A Study Comparing Obinutuzumab (RO5072759; GA101) 1000 Milligram (mg) Versus 2000 mg in Participants With Previously Untreated Chronic Lymphocytic Leukemia (CLL) (GAGE)
- Conditions
- Lymphocytic Leukemia, Chronic
- Interventions
- Drug: Corticosteroids
- Registration Number
- NCT01414205
- Lead Sponsor
- Genentech, Inc.
- Brief Summary
This open-label, multicenter, randomized study compared the efficacy, safety and pharmacokinetics of obinutuzumab (RO5072759; GA101) 1000 mg versus 2000 mg in participants with previously untreated CLL. Participants were randomized to receive a maximum of 8 cycles (28-day cycle) of obinutuzumab (1000 mg intravenous \[IV\] infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of each subsequent cycle up to 8 cycles or maximum of 8 cycles of obinutuzumab (2000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of each subsequent cycle up to 8 cycles.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 80
- Confirmed diagnosis of CD20-positive B-cell CLL (per International Workshop on Chronic Lymphocytic Leukemia [IWCLL] guidelines)
- Rai Stage III/IV or Binet Stage C disease, or Rai Stage I/II or Binet Stage B disease that requires treatment according to IWCLL guidelines
- No previous treatment for CLL chemotherapy, radiotherapy or immunotherapy; no previous rituximab treatment for autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP); prior use of steroids for AIHA or ITP is allowed
- Eastern Cooperative Oncology Group performance status of 0, 1 or 2
- Confirmed diagnosis of Transformation of CLL to aggressive B-cell malignancy
- History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
- Evidence of severe, uncontrolled concomitant disease
- Known active infection or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks before the start of Cycle 1
- Seropositive for human immunodeficiency virus (HIV)
- Positive for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology)
- Positive for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
- Pregnant or lactating women
- Concurrent (or within 7 days prior to first dose of study treatment) systemic corticosteroid use, except for low-dose corticosteroid therapy used to treat chronic medical conditions
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Obinutuzumab 2000 mg Corticosteroids Participants received a 2000 mg IV infusion, on days 1 (split dose 100 mg Day 1, 900 mg Day 2 and 1000 mg Day 3), 8 and 15 of cycle 1 and day 1 of cycles 2 -8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose. Obinutuzumab 1000 mg Corticosteroids Participants received a 1000 mg intravenous (IV) infusion, on days 1 (split dose 100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of cycle 1 and day 1 of cycles 2 - 8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose. Obinutuzumab 1000 mg Obinutuzumab Participants received a 1000 mg intravenous (IV) infusion, on days 1 (split dose 100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of cycle 1 and day 1 of cycles 2 - 8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose. Obinutuzumab 2000 mg Obinutuzumab Participants received a 2000 mg IV infusion, on days 1 (split dose 100 mg Day 1, 900 mg Day 2 and 1000 mg Day 3), 8 and 15 of cycle 1 and day 1 of cycles 2 -8, 21 day cycles. All participants received corticosteroids IV prior to the initial dose.
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) Week 32 ORR was defined as the percentage of participants with complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR) as assessed by the investigator according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines two months after last treatment. CR required: blood lymphocytes \< 4 x 10\^9/Liter (L), absence of lymphadenopathy (≤ 1.5 centimeter (cm) in long axis by Computed Tomography), no hepatomegaly or splenomegaly, absence of disease, Neutrophils \> 1.5 x 10\^9/L, Platelets \> 100 x 10\^9/L, Hemoglobin \>11 g/dL, bone marrow normal and lymphoid nodules absent. CRi was CR with incomplete marrow recovery. PR required: 50% decrease in peripheral blood lymphocyte count, 50% reduction in lymphadenopathy, 50% reduction of liver and/or spleen enlargement if enlarged at baseline, Neutrophils \> 1.5 x 10\^9/L or \> 50% of pretreatment value, Platelets \> 100 x 10\^9/L or 50% of pretreatment value and Hemoglobin \> 11 g/dL or \> 50% of pretreatment value.
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) Up to 4 years, 5 months PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first.
Number of Participants Surviving at End-of-Study Up to 4 years, 5 months Percentage of Participants With Adverse Events of Interest Up to 4 years, 5 months Adverse Events of interest for this study were: serious infusion related reactions during or within 24 hours of infusion, serious neutropenia, serious infection, tumor lysis syndrome and Hepatitis B reactivation.
