A Study of Obinutuzumab (GA101; RO5072759) in Combination With Chemotherapy in Participants With Previously Untreated Chronic Lymphocytic Leukemia (CLL) (GALTON)

Study Overview
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Brief Summary
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This open-label, 2-arm, nonrandomized, multicenter, Phase Ib study will investigate the safety and efficacy of obinutuzumab (RO5072759; GA101) administered in combination with chemotherapy (bendamustine or fludarabine + cyclophosphamide [FC] regimens) in participants with previously untreated cluster of differentiation 20 (CD20)-positive B-CLL. Participants will be enrolled to receive a maximum of 6 cycles of obinutuzumab (1000 milligrams [mg] intravenous [IV] infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2 - 6) plus bendamustine (90 milligrams per meter square [mg/m^2] IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2 - 6) on 28 day cycles or a maximum of 6 cycles of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2 - 6) plus FC (fludarabine 25 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2 - 6; cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2 - 6) on 28 day cycles.

Official Title
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An Open-Label, Multicenter, Phase Ib Trial of GA101 (RO5072759) in Combination With Chemotherapy in Patients With Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Lymphocytic Leukemia, Chronic

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Obinutuzumab
* Drug: Bendamustine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CD20-positive B-CLL Rai Stage III/IV or Binet Stage C disease Rai Stage I/II or Binet Stage B disease that requires treatment Adequate baseline bone marrow function, unless there is clear evidence of extensive bone marrow involvement with tumor infiltration, myelodysplasia, or hypocellularity No previous treatment for CLL by chemotherapy, radiotherapy, or immunotherapy Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Life expectancy of greater than (>) 6 months Exclusion Criteria: Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to the start of Cycle 1 Transformation of CLL to aggressive B-cell malignancy Creatinine clearance less than equal to (<=) 60 milliliters per minute (mL/min), calculated according to the formula of Cockcroft and Gault Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) Total bilirubin greater than equal to (>=) 3 x ULN History of severe allergic or anaphylactic reactions to monoclonal antibody therapy History of sensitivity to mannitol (if bendamustine is to be administered) History of other malignancy that could affect compliance with the protocol or interpretation of results Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of Cycle 1 Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis Known infection with human immunodeficiency virus (HIV) seropositive status Presence of positive test results for hepatitis B (hepatitis B virus [HBV] surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or hepatitis C (hepatitis C virus [HCV] antibody serology testing). Participants with chronic HBV infection, occult HBV infection, or past HBV infection will be excluded. Participants who have received IV immunoglobulin within 3 months of enrollment and who are anti-HBc positive but HBV deoxyribonucleic acid (DNA) negative will be considered for inclusion on the study by the Medical Monitor on a case-by-case basis. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). Women who are pregnant or lactating Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly Concurrent (or within 7 days prior to the first dose of study treatment) systemic corticosteroid use except low-dose corticosteroid therapy used to treat an illness other than 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab + Fludarabine + Cyclophosphamide<br>Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6), and cyclophosphamide (250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). | Drug: Fludarabine<br>* Participants will receive 6 cycles (each 28-day cycle) of fludarabine at dose of 25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6.<br>Drug: Obinutuzumab<br>* Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab at dose of 1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6.<br>* Other names: RO5072759; GA101;Drug: Cyclophosphamide<br>* Participants will receive 6 cycles (each 28-day cycle) of cyclophosphamide at dose of 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6.<br>|
| Experimental: Obinutuzumab + Bendamustine<br>Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6). | Drug: Obinutuzumab<br>* Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab at dose of 1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6.<br>* Other names: RO5072759; GA101;Drug: Bendamustine<br>* Participants will receive 6 cycles (each 28-day cycle) of bendamustine at dose of 90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Human Anti-Human Antibodies (HAHAs) |  | Cycle 1 Day 1 (cycle length = 28 days) up to clinical data cutoff date 24 January 2013 (up to approximately 1.75 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve (AUC) of Obinutuzumab | AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. | Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall) | 
| Maximum Plasma Concentration (Cmax) of Obinutuzumab |  | Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall) | 
| Trough Plasma Concentration (Ctrough) of Obinutuzumab |  | Pre-dose on C1D1, C1D3, 8, 15, C2D1, C4D1, C6D1 | 
| Clearance of Obinutuzumab | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Pre-dose on C1D1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall) | 
| Volume of Distribution of Obinutuzumab | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. | Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall) | 
| Half-Life of Obinutuzumab | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall) | 
| Percentage of Participants With Objective Response, Assessed According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines | Objective response was defined as a complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR), as determined by investigator. CR:required peripheral blood lymphocytes <4x10^9/L; absence of lymphadenopathy; no hepatomegaly or splenomegaly by physical examination as determined by measurement below relevant costal margin; absence of disease/constitutional symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR:Greater than equal to (>=) 50% decrease in peripheral blood lymphocyte count, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi:met all CR criteria including confirmed lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery. The 95% confidence interval (CI) was estimated by Clopper-Pearson method. The end of treatment response visit occurred 2-3 months after end of treatment. | Baseline up to relapse or progression or death from any cause, whichever occurred first up to end of treatment response visit (up to approximately 9 months) | 
| Duration of Objective Response (DOR), Assessed by the Investigator According to IWCLL Guidelines | DOR for participants with OR: time from first CR, CRi or PR to disease progression (DP), relapse, or death, assessed by the investigator. DP: >=50% increase in lymphocytes to at least 5x10^9/L;new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology. CR:peripheral blood lymphocytes (PBL) <4x10^9/L; no lymphadenopathy; no hepatomegaly or splenomegaly (below relevant costal margin); no symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR: >=50% decrease in PBL, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi: met CR criteria, lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery. | From first documented objective response up to disease progression or relapse or death, whichever occurred first (up to approximately 6 months) | 
| Percentage of Participants Who Were Alive and Progression Free | Progressive disease assessed using IWCLL: >=50% increase in the absolute number of circulating lymphocytes to at least 5x10^9/L; Appearance of new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology. | Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years) | 
| Percentage of Participants Who Were Alive |  | Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years) | 
| Percentage of Participants Who Had B-Cell Depletion | B-cell depletion was defined as cluster of differentiation 19 (CD19) <0.07×10^9/L and could occur only after at least one dose of study drug had been administered. | Up to the end of the treatment period, and follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years) | 
| Percentage of Participants Who Had B-Cell Recovery | B-cell recovery was defined as CD19 >=0.07×10^9/L, where participants' CD19 were previously depleted. B-cell recovery was only considered possible when the participant had received the last dose of study treatment. | Follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years) |