A Phase 2 interventional study of Obinutuzumab and Corticosteroids in Lymphocytic Leukemia, Chronic, sponsored by Genentech, Inc.. Completed at 31 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-04-17.
Sponsored by Genentech, Inc. · Phase 2, Interventional, and Treatment
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.
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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.
Drug: Obinutuzumab · Drug: 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.
Drug: Obinutuzumab · Drug: Corticosteroids
Participants were administered obinutuzumab either at 1000 mg or 2000 mg on Day 1, 8, 15 of Cycle 1 and then on Day 1 of each 21 day cycles for up to 8 cycles.
Also known as: RO5072759; GA101
Participants were administered corticosteroids IV prior to the initial dose.
Objective Response Rate (ORR)
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.
Time frame: Week 32
Progression-free Survival (PFS)
PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first.
Time frame: Up to 4 years, 5 months
Duration of Response
Time frame: Up to 4 years, 5 months
Number of Participants Surviving at End-of-Study
Time frame: Up to 4 years, 5 months
Percentage of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
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.
Time frame: Up to 4 years, 5 months
Percentage of Participants With Adverse Events of Interest
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.
Time frame: Up to 4 years, 5 months
Percentage of Participants With Adverse Events Leading to Study Discontinuation
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.
Time frame: Up to 4 years, 5 months
PK Parameter: Maximum Serum Concentration (Cmax)
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).
Time frame: Day 148 (at end of infusion)
PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt )
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).
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
PK Parameter: Clearance at Steady State (CLss)
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).
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
PK Parameter: Volume of Distribution at Steady State (Vss)
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.
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
PK Parameter: Terminal Half-Life (t1/2)
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.
Time frame: Day 148 (pre-infusion, at end of infusion, 5, 8 and 12 days after start of infusion)
PK: Serum Concentrations of Obinutuzumab (Follow-Up Visits)
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).
Time frame: Months 3, 6, 9, and 12
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Depletion
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.
Time frame: Up to 4 years, 5 months
Pharmacodynamics: Number of Participants With Peripheral Blood B-cell Recovery
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.
Time frame: Up to 4 years, 5 months
| Milestone | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Started | 41 | 39 |
| Received study drug | 40 | 38 |
| Completed | 34 | 32 |
| Not completed | 7 | 7 |
| Withdrew: Death | 5 | 1 |
| Withdrew: Lost to follow-up | 1 | 4 |
| Withdrew: Physician decision | 0 | 1 |
| Withdrew: Randomized but not treated | 1 | 1 |
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.
| Percentage of participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Objective Response Rate (ORR) | 48.8 | 66.7 |
PFS was defined as the time from the randomization to the first occurrence of progression or death, whichever occurred first.
| Months | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Progression-free Survival (PFS) | 25.2 (15.9 to 30.4) | 26.0 (20.2 to 34.2) |
Results for this outcome have not been posted.
| Participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Number of Participants Surviving at End-of-Study | 35 | 37 |
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 | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Adverse Events | 100.0 | 100.0 |
| Serious Adverse Events | 20.0 | 21.1 |
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.
| Percentage of participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Serious Infusion-Related Reactions (IRR) | 7.5 | 5.3 |
| Serious Neutropenia | 5.0 | 5.3 |
| Serious Infection | 5.0 | 5.3 |
| Tumor Lysis Syndrome | 0.0 | 2.6 |
| Hepatitis B Reactivation | 0.0 | 0.0 |
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.
| Percentage of participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Percentage of Participants With Adverse Events Leading to Study Discontinuation | 0 | 0 |
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).
| μg/mL | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| PK Parameter: Maximum Serum Concentration (Cmax) | 600 ± 45.6 | 1190 ± 34.9 |
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).
| day*μg/mL | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| PK Parameter: Area Under the Serum Concentration-Time Curve Between Dosing Interval Tau (AUCt ) | 8230 ± 58.3 | 16500 ± 50.3 |
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).
| mL/day | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| PK Parameter: Clearance at Steady State (CLss) | 121 ± 58.3 | 122 ± 50.3 |
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.
| Liters | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| PK Parameter: Volume of Distribution at Steady State (Vss) | 7.08 ± 73.2 | 6.68 ± 74.7 |
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.
| Days | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| PK Parameter: Terminal Half-Life (t1/2) | 30.6 ± 87.1 | 26.3 ± 80.1 |
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).
| μg/mL | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Month 3 (n=14, 10) | 41.2 ± 63.3 | 98.9 ± 88.9 |
| Month 6 (n=19, 15) | 15 ± 21.4 | 12.6 ± 17.7 |
| Month 9 (n=24, 23) | 2.63 ± 4.4 | 4.09 ± 9.42 |
| Month 12 (n=16, 18) | 0.633 ± 1.11 | 0.857 ± 1.74 |
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.
| Participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| At Last Antibody Administration (n=40, 38) | 31 | 31 |
| Up to 6 Months of Follow-Up (FU) (n=30, 31) | 28 | 28 |
| Within 6-12 Months of Follow-up (n=24, 24) | 16 | 17 |
| Within 12-18 Months of Follow-up (n=17, 17) | 11 | 9 |
| Within 18-24 Months of Follow-up (n=10, 9) | 5 | 8 |
| Within 24-30 Months of Follow-up (n=4, 6) | 2 | 5 |
| Within 30-36 Months of Follow-up (n=1, 3) | 1 | 3 |
| Within 36-42 Months of Follow-up (n=0, 0) | 0 | 0 |
| After 42 Months of Follow-up (n=0, 0) | 0 | 0 |
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.
| Participants | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Up to 6 Months FU: Recovery with PD (n=30, 31) | 0 | 0 |
| Up to 6 Months FU: Recovery without PD (n=30, 31) | 2 | 3 |
| 6-12 Months FU: Recovery with PD (n=24, 24) | 1 | 0 |
| 6-12 Months FU: Recovery without PD (n=24, 24) | 7 | 7 |
| 12-18 Months FU: Recovery with PD (n=17, 17) | 0 | 0 |
| 12-18 Months FU: Recovery without PD (n=17, 17) | 6 | 8 |
| 18-24 Months FU: Recovery with PD (n=10, 9) | 0 | 0 |
| 18-24 Months FU: Recovery without PD (n=10, 9) | 5 | 1 |
| 24-30 Months FU: Recovery with PD (n=4, 6) | 0 | 0 |
| 24-30 Months FU: Recovery without PD (n=4, 6) | 2 | 1 |
| 30-36 Months FU: Recovery with PD (n=1, 3) | 0 | 0 |
| 30-36 Months FU: Recovery without PD (n=1, 3) | 0 | 0 |
| 36-42 Months FU: Recovery with PD (n=0, 0) | 0 | 0 |
| 36-42 Months FU: Recovery without PD (n=0, 0) | 0 | 0 |
| After 42 Months FU: Recovery with PD (n=0, 0) | 0 | 0 |
| After 42 Months FU: Recovery without PD (n=0, 0) | 0 | 0 |
Collected over Up to 4 years, 5 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Obinutuzumab 1000 mg | — | 8/40 (20%) | 40/40 (100%) |
| Obinutuzumab 2000 mg | — | 8/38 (21.1%) | 38/38 (100%) |
| Event | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 2/40 | 1/38 |
| Infusion related reactionInjury, poisoning and procedural complications | 2/40 | 0/38 |
| NeutropeniaBlood and lymphatic system disorders | 0/40 | 1/38 |
| ThrombocytopeniaBlood and lymphatic system disorders | 0/40 | 1/38 |
| SepsisInfections and infestations | 0/40 | 1/38 |
| UrosepsisInfections and infestations | 0/40 | 1/38 |
| Acute coronary syndromeCardiac disorders | 0/40 | 1/38 |
| Sinus bradycardiaCardiac disorders | 0/40 | 1/38 |
| FallInjury, poisoning and procedural complications | 0/40 | 1/38 |
| HypoglycaemiaMetabolism and nutrition disorders | 0/40 | 1/38 |
| Event | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg |
|---|---|---|
| Infusion related reactionInjury, poisoning and procedural complications | 30/40 | 24/38 |
| PyrexiaGeneral disorders | 16/40 | 18/38 |
| FatigueGeneral disorders | 16/40 | 12/38 |
| NauseaGastrointestinal disorders | 15/40 | 10/38 |
| NeutropeniaBlood and lymphatic system disorders | 14/40 | 12/38 |
| DyspnoeaRespiratory, thoracic and mediastinal disorders | 6/40 | 11/38 |
| VomitingGastrointestinal disorders | 11/40 | 5/38 |
| HeadacheNervous system disorders | 11/40 | 4/38 |
| DizzinessNervous system disorders | 10/40 | 7/38 |
| FlushingVascular disorders | 8/40 | 9/38 |
| Age, Continuous(years) | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg | Total |
|---|---|---|---|
| Mean | 67.0 ± 10.0 | 64.3 ± 12.4 | 65.7 ± 11.2 |
| Sex: Female, Male(Participants) | Obinutuzumab 1000 mg | Obinutuzumab 2000 mg | Total |
|---|---|---|---|
| Female | 16 | 13 | 29 |
| Male | 25 | 26 | 51 |
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Genentech, Inc.