Chronic Lymphocytic Leukemia
Conditions
Keywords
Zydelig, CLL, CAL-101, GS 1101, GS-1101, PI3K, Rituxan, Rituximab, Bendamustine, Leukemia, idelalisib
Brief summary
The primary objective of this study is to evaluate the effect of the addition of idelalisib (formerly GS-1101) to bendamustine + rituximab (BR) on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL)
Interventions
DRUGIdelalisib
Idelalisib 150 mg administered orally twice daily
DRUGRituximab
Rituximab 375 mg/m\^2 on Day 1, then 500 mg/m\^2 every 28 days administered intravenously for a maximum of 6 infusions
DRUGBendamustine
Bendamustine 70 mg/mg\^2/day on 2 consecutive days every 28 days administered intravenously for a maximum of 12 infusions
Placebo to match idelalisib administered orally twice daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Previously treated recurrent CLL * Measurable lymphadenopathy * Requires therapy for CLL * Has experienced CLL progression \< 36 months since the completion of the last prior therapy Key
Exclusion criteria
* Recent history of a major non-CLL malignancy * Evidence of an ongoing infection * CLL refractory to bendamustine * Concurrent participation in another therapeutic clinical trial NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to 84 months | PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. PFS (months) = (minimum (date of disease progression, date of death) - date of randomization + 1)/30.4375. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 84 months | ORR was the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi,) or partial response (PR) and maintained the response for at least 12 weeks. CR was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. PR was defined as \>1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, \> 100000/μL platelets, \> 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors. CRi was defined as all criteria for CR met but with persistent anemia, thrombocytopenia, neutropenia or a hypocellular bone marrow. |
| Lymph Node Response Rate | Up to 84 months | Lymph node response rate was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions. |
| Overall Survival | Up to 84 months | Overall survival (OS) was defined as the interval from randomization to death from any cause. Overall survival (months) = (date of death - date of randomization + 1)/30.4375. |
| Complete Response Rate | Up to 84 months | Complete response (CR) rate was defined as the percentage of participants who achieved a CR. |
Countries
Australia, Belgium, Canada, Croatia, Czechia, France, Greece, Hungary, Ireland, Italy, Poland, Portugal, Romania, Russia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at a total of 110 sites in Australia, New Zealand, Europe, Asia and North America. The first participant was screened on 15 June 2012. The last study visit occurred on 10 June 2019.
Pre-assignment details
540 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib + Bendamustine + Rituximab Idelalisib 150 mg tablet administered orally twice daily (until the earliest of participant withdrawal from study, definitive progression of CLL, intolerable toxicity, pregnancy, substantial noncompliance with study procedures, or study discontinuation) + rituximab 375 mg/m\^2 on Day 1, then 500 mg/m\^2 every 28 days administered intravenously for a total of 6 infusions + bendamustine 70 mg/mg\^2/infusion on days 1 and 2 of each 28 day cycle, administered intravenously for a total of 6 cycles (12 infusions). | 207 |
| Placebo + Bendamustine + Rituximab Placebo to match idelalisib administered orally twice daily + rituximab 375 mg/m\^2 on Day 1, then 500 mg/ m\^2 every 28 days administered intravenously for a total of 6 infusions + bendamustine 70 mg/m\^2/infusion on days 1 and 2 of each 28 day cycle administered intravenously for a total of