A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA)

Study Overview
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Brief Summary
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This open-label, randomized, parallel group study will evaluate the efficacy and safety of obinutuzumab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone or prednisone (CHOP) chemotherapy versus rituximab (MabThera/Rituxan) with CHOP in previously untreated participants with cluster of differentiation 20 (CD20)-positive diffuse large B-cell lymphoma (DLBCL). Participants will be randomized to receive either obinutuzumab 1000 milligrams (mg) intravenously (IV) every 21 days or rituximab 375 milligrams per square meter (mg/m^2) IV every 21 days for 8 cycles, in addition to 6-8 cycles of CHOP chemotherapy IV every 21 days. Participants randomized to the obinutuzumab arm will receive an additional two doses on Days 8 and 15 of Cycle 1. Anticipated time on study treatment is 24 weeks.

Official Title
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A Phase III, Multicenter, Open-Label Randomized Trial Comparing the Efficacy of GA101 (RO5072759) in Combination With CHOP (G-CHOP) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With CD20-Positive Diffuse Large B-Cell Lymphoma (DLBCL)

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Obinutuzumab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated CD20-positive DLBCL At least 1 bi-dimensionally measurable lesion (greater than [>]1.5 centimeters [cm] in its largest dimension on the computed tomography [CT] scan) Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Adequate hematological function Low-intermediate, high-intermediate or high-risk International Prognostic Index (IPI) score (low-risk IPI score: IPI 1 irrespective of bulky disease or IPI 0 with bulky disease, defined as one lesion greater than equal to (>/=) 7.5 cm) Left ventricular ejection fraction (LVEF) >/=50 percent (%) on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram Exclusion Criteria: History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products or to any component of CHOP or obinutuzumab Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines Participants with transformed lymphoma and participants with follicular lymphoma IIIB Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation Prior treatment with cytotoxic drugs or rituximab for another condition (for example, rheumatoid arthritis) or prior use of an anti-CD20 antibody Prior use of any monoclonal antibody within 3 months of the start of Cycle 1 Corticosteroid use of >30 milligrams per day (mg/day) of prednisone or equivalent, for purposes other than lymphoma symptom control Primary central nervous system (CNS) lymphoma and secondary CNS involvement by lymphoma, mantle-cell lymphoma (MCL), or histologic evidence of transformation to a Burkitt lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, plasmablastic lymphoma, and primary cutaneous DLBCL

