GAUSS: A Study of Obinutuzumab (RO5072759) in Patients With Indolent Non-Hodgkin's Lymphoma

Overall response was defined as Complete Response (CR), Complete Response/Unconfirmed (CRu) or Partial Response (PR) as assessed by investigator at end of induction treatment. Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. CR was defined as the disappearance of all clinical and radiographic evidence of disease, disease-related symptoms and normalization of biochemical abnormalities of NHL. CRu was CR plus one or more of the following: A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameter (tumors)(SPD) and/or indeterminate bone marrow. PR was defined as 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. No new sites of disease.

Time frame: Randomization to clinical cutoff: 01 September 2011 (Up to 70 days)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

Duration of Response was defined as the date the response, either Complete Response (CR) or Partial Response (PR), was first recorded until the date of Disease Progression or death due to any cause. Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. CR was defined as the disappearance of all clinical and radiographic evidence of disease, disease-related symptoms and normalization of biochemical abnormalities of NHL. PR was defined as 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. No new sites of disease. Disease Progression was defined as a ≥ 50% increase from nadir in the SPD of any previously identified abnormal node and/or the appearance of any new lesion during or at the end of therapy.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Participants from the ITT population (all randomized participants with follicular NHL at the time of diagnosis N=75/74\] with response. Patients with no documented progression after CR or PR will be censored at the last tumor assessment. If no assessment available patients will be censored at the first study drug.

Event-free survival (EFS) was defined as the time between date of randomization and the date of disease progression/relapse, death, or start of a new anti-leukemic therapy. Progression was defined as a ≥ 50% increase from nadir in the SPD of any previously identified abnormal node and/or the appearance of any new lesion during or at the end of therapy. Relapse was defined as the appearance of any new lesion or increase by ≥ 50% in the size of previously involved sites and/or a ≥ 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: ITT population included all randomized participants with follicular non-Hodgkin's lymphoma at the time of diagnosis. If no EFS event occurred, EFS was censored at the date of the last tumor assessment. If no tumor assessment is available patient was censored at the date of the first study drug administration.

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory result), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution. A SAE was any AE that was one of the following: fatal, life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product or considered a significant medical event by the investigator. Additional information about AEs can be found in the Adverse Event Section.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) [Includes all AEs reported 28 days after last dose and all Related SAEs regardless of time of last dose.]

Population: Safety Population included all randomized participants who received study drug.

Blood was collected on Day 1 and was sent to a central laboratory for analysis of human anti-chimeric antibodies (anti-rituximab antibodies) using a validated enzyme-linked immunosorbent assay (ELISA). HACA samples were not collected for participants randomized to the rituximab arm.

Time frame: Day 1

Population: Participants from the Safety Population, all randomized participants who received study drug, who had samples available for HACA analysis.

Blood was collected on Day 1 pre-infusion, during the safety follow-up for those patients who did not enter the Extension period and 6 months after the last infusion of the Extension Period if applicable. Blood was sent to a central laboratory and was tested for anti-obinutuzumab antibodies using a validated enzyme-linked immunosorbent assay (ELISA). HAHA samples were not collected for participants randomized to the rituximab arm.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Safety Population included all randomized participants who received study drug.

Overall response was defined as Complete Response (CR), Complete Response/Unconfirmed (CRu) or Partial Response (PR) as assessed by investigators at end of induction treatment. Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis who received treatment in the extension period.

Infusion Related Reactions were AEs that occurred during the infusion or within 24 hours of the infusion.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Safety Population included all randomized participants who received at least once dose of study drug.

Blood was collected and sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry at the end of the induction period. B-cell depletion was defined as a CD19 result 5 % of the Baseline value after at least one dose of study drug was administered.

Time frame: Day 22

Population: Participants from the Safety Population, all randomized participants who received study drug, with data available for analysis.

Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell recovery was defined as the time point when the CD-19 values return to ≥ 50% of baseline levels. The number of participants with B-cell recovery from End of Induction (treatment) Phase to 6 months of Follow-up is reported in two categories: Recovery with Progressive Disease (PD) or Recovery without PD. PD required one of the following: 50 % increase in the absolute number of circulating lymphocytes, Appearance of new palpable lymph nodes, 50 % increase in the longest diameter of any previous site of lymphadenopathy, 50 % increase in the enlargement of the liver and/or spleen or Transformation to a more aggressive histology.

Time frame: End of last dose + 6 Months Follow-Up

Population: Participants from the Safety Population, all randomized participants who received study drug, with previous B-Cell Depletion and B-Cell assessment at 6 Month Follow-up.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycle 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). AUClast was calculated in days\* micrograms/milliliter (μg/mL)

Time frame: Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycle 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). AUCtau was calculated in days\* micrograms/milliliter (μg/mL)

Time frame: Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycle 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). CLsst was calculated in milliliter/day (mL/day)

Time frame: Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycles 1, 2, 3 and 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Cmax was calculated in micrograms/milliliter (μg/mL).

