Trial Outcomes & Findings for A Safety and Efficacy Study of Obinutuzumab Alone or in Combination With Chemotherapy in Participants With Chronic Lymphocytic Leukemia (NCT NCT01905943)

The study was conducted at 195 centers in 31 countries

A total of 1131 subjects were screened and 979 subjects were enrolled. Due to compliance issues a site in Romania was closed. Seven subjects were excluded from the analysis, because data integrity was impacted by the site's non-compliance. Hence, data analysis is reported for 972 enrolled subjects.

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

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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

Kaplan Meier estimate of median TTNT was defined as the time at which half of the participants have initiated a new anti-leukemic therapy.

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.