A Study of Obinutuzumab [RO5072759 (GA101)] in Combination With CHOP Chemotherapy in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma (GATHER)

Study Overview
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Brief Summary
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This open-label, multicenter study will evaluate the efficacy and safety of obinutuzumab [RO5072759 (GA101)] in combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemotherapy in patients with advanced diffuse large B-cell lymphoma. Patients will receive 8 cycles of obinutuzumab (1000 mg intravenously on Day 1 of each 21-day cycle, during Cycle 1 obinutuzumab will also be infused on Days 8 and 15) in combination with CHOP chemotherapy on Day 1 of cycles 1 to 6. A substudy will investigate the drug-drug interaction of obinutuzumab with CHOP chemotherapy agents. For the substudy, an additional cohort of approximately 15 patients are planned to be enrolled at a subset of investigational sites.

Official Title
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A Phase II, Open-Label, Multicenter Study of Efficacy, Safety, and Biomarkers in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma Treated With GA101 (RO5072759) in Combination With CHOP Chemotherapy

Conditions
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Lymphoma, B-Cell

Intervention / Treatment
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* Drug: obinutuzumab
* Drug: cyclophosphamide
* Drug: doxorubicin
* Drug: prednisone
* Drug: vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, ≥18 years of age Previously untreated cluster of differentiation antigen 20 (CD20)-positive diffuse large B-cell lymphoma Ann Arbour Stage III/IV and bulky II (mass >10 cm) At least one bi-dimensionally measurable lesion defined as >1.5 cm in its largest dimension by CT scan Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Left ventricular ejection fraction ≥50% Adequate hematologic function Exclusion Criteria: Transformed lymphoma (follicular IIIB) if previously treated with chemotherapy or immunotherapy Prior therapy for diffuse large B-cell lymphoma except for nodal biopsy or local irradiation Central nervous system (CNS) lymphoma, primary mediastinal large cell lymphoma, primary cutaneous lymphoma, primary effusion lymphoma Patients who received cytotoxic drugs or rituximab as part of their treatment for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1 Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines History of severe allergic or anaphylactic reactions to monoclonal antibody therapy History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or malignancy treated with or without curative intent and in remission without treatment for ≥2 years prior to enrolment Positive for hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or human T-cell leukemia virus (HTLV-1) infection Pregnant or lactating women

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: obinutuzumab + CHOP<br>Participants received 1000 mg obinutuzumab intravenously on Day 1 of each 21-day cycle for 8 cycles; during Cycle 1 administration also on Days 8 and 15. Participants also received standard CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisone) for 6 cycles. | Drug: obinutuzumab<br>* 1000 mg intravenously on Day 1 of each 21-day cycle, 8 cycles; during Cycle 1 administration also on Days 8 and 15.<br>Drug: cyclophosphamide<br>* 750 mg/m^2 intravenous (IV), Day 1 of each 21-day cycle, 6 cycles.<br>Drug: doxorubicin<br>* 50 mg/m^2 IV, Day 1 of each 21-cycle, 6 cycles.<br>Drug: prednisone<br>* 100 mg/day, Days 1 through 5 of each 21-day cycle, 6 cycles.<br>Drug: vincristine<br>* 1.4 mg/m^2 IV, Day 1 of each 21-day cycle, 6 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate as Assessed by the Investigator at the End of Treatment | Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT). CR is the disappearance of all evidence of disease. | From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days) | 
| Overall Response Rate (ORR) as Assessed by the Investigator at the End of Treatment | Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the investigator using regular clinical and laboratory examinations, FDG-PET and computed tomography (CT). CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites. | From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) Rate as Assessed by the Independent Review Facility (IRF) at the End of Treatment | Complete response rate is defined as the percentage of participants with Complete Response (CR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. | From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days) | 
| Overall Response Rate (ORR) as Assessed by the IRF at the End of Treatment | Overall response rate was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007). Disease response was evaluated by the IRF using CT scans, PET scans and pertinent clinical information. CR is the disappearance of all evidence of disease. PR is at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites. | From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days) | 
| Progression-Free Survival (PFS) as Assessed by the Investigator | PFS was defined as the time from the date of the first dose of study treatment until the date of disease progression, relapse, or death from any cause. | From the first dose of study treatment to PFS assessment (up to 64 months) | 
| Duration of Response (DOR) | DOR is defined as first occurrence of documented response (CR or PR) until the first occurrence of relapse or progression or death of any cause. CR: disappearance of all evidence of disease. PR: at least 50% regression of measurable disease compared to tumors measured by a baseline scan and no new sites. | From the response assessment to relapse, progression, or death (up to 64 months) | 
| Percentage of Participants With Adverse Events as a Measure of Safety | An adverse event was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug or other protocol-imposed intervention. Preexisting conditions that worsened during the study were reported as adverse events. | From the first dose of study treatment to end of study (up to 5 years 4 months) | 
| Number of Participants With Grade 3 to 4 Infusion-Related (IRR) Adverse Events (AE) in Participants Receiving Shorter Duration Infusion (SDI) | SDI 120 is a shorter duration infusion of 120 minutes and SDI 90 is shorter duration infusion of 90 minutes. Grade 3 IRR AE: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae. Grade 4 IRR AE: Life-threatening consequences; urgent intervention indicated. | From the first dose of study treatment to end of treatment response assessment (approximately 228 to 258 days) | 
| Pharmacokinetics (PK): Maximum Concentration Observed (Cmax) for Obinutuzumab | Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in micrograms per milliliter (μg/mL). | Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12 | 
| Pharmacokinetics: Terminal Half-Life (t1/2) for Obinutuzumab | T1/2 is the time required for the concentration of the drug to reach half of its original value. Blood was collected for PK Parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in days | Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12 | 
| Pharmacokinetics: Clearance (Cl) for Obinutuzumab | Cl is the volume of serum cleared of the drug per unit of time. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters/day (mL/day). | Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12 | 
| Pharmacokinetics: Volume of Distribution (V) for Obinutuzumab | V is the apparent volume in which a drug is distributed in the body. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in milliliters (mL). | Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12 | 
| Pharmacokinetics: Area Under the Concentration-Time Curve 7 Day (AUC7day) | Blood was collected for PK parameters. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in in day times micrograms per milliliter (day*μg/mL). | Cycle 1 Day 1 pre and post dose, Days 3,5, Day 8 pre and post-dose, Day 15 pre-dose. Cycle 8 Day 1 pre and post-dose, Days 5,8,12 | 
| Pharmacodynamics: Peripheral Blood CD19-positive B-cell Count |  | Up to approximately 24 months |