Time frame: Day 1 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours post-infusion), Days 8 and 15 (pre-infusion, at end of infusion), Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for Pharmacokinetic (PK) Parameters before and after dose administration of obinutuzumab in Induction Phase Cycle 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Terminal Half-Life was calculated in days.

Time frame: Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycle 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Vss was calculated in liters (L).

Time frame: Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Blood was collected for PK Parameters before and after dose administration of obinutuzumab in Induction Phase Cycles 2, 3 and 4. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Ctrough was calculated in micrograms/milliliter (μg/mL).

Time frame: Days 8 and 15 (pre-infusion, at end of infusion), Day 22 (pre-infusion, at end of infusion, 3-6, 20-28, 66-80 hours, 6-8, 12-16, 18-24, 28-56 days post-infusion)

Population: PK Analysis Population included all participants who received obinutuzumab and had PK samples collected as per protocol. Patients with limited PK sampling time-points were excluded from the analysis.

Overall response was defined as Complete Response (CR), Complete Response/Unconfirmed (CRu) or Partial Response (PR) as assessed by investigators during study treatment (induction or extended treatment phase). Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. CR was defined as the disappearance of all clinical and radiographic evidence of disease, disease-related symptoms and normalization of biochemical abnormalities of NHL. CRu was CR plus one or more of the following: A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameter (tumors)(SPD) and/or indeterminate bone marrow. PR was defined as 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. No new sites of disease.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

Overall response was defined as Complete Response (CR), Complete Response/Unconfirmed (CRu) or Partial Response (PR) as assessed by investigators during study treatment (induction or extended treatment phase). Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. CR was defined as the disappearance of all clinical and radiographic evidence of disease, disease-related symptoms and normalization of biochemical abnormalities of NHL. CRu was CR plus one or more of the following: A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameter (tumors)(SPD) and/or indeterminate bone marrow. PR was defined as 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. No new sites of disease.

Time frame: Randomization to clinical cutoff : 01 September 2011 (Up to 70 days)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. CR is defined as the disappearance of all clinical and radiographic evidence of disease, disease-related symptoms and normalization of biochemical abnormalities of NHL. All lymph nodes and nodal masses must have regressed to normal size. The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. Any macroscopic nodules in any organs detectable on imaging techniques should no longer be present. Other organs considered to be enlarged before therapy due to involvement by lymphoma, such as liver and kidneys, must have decreased in size. If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site.

Time frame: Randomization to clinical cutoff : 01 September 2011 (Up to 70 days)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

Percentage of participants with Event Free Events: disease progression/relapse, death, or start of a new anti-leukemic therapy. Progression was defined as a ≥ 50% increase from nadir in the SPD of any previously identified abnormal node and/or the appearance of any new lesion during or at the end of therapy. Relapse was defined as the appearance of any new lesion or increase by ≥ 50% in the size of previously involved sites and/or a ≥ 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

Computed tomography imaging was used for the primary assessment of tumor response per 1999 criteria by Cheson. PR was defined as 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. No new sites of disease.

Time frame: Randomization to clinical cutoff : 01 September 2011 (Up to 70 days)

Population: Participants from the Intent-to-treat (ITT) population (all randomized participants) with follicular non-Hodgkin's lymphoma (NHL) at the time of diagnosis.

The percentage of participants with progression, relapse, or death events from any cause as assessed by the Investigator. Progression was defined as a ≥ 50% increase from nadir in the SPD of any previously identified abnormal node and/or the appearance of any new lesion during or at the end of therapy. Relapse was defined as the appearance of any new lesion or increase by ≥ 50% in the size of previously involved sites and/or a ≥ 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: Participants from the ITT population (all randomized participants) with follicular non-Hodgkin's lymphoma at the time of diagnosis. If event did not occur, PFS was censored at the date of the last tumor assessment. If no tumor assessment is available patient was censored at the date of the first study drug administration.

PFS was defined as the time from randomization to the first occurrence of progression, relapse, or death from any cause as assessed by the Investigator. Progression was defined as a ≥ 50% increase from nadir in the SPD of any previously identified abnormal node and/or the appearance of any new lesion during or at the end of therapy. Relapse was defined as the appearance of any new lesion or increase by ≥ 50% in the size of previously involved sites and/or a ≥ 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node.

Time frame: Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months)

Population: ITT population included all randomized participants with follicular non-Hodgkin's lymphoma at the time of diagnosis. If no PFS even occurred, PFS was censored at the date of the last tumor assessment. If no tumor assessment was available patient was censored at the date of the first study drug administration.