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

Study Overview
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Brief Summary
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This study will investigate the efficacy of weekly intravenous obinutuzumab [GA101 (RO5072759)] monotherapy, in patients with relapsed CD20+ indolent Non-Hodgkin's Lymphoma. Patients will be randomized to receive either GA101 or rituximab, given as four weekly infusions. At the conclusion of the initial trial patients may be eligible to continue therapy up to 24 months. The anticipated time on study treatment is 3- 24 months, and the target sample size is 100-500 individuals.

Official Title
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An Open-label, Multi-center, Randomized Study to Evaluate the Efficacy on Tumor Response of GA101 (RO5072759) Monotherapy Versus Rituximab Monotherapy in Patients With Relapsed CD20+ Indolent Non-Hodgkin's Lymphoma

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: obinutuzumab (RO5072759)
* Drug: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, >=18 years of age relapsed CD20+ indolent B-cell non-Hodgkin's lymphoma documented history of response of >/= 6 months duration from last rituximab-containing regimen clinical indication for treatment as determined by the investigator Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Exclusion Criteria: prior use of any investigational monoclonal antibody within 6 months of study start prior use of any anti-cancer vaccine prior use of rituximab within 8 weeks of study entry radioimmunotherapy within 3 months prior to study entry Central Nervous System (CNS) lymphoma or evidence of transformation to high-grade or diffuse large B-cell lymphoma

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab<br>Participants received 1000 mg obinutuzumab intravenous (IV) infusion once a week on Days 1, 8, 15, and 22 in the Induction Period. 2 months following the last infusion, participants without disease progression, were eligible to receive a 1000 mg IV infusion every two months for 2 years in the Extension Period. All participants received oral acetaminophen/ paracetamol (1000 mg) and an antihistamine such as diphenhydramine (50-100 mg), 30-60 minutes prior to each infusion. | Drug: obinutuzumab (RO5072759)<br>* 1000 mg obinutuzumab intravenous (IV) infusion once a week for 4 weeks.<br>* Other names: GAZYVA®;|
| Active Comparator: Rituximab<br>Participants received 375 mg/m^2 rituximab IV infusion once a week on Days 1, 8, 15 and 22 in the Induction Period. 2 months following the last infusion, participants without disease progression were eligible to receive a 375 mg/m^2 rituximab IV infusion once every two months for 2 years in the Extension Period. All participants received oral acetaminophen/ paracetamol (1000 mg) and an antihistamine such as diphenhydramine (50-100 mg), 30-60 minutes prior to each infusion. | Drug: rituximab<br>* 375 mg/m^2 rituximab IV infusion once a week for 4 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response At the End of Induction Period | 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. | Randomization to clinical cutoff: 01 September 2011 (Up to 70 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response at the End of the Induction Period | 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. | Randomization to clinical cutoff : 01 September 2011 (Up to 70 days) | 
| Percentage of Participants With Partial Response (PR) at the End of the Induction Period | 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. | Randomization to clinical cutoff : 01 September 2011 (Up to 70 days) | 
| Percentage of Participants With Best Overall Response Achieved at Any Time During the Study Treatment | 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. | Randomization to clinical cutoff : 01 September 2011 (Up to 70 days) | 
| Number of Participants With Improved Overall Response During the Extended Treatment Period | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Percentage of Participants With Best Overall Response Achieved at Any Time During the Study Treatment | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Progression-Free Survival (PFS) | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Percentage of Participants With Progression-Free Survival (PFS) Events | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Event Free Survival | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Percentage of Participants With Event Free Survival (EFS) Events | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Duration of Response | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Obinutuzumab Serum PK Parameter: Terminal Half-Life (t1/2) | 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. | 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) | 
| Obinutuzumab Serum PK Parameter: Maximum Serum Concentration (Cmax) | 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). | 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) | 
| Obinutuzumab Serum PK Parameter: Area Under the Concentration Curve (AUClast) | 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) | 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) | 
| Obinutuzumab Serum PK Parameter: Clearance at Steady-State (CLss) | 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) | 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) | 
| Obinutuzumab Serum PK Parameter: Volume of Distribution at Steady-State (Vss) | 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). | 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) | 
| Obinutuzumab Serum PK Parameter: Area Under the Concentration Curve Between Dosing Interval (AUCtau) | 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) | 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) | 
| Obinutuzumab Trough Serum Concentration (Ctrough) | 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). | 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) | 
| Number of Participants With Peripheral Blood B-Cell Depletion | 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. | Day 22 | 
| Number of Participants With Peripheral Blood B-Cell Recovery | 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. | End of last dose + 6 Months Follow-Up | 
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | 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. | 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.] | 
| Number of Participants With Infusion Related Reactions | Infusion Related Reactions were AEs that occurred during the infusion or within 24 hours of the infusion. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) | 
| Number of Participants With Human Anti-Chimeric Antibodies (HACA) | 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. | Day 1 | 
| Number of Participants With Human Anti-Human Antibodies (HAHA) | 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. | Randomization to Clinical cutoff: 07 March 2013 (Up to 43.2 months) |