A Safety and Efficacy Study of Obinutuzumab Alone or in Combination With Chemotherapy in Participants With Chronic Lymphocytic Leukemia

Phase 3

Completed

Conditions: Chronic Lymphocytic Leukemia

Interventions: Drug: Bendamustine
Drug: Chlorambucil
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Obinutuzumab

Registration Number: NCT01905943

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This multicenter, open-label, single-arm study will evaluate the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in participants with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). This is a Post-Authorization Safety Study. Participants will receive 6 cycles of single-agent obinutuzumab or obinutuzumab in combination with chemotherapy at the investigator's discretion. Each participant will be followed until 30 months after the last participant has been enrolled. Total length of the study is anticipated to be approximately 5 years.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 979

Inclusion Criteria

Previously untreated documented CLL according to National Cancer Institute/international workshop on CLL (NCI/iwCLL) criteria OR relapsed and/or refractory documented CLL participants requiring treatment according to NCI/iwCLL criteria; participants with up to 3 relapses are eligible
Refractory participants if last treatment was with single-agent therapy, single-agent chemotherapy, or single-agent antibody
Participants with 17p-deletion and/or p53 mutation may be included at the investigator's discretion
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Life expectancy greater than (>) 6 months according to the investigator's opinion
Adequate hematological function

Exclusion Criteria

Participants who have received more than 3 previous CLL treatment lines
Documented transformation of CLL to aggressive lymphoma (Richter's transformation)
Participants who are refractory to immunochemotherapy
Participants with abnormal laboratory values
One or more individual organ/system impairment score of 4 as assessed by the cumulative illness rating scale (CIRS) definition, excluding the eyes, ears, nose, throat and larynx organ systems
Participants with a history of progressive multifocal leukoencephalopathy (PML)
History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
Known hypersensitivity to the study drugs
History of prior malignancy unless the malignancy has been treated with a curative intent and in remission without treatment for greater than or equal to (>/=) 5 years prior to enrollment and with the exception of curatively-treated basal cell carcinoma, 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
Regular treatment with corticosteroids during the 28 days prior to the start of Cycle 1, Day 1, unless administered for indications other than CLL at a dose equivalent to less than or equal to (</=) 30 milligrams per day (mg/day) prednisone
Regular treatment with immunosuppressive medications following previous organ transplantation
Evidence of significant, uncontrolled concomitant diseases
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) or a major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization within 28 days prior to the start of Cycle 1, Day 1
Vaccination with live vaccines within 28 days prior to start of Cycle 1, Day 1
Major surgery (within 28 days prior to the start of Cycle 1, Day 1), other than for diagnosis
Positive for chronic hepatitis B, hepatitis C, human T-lymphotropic virus 1 (HTLV 1) or human immunodeficiency virus (HIV) infection
Pregnant or lactating women
Fertile men or women of childbearing potential
Participation in another clinical trial with drug intervention within 28 days prior to start of Cycle 1, Day 1 and during the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Obinutuzumab	Obinutuzumab	Participants will receive obinutuzumab either alone as single agent or in combination with chemotherapy (Fludarabine/Cyclophosphamide \[FC\], Bendamustine or Chlorambucil) at the investigator's discretion. Each cycle is of 28-days duration.
Obinutuzumab	Bendamustine	Participants will receive obinutuzumab either alone as single agent or in combination with chemotherapy (Fludarabine/Cyclophosphamide \[FC\], Bendamustine or Chlorambucil) at the investigator's discretion. Each cycle is of 28-days duration.
Obinutuzumab	Chlorambucil	Participants will receive obinutuzumab either alone as single agent or in combination with chemotherapy (Fludarabine/Cyclophosphamide \[FC\], Bendamustine or Chlorambucil) at the investigator's discretion. Each cycle is of 28-days duration.
Obinutuzumab	Cyclophosphamide	Participants will receive obinutuzumab either alone as single agent or in combination with chemotherapy (Fludarabine/Cyclophosphamide \[FC\], Bendamustine or Chlorambucil) at the investigator's discretion. Each cycle is of 28-days duration.
Obinutuzumab	Fludarabine	Participants will receive obinutuzumab either alone as single agent or in combination with chemotherapy (Fludarabine/Cyclophosphamide \[FC\], Bendamustine or Chlorambucil) at the investigator's discretion. Each cycle is of 28-days duration.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs)	Baseline up to time of primary completion (3 years)	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).
Number of Participants With Adverse Events of Special Interest (AESIs)	Baseline up to time of primary completion (3 years)	The following AEs were defined as AESIs: AEs with the preferred term Tumour Lysis Syndrome (TLS), Infusion-Related Reactions (IRRs) defined as AEs that occurred during or within 24 hours of the completion of obinutuzumab infusion and were assessed as related to obinutuzumab by the Investigator, Infections defined as AEs from System Organ Class (SOC) "Infections and infestations" and AEs with the preferred term Neutropenia. Reported are number of participants with total AESIs, IRRs, Infections, Neutropenia and TLS.
Number of Participants With Adverse Events of Particular Interest (AEPIs)	Baseline up to time of primary completion (3 years)	The following AEs were defined as AEPIs: AEs with the preferred term Progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation defined as AEs with preferred term containing "Hepatitis B" or "hepatitis acute", thrombocytopenia defined via Roche MedDRA basket subgroup "haematopoietic thrombocytopenia", second malignancies defined as AEs from the SOC "Neoplasms benign, malignant and unspecified" starting 6 months after the first study drug intake, second malignancies based on standardised MedDRA queries (SMQ) starting 6 months after the first study drug intake based on the MedDRA SMQ "Malignant or unspecified tumours", in which benign neoplasms are not included, Cardiac events including AEs from the SOC "Cardiac disorders", and hemorrhagic events defined via Roche MedDRA basket subgroup "Haemorrhagic events". Reported are number of participants with total AEPIs and each of the AEPI categories.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Minimal Residual Disease (MRD)-Negativity as Assessed by Flow Cytometry	3 months after the last dose of study treatment (up to approximately 5 years)	MRD-negativity was defined as the presence of less than 1 chronic lymphocytic leukemia (CLL) cell per 10,000 leukocytes in blood and bone marrow as assessed by flow cytometry 3 months after last dose of study treatment (i.e. at final response assessment \[FRA\] visit).
Median Time to Response (TTR)	Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)	Kaplan Meier estimate of median TTR was defined as the time at which half of the participants reached CR or PR based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L and bone marrow normocellular for age. PR: \>/= 50% decrease in peripheral blood lymphocyte count AND \>/= 50% reduction in lymphadenopathy OR \>/= 50% reduction of liver enlargement OR \>/= 50% reduction of spleen PLUS one of the following: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L OR \>/= 50% increase in neutrophils, platelets or hemoglobin.
Median Time to Progression-Free Survival (PFS)	Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)	Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease \[PD\]) based on IWCLL tumor response criteria or died from any cause, whichever occurred first. PD: at least one of the following: \>/= 50% increase in the absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, \>/= 50% increase in the longest diameter of any previous site of clinically significant lymphadenopathy, \>/= 50% increase in the enlargement of the liver and/or spleen, transformation to more aggressive histology, progression of any cytopenia, decrease of hemoglobin levels by more than 20 g/L or to less than 100 g/L, decrease of platelet counts by more than 50% or to less than 100,000 /mcL, decrease of neutrophil counts by more than 50% or to less than 1,000/mcL.
Percentage of Participants With Overall Response (OR) at Final Response Assessment (FRA)	3 months after the last dose of study treatment (up to approximately 5 years)	OR: percentage of participants with complete response (CR) or CR with incomplete marrow recovery (CRi), or partial response (PR), as determined by the investigator based on International Workshop on Chronic Lymphocytic Leukemia (IWCLL) tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: \>/= 50% decrease in peripheral blood lymphocyte count AND \>/= 50% reduction in lymphadenopathy OR \>/= 50% reduction of liver enlargement OR \>/= 50% reduction of spleen PLUS one of the following: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L OR \>/= 50% increase in neutrophils, platelets or hemoglobin.
Median Time to Duration of Response (DoR)	Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)	Kaplan Meier estimate of median DoR was defined as the time at which half of the responding (PR or CR) participants had progressed (PD) or died from any cause, whichever occurred first. PR: \>/= 50% decrease in peripheral blood lymphocyte count AND \>/= 50% reduction in lymphadenopathy OR \>/= 50% reduction of liver enlargement OR \>/= 50% reduction of spleen PLUS one of the following: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L OR \>/= 50% increase in neutrophils, platelets or hemoglobin. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L and bone marrow normocellular for age. PD: as defined in the description for Event-Free Survival outcome measure.
Percentage of Participants With Best Overall Response (BOR)	Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)	BOR was defined as the percentage of participants with the best response obtained throughout the trial with CR, CRi, or PR, as determined by the investigator based on IWCLL tumor response criteria. CR: Peripheral blood lymphocytes 4,000/mcL, no significant lymphadenopathy, no hepatomegaly and splenomegaly, no disease symptoms, blood counts: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L and bone marrow normocellular for age. Cri: CR with persistent cytopenia. PR: \>/= 50% decrease in peripheral blood lymphocyte count AND \>/= 50% reduction in lymphadenopathy OR \>/= 50% reduction of liver enlargement OR \>/= 50% reduction of spleen PLUS one of the following: neutrophils \>1,500/mcL, platelets \> 100,000/mcL, hemoglobin \> 110 g/L OR \>/= 50% increase in neutrophils, platelets or hemoglobin.
Median Time to New Anti-Leukemia Therapy (TTNT)	Baseline until end of study (up to approximately 5 years)	Kaplan Meier estimate of median TTNT was defined as the time at which half of the participants have initiated a new anti-leukemic therapy.
Median Time to Event-Free Survival (EFS)	Baseline, Day 85, end of treatment or early termination, and follow-up, assessed up to disease progression or death, whichever occurs first (up to approximately 5 years)	Kaplan Meier estimate of median EFS is the time at which half of the participants have progressed as assessed by investigator based on IWCLL tumor response criteria, or have initiated a non-protocol-specified anti-leukemia therapy or died, whichever occurs first. PD: at least 1 of the following: \>/= 50% increase in absolute number of circulating lymphocytes to at least 5,000/mcL, appearance of new palpable lymph nodes, \>/= 50% increase in longest diameter of any previous site of clinically significant lymphadenopathy, \>/= 50% increase in enlargement of liver and/or spleen, transformation to more aggressive histology, progression of any cytopenia, decrease of hemoglobin levels by more than 20 g/L or to less than 100 g/L, decrease of platelet counts by more than 50% or to less than 100,000 /mcL, decrease of neutrophil counts by more than 50% or to less than 1,000/mcL.
Median Time to Overall Survival (OS)	Baseline until death (Approximately up to 5 years)	Kaplan Meier estimate of median OS was defined as the time at which half of the participants had died, regardless of the cause of death.

Trial Locations

Locations (174): Hospital Iturraspe
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Santa Fé, Argentina
Hospital Erasme; Neurologie
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Bruxelles, Belgium
Cliniques Universitaires St-Luc
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Bruxelles, Belgium
Jessa Zkh (Campus Virga Jesse)
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Hasselt, Belgium
CHU Sart-Tilman
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Liège, Belgium
Sint Augustinus Wilrijk
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Wilrijk, Belgium
University Clinical Center of the Republic of Srpska, Clinic for Internal Disease, Hematology Dept
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Banja Luka, Bosnia and Herzegovina
University Clinical Center Sarajevo, Clinic for Hematology
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Sarajevo, Bosnia and Herzegovina
Hospital das Clinicas - UFRGS
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Porto Alegre, RS, Brazil
Hospital de Cancer de Barretos
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Barretos, SP, Brazil
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Hospital Iturraspe
🇦🇷Santa Fé, Argentina