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 |
| --- | --- |
| Active Comparator: Rituximab+Chemotherapy<br>Participants received eight 21-day cycles of rituximab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy. | Drug: Rituximab<br>* Rituximab at a dose of 375 mg/m^2, administered by intravenous (IV) infusion on Day 1 of each 21-day cycle for 8 cycles.<br>* Other names: MabThera, Rituxan;Drug: Cyclophosphamide<br>* Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle.<br>Drug: Doxorubicin<br>* Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle.<br>Drug: Vincristine<br>* Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle.<br>Drug: Prednisone<br>* Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle.<br>|
| Experimental: Obinutuzumab+Chemotherapy<br>Participants received eight 21-day cycles of obinutuzumab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy. | Drug: Obinutuzumab<br>* Obinutuzumab 1000 mg IV infusion, administered on Day 1 of each 21-day cycle for 8 cycles. During Cycle 1, obinutuzumab was also infused on Days 8 and 15.<br>* Other names: GA101, RO5072759;Drug: Cyclophosphamide<br>* Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle.<br>Drug: Doxorubicin<br>* Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle.<br>Drug: Vincristine<br>* Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle.<br>Drug: Prednisone<br>* Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression-Free Survival (PFS), Investigator-Assessed | Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]). Progression-free survival was defined as the time from randomization until the first documented day of disease progression or relapse, using a modified version of the Revised Response Criteria for Malignant Lymphoma, or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by computed tomography (CT) or magnetic resonance imaging (MRI). | Baseline up to approximately 6.5 years (up to 31 January 2018) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression-Free Survival (PFS), Independent Review Committee (IRC)-Assessed | Kaplan Meier estimate of median PFS was defined as time at which half of participants have progressed (progressive disease [PD]). Progression-free survival was defined as time from randomization until first documented day of disease progression or relapse, using a modified version of Revised Response Criteria for Malignant Lymphoma, or death from any cause, whichever occurred first, on basis of IRC assessments. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 cm or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by CT or MRI. This outcome measure used data from primary analysis which included all 1418 participants. | Baseline up to approximately 4 years and 9 months (up to 29 April 2016) | 
| Median Time to Overall Survival (OS) | 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. Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. | Baseline up to approximately 6.5 years (up to 31 January 2018) | 
| Overall Response Rate (ORR), Investigator-Assessed | Overall response was determined on the basis of investigator assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Overall response was defined as the disappearance of all evidence of disease, regression of measurable disease, and no new sites. | Baseline up to approximately 6.5 years (up to 31 January 2018) | 
| Overall Response Rate (ORR), IRC-Assessed | Overall response was determined on the basis of IRC assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Overall response was defined as the disappearance of all evidence of disease, regression of measurable disease, and no new sites. This outcome measure used data from primary analysis which included all 1418 participants. | Baseline up to approximately 4 years and 9 months (up to 29 April 2016) | 
| Complete Response (CR) at the End of Treatment, Investigator-Assessed | Percentage of participants with complete response was determined on the basis of investigator assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Complete response was defined as the disappearance of all evidence of disease. | Baseline up to approximately 6.5 years (up to 31 January 2018) | 
| Complete Response (CR) at the End of Treatment, IRC-Assessed | Percentage of participants with complete response was determined on the basis of IRC assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Complete response was defined as the disappearance of all evidence of disease. This outcome measure used data from primary analysis which included all 1418 participants. | Baseline up to approximately 4 years and 9 months (up to 29 April 2016) | 
| Median Time to Event-Free Survival (EFS), Investigator-Assessed | Kaplan Meier estimate of median EFS is the time at which half of the participants have progressed. Event-free survival was defined as the time from the date of randomization until the date of disease progression, relapse, initiation of a new non-protocol-specified anti-lymphoma treatment, or death from any cause on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Disease progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by CT/MRI. | Baseline up to death or disease progression, or initiation of new anti-lymphoma treatment (NALT), whichever occurred first, approximately 6.5 years (up to 31 January 2018) | 
| Median Time to Disease-Free Survival (DFS), Investigator-Assessed | Kaplan Meier estimate of median DFS was defined as time at which half of participants have disease progression/relapse or death from any cause. Disease-free survival was defined as time from date of the first occurrence of a documented CR to date of disease progression/relapse or death from any cause on basis of investigator assessments with use of Revised Response Criteria for Malignant Lymphoma. Tumor assessments were performed with CT/MRI. CR was defined as disappearance of all target lesions. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. | Baseline up to death or disease progression, whichever occurred first, approximately 6.5 years (up to 31 January 2018) | 
| Duration of Response (DOR), Investigator-Assessed | DOR: time from first occurrence of documented CR or PR to disease progression/relapse, or death from any cause for participants with a response of CR or PR. Tumor assessments were performed with CT/MRI. CR: disappearance of all target lesions. PR: >/=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodule regression >/= 50%. Progression/relapse: at least 50% increase in nodal lesions or >/=50% increase in any node > 1 cm or >/= 50% increase in other target lesions (e.g., splenic or hepatic nodules) and/or any new bone marrow involvement and/or any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. A participant in the Rituximab+CHOP arm with the longest follow-up, 53 months, had an event. The criterion for median was the minimum time when survival went below 50%. | Baseline up to death or disease progression, whichever occurred first, approximately 6.5 years (up to 31 January 2018) | 
| Time to Next Anti-Lymphoma Treatment (TTNALT) | Time to next anti-lymphoma treatment was defined as the time from the date of randomization to the start date of the next anti-lymphoma treatment or death from any cause. | Baseline up to start of next anti-lymphoma treatment or death due to any cause, whichever occurred first, approximately 6.5 years (31 January 2018) | 
| Percentage of Participants With Adverse Events (AEs) | 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. | Baseline up to approximately 6.5 years (up to 31 January 2018) | 
| Percentage of Participants With Human Anti-Human Antibodies (HAHAs) to Obinutuzumab | The presence of HAHAs to obinutuzumab was assessed in the first 100 randomized participants. | Pre-dose (Hour 0) on Cycle (C) 4 Day (D) 1, at end of treatment/early termination (up to Month 6), every 6 months thereafter for 30 months (cycle length = 21 days) | 
| Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale Score | The FACT-Lym subscale was developed to assess health-related quality of life in participants with non-Hodgkin lymphoma. The score range is 0-60, with higher scores indicating better outcomes. A positive change from baseline indicates an improvement. | Baseline (pre-dose [Hour 0] on C1D1), C3D1, end of treatment (up to Month 6), every 12 months thereafter up to approximately 6.5 years, (cycle length = 21 days) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) Domain Scores | The EORTC QLQ-C30 is a health-related quality of life questionnaire. A higher score indicates better quality of life, with changes of 5 to 10 points considered to be a minimally important difference to participants. | Baseline (pre-dose [Hour 0] on C1D1), C3D1, end of treatment (up to Month 6), every 12 months thereafter up to data cut-off, up to approximately 6.5 years, (cycle length = 21 days) | 
| Serum Concentrations of Obinutuzumab in Japanese Participants With Diffuse Large B-Cell Lymphoma (DLBCL) | Serum samples for assessment of obinutuzumab serum concentrations were collected only from a subset of Japanese participants following administration of 1000 mg obinutuzumab. | C1: D1 post-infusion and 20-28 and 66-80 hours after end of infusion, D8 and D15 pre-and post-infusion; C2: D1 pre- and post-infusion; C4: D1 pre- and post-infusion; C6: D1 pre- and post-infusion; C8: D1 pre- and post-infusion (cycle length = 21 days) |