A Dose-Escalating Study of Obinutuzumab in Patients With B-lymphocyte Antigen (CD20+) Malignant Disease (GAUGUIN)

Dose-limiting toxicities were defined as obinutuzumab-related adverse events occurring within the first 28 days of each administration of obinutuzumab, with the exception of B-cell depletion and lymphopenia which are expected outcomes of treatment with obinutuzumab.

Time frame: Baseline to 28 days after the last infusion of obinutuzumab (up to 6 months)

Population: Safety population: All enrolled participants in Phase I, who had received at least 1 dose of obinutuzumab by 6 months.

Best overall response (BOR) was defined as the percentage of participants with a complete response (CR) or partial response (PR)

Time frame: by Cutoff Date: 31 March 2012 (within 3 years, 4 months)

Population: Safety population: All enrolled participants in Phase II, who had received at least 1 dose of obinutuzumab.

Blood samples were taken on Day 1 (pre-infusion, end of infusion, 3-6 hours post-infusion) of Cycle 1. Nonlinear mixed-effects modeling (with NONMEM software) was used to analyze the pooled samples for dose-concentration-time data of obinutuzumab.

Time frame: Day 1 of Cycle 1

Population: Pharmacokinetics (PK)- evaluable population at the given dose (e.g., 3 or more participants). Other doses did not have a PK-evaluable population, so were not included in the table of results. Due to the limited sampling schedule derived PK parameters could not be accurately obtained during Cycle 1 and Cycle 8.

Duration of complete response was defined as the time from the first complete or partial response until disease progression (PD) or death, whichever occurred first. For non-Hodgkin's lymphoma participants, PD was defined as \>= 50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal node for participants with a partial response or non-responders or the appearance of any new lesion during or at the end of therapy. For chronic lymphocytic leukemia participants, PD was defined as: (1) A \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules); a lymph node with a short axis of \< 1.0 cm must increase by \>= 50% and to a size of 1.5×1.5 cm or \> 1.5 cm in the longest axis. (2) Appearance of any new lesion \> 1 cm in the short axis. (4) A new site that is PET-positive with histological confirmation.

Time frame: by the end of the follow-up period in Phase II of the study (within 3 years, 4 months)

Population: Safety population: All enrolled participants in Phase II, who had received at least 1 dose of obinutuzumab. Data reported for each disease cohort.

Obinutuzumab serum pharmacokinetic (PK) parameters in NHL participants following ascending doses.

Time frame: at Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 8 (over 168 days)

Population: Pharmacokinetics (PK)- evaluable population at the given dose (e.g., 3 or more participants at any of the given time points). Other doses did not have a PK-evaluable population, so were not included in the table of results. Due to the limited sampling schedule derived PK parameters could not be accurately obtained during Cycle 1 and Cycle 8.

EFS is defined as the time from start of treatment to disease progression/relapse, death or, in case of early withdrawal from the treatment period, the (end) date of last dose, whatever comes first.

Time frame: by the end of the follow-up period in Phase II of the study (within 3 years, 4 months)

A complete response was defined as the disappearance of all evidence of disease (NHL) and symptoms; normalization of biochemical abnormalities (NHL); regression of lymph nodes and nodal masses to normal size; decrease of nodes in the sum of the products of the greatest diameters (SPD); regression in size of the spleen and/or liver, should not be palpable, and disappearance of nodules related to lymphoma (CLL). Complete/unconfirmed (CRu) response includes NHL patients with one or more of the following: 1) a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the SPD; 2) Indeterminate bone marrow (increased number or size of aggregates without cytologic or architectural atypia). Complete Response with Incomplete Bone Marrow Recovery (CRi) was measured only in patients with CLL.

Time frame: by Cutoff Date: 31 March 2012 (within 3 years, 4 months)

A PR was defined as a \>=50% decrease in SPD of the 6 largest nodes or nodal masses; no increase in size of other nodes, liver, or spleen; regression of splenic and hepatic nodules by \>=50% in their SPD or, for single nodules, in the long axis (CLL only); and no new disease sites.

Time frame: by Cutoff Date: 31 March 2012 (within 3 years, 4 months)

Patients who might benefit from retreatment were allowed to be treated again at the request of the investigator.

Time frame: by Cutoff Date: 25 November 2013 (within 4 years, 2 months)

Population: Retreated participants

B-cell depletion was defined in two ways: definition 1 - decrease below 5% baseline level and definition 2 - decrease below 0.04 x 109/L. B-cell recovery was defined in two ways: definition 1 - return to at least 50% of baseline level and definition 2 - return to at least 0.08 x 109/L.

Time frame: by the end of Phase II (within 3 years, 4 months)

Population: Participants analyzed include those with B-cell depletion at the end of treatment (N), with assessments (n) at each time point.

PFS was defined as the time from start of treatment to disease progression (PD) or death due to any cause, whichever occurred first. For non-Hodgkin's lymphoma participants, PD was defined as \>= 50% increase from nadir in the sum of the products of the greatest diameters (SPD) of any previously identified abnormal node for participants with a partial response or non-responders or the appearance of any new lesion during or at the end of therapy. For chronic lymphocytic leukemia participants, PD was defined as: (1) A \>= 50% increase from nadir in the SPD of any previously involved nodes, or in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules); a lymph node with a short axis of \< 1.0 cm must increase by \>= 50% and to a size of 1.5×1.5 cm or \> 1.5 cm in the longest axis. (2) Appearance of any new lesion \> 1 cm in the short axis. (4) A new site that is positron emission tomography (PET)-positive with histological confirmation.

Time frame: by the end of the follow-up period in Phase II of the study (within 3 years, 4 months)

Population: Safety population: All enrolled participants in Phase II, who had received at least 1 dose of obinutuzumab.

Time frame: at Cycle 1 Day 1, Cycle 1 Day 8 and Cycle 8 (over 168 days)