Tocilizumab [ Time Frame: 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) ]
  16. t1/2 of Tocilizumab [ Time Frame: 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) ]
  17. AUC(0-last) of Tocilizumab [ Time Frame: 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) ]
  18. Change From Baseline in Interleukin (IL)-6 Level [ Time Frame: 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

  19. Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble IL-6 Receptor (sIL-6R) [ Time Frame: 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

  20. Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Ferritin [ Time Frame: 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

  21. Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: C-Reactive Protein (CRP) [ Time Frame: 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

  22. Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Soluble Glycoprotein (gp) 130 [ Time Frame: 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

  23. Change From Baseline in Level of Downstream Biomarker of IL-6 Activation: Serum Amyloid A (SAA) [ Time Frame: 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

  24. Percentage of Participants With Depletion in Absolute Lymphocyte Count (ALC) [ Time Frame: 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) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02336048


Locations
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Israel
Rambam Medical Center; Heamatology & Bone Marrow Transplantation
Haifa, Israel, 3109601
Carmel medical center
Haifa, Israel, 3436212
Meir Medical Center; Heamatology Dept
Kfar Saba, Israel, 4428164
Kaplan Medical Center; Hematology Institute; Hematolgy Institute
Rehovot, Israel, 7610001
Ichilov Sourasky Medical Center; Heamatology
Tel Aviv, Israel, 6423906
Ziv Medical Center
Zfat, Israel, 1311001
Italy
A.O. Universitaria S. Martino Di Genova; Ematologia 1
Genova, Liguria, Italy, 16132
Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
Milano, Lombardia, Italy, 20162
A.O.U. Maggiore della Carità
Novara, Piemonte, Italy, 28100
Ospedale Businco; Ematologia
Cagliari, Sardegna, Italy, 09121
Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
Perugia, Umbria, Italy, 06156
Latvia
RECUH, Oncology Centre of Latvia; Clinic of Chemotherapy and Heamatology
Riga, Latvia, 1079
Spain
Hospital Universitari Vall d'Hebron; Servicio de Hematologia
Barcelona, Spain, 08035
Hospital Clínic i Provincial; Servicio de Hematología y Oncología
Barcelona, Spain, 08036
Hospital Univ. 12 de Octubre; Servicio de Hematologia
Madrid, Spain, 28041
Hospital Universitario Virgen del Rocio; Servicio de Hematologia
Sevilla, Spain, 41013
United Kingdom
Barts & London School of Med; Medical Oncology
London, United Kingdom, EC1A 7BE
University College Hospital; Department of Oncology
London, United Kingdom, N7 9NH
Christie Hospital Nhs Trust; Medical Oncology
Manchester, United Kingdom, M2O 4BX
Queens Hospital; R&D
Romford, United Kingdom, RM7 0AE
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02336048     History of Changes
Other Study ID Numbers: BO29448
2014-004594-16 ( EudraCT Number )
First Posted: January 12, 2015    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Obinutuzumab
Chlorambucil
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action