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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphocytic Leukemia, Chronic
• Intervention / Treatment: Drug: Fludarabine; Drug: Obinutuzumab; Drug: Cyclophosphamide; Drug: Bendamustine

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
  • California
    • Duarte, California, United States, 91010
    • La Jolla, California, United States, 92093
    • Los Angeles, California, United States, 90095
  • Connecticut
    • Southington, Connecticut, United States, 06489
  • Florida
    • Tampa, Florida, United States, 33612-9497
  • Georgia
    • Atlanta, Georgia, United States, 30322
    • Marietta, Georgia, United States, 30060
  • Illinois
    • Chicago, Illinois, United States, 60637
  • Maryland
    • Boston, Maryland, United States, 02115
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
  • Minnesota
    • St. Louis Park, Minnesota, United States, 55426
  • Missouri
    • Springfield, Missouri, United States, 65807
  • New York
    • Rochester, New York, United States, 14642
  • Texas
    • Houston, Texas, United States, 77030
  • Washington
    • Seattle, Washington, United States, 98109
    • Tacoma, Washington, United States, 98405
  • Wisconsin
    • Madison, Wisconsin, United States, 53705

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Obinutuzumab + Fludarabine + Cyclophosphamide; 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; 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.; Drug: Obinutuzumab; 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.; Other Names: RO5072759; GA101; Drug: Cyclophosphamide; 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.
Experimental: Obinutuzumab + Bendamustine; 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; 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.; Other Names: RO5072759; GA101; Drug: Bendamustine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Publications and helpful links

General Publications

• Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. doi: 10.1182/blood-2014-12-613570. Epub 2015 Mar 13.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: February 14, 2011
• First Submitted That Met QC Criteria: February 17, 2011
• First Posted (Estimate): February 21, 2011

Study Record Updates

• Last Update Posted (Estimate): February 2, 2017
• Last Update Submitted That Met QC Criteria: December 8, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Bendamustine Hydrochloride; Fludarabine; Obinutuzumab
• Other Study ID Numbers: GAO4779g; GO01298 (Other Identifier: Hoffmann-La Roche)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No