Duration of Response Up to 4 years, 5 months PK Parameter: Maximum Serum Concentration (Cmax) Day 148 (at end of infusion) Blood was collected for Pharmacokinetic (PK) Parameter Cmax after dose administration on Day 1 of Cycle 8. 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).
PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt ) Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA) measured in day times micrograms per milliliter (day\*μg/mL).
Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) Up to 4 years, 5 months An AE was defined as any unfavorable and unintended sign, 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.
Percentage of Participants With Adverse Events Leading to Study Discontinuation Up to 4 years, 5 months An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless of attribution.
PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits) Months 3, 6, 9, and 12 Blood 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).
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion Up to 4 years, 5 months Blood was sent to a central laboratory for the evaluation of cluster of differentiation 19 (CD19) by flow cytometry. B-cell depletion was defined as a CD19 result \< 0.07 × 10\^9/L after at least one dose of study drug has been administered.
PK Parameter: Clearance at Steady State (CLss) Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). CLss is reported in milliliters per day (mL/day).
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery Up to 4 years, 5 months 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 a CD19 result ≥ 0.07 × 10\^9/L, where CD19 was previously depleted. B-cell recovery was only considered possible following the last dose of study treatment. The number of participants with B-cell recovery from End of Treatment to 6 months of Follow-up is reported in two categories: Recovery with Progressive Disease (PD) \[PD before B-cell recovery or PD within 45 days after recovery\] 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.
PK Parameter: Volume of Distribution at Steady State (Vss) Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). Vss is reported in liters.
PK Parameter: Terminal Half-Life (t1/2) Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion) Blood was collected for PK Parameters before and after dose administration on Day 1 of Cycle 8. Serum samples were sent to a central lab and were analyzed for obinutuzumab using a validated enzyme-linked immunosorbent assay (ELISA). T1/2 was reported in Days.
Trial Locations
- Locations (31)
Arizona Oncology
🇺🇸Tucson, Arizona, United States
Willamette Valley Cancer Ctr - 520 Country Club
🇺🇸Eugene, Oregon, United States
Arizona Clinical Research Ctr
🇺🇸Tucson, Arizona, United States
Ventura County Hematology-Oncology Specialists
🇺🇸Oxnard, California, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
University of California; Moores Cancer Center
🇺🇸La Jolla, California, United States
Wilshire Oncology Medical Group
🇺🇸Pasadena, California, United States
Goshen Hlth Sys Ctr Can Care
🇺🇸Goshen, Indiana, United States
US Oncology Research Pharm.
🇺🇸Fort Worth, Texas, United States
Texas Cancer Center - Sherman
🇺🇸Sherman, Texas, United States
Horizon Oncology Research, Inc.
🇺🇸Lafayette, Indiana, United States
Hem Onc Assoc of Northern NJ; Carol G. Simon Canc Ctr
🇺🇸Morristown, New Jersey, United States
SW Virginia Hem Onc
🇺🇸Roanoke, Virginia, United States
Shenandoah Oncology Associates
🇺🇸Winchester, Virginia, United States
Yakima Valley Memorial Hospital/North Star Lodge
🇺🇸Yakima, Washington, United States
Northwest Cancer Specialists - Vancouver
🇺🇸Vancouver, Washington, United States
Univ of Alabama at Birmingham; UAB Comprehensive Cancer Ctr
🇺🇸Birmingham, Alabama, United States
USC Norris Cancer Center
🇺🇸Los Angeles, California, United States
USC/Norris Can Ctr; IDS Pharm
🇺🇸Los Angeles, California, United States
Univ of Colorado Canc Ctr
🇺🇸Aurora, Colorado, United States
Rocky Mountain Cancer Center; Medical Oncology
🇺🇸Denver, Colorado, United States
Kootenai Cancer Center
🇺🇸Post Falls, Idaho, United States
Indiana University Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Purchase Cancer Group
🇺🇸Paducah, Kentucky, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
Mark H. Zangmeister Center
🇺🇸Columbus, Ohio, United States
Kettering Medical Center
🇺🇸Kettering, Ohio, United States
INTEGRIS Cancer Inst of OK
🇺🇸Oklahoma City, Oklahoma, United States
Texas Oncology-Medical City Dallas
🇺🇸Dallas, Texas, United States
Texas Oncology - Dallas Presbyterian Hospital
🇺🇸Dallas, Texas, United States
Virginia Cancer Specialists, PC
🇺🇸Fairfax, Virginia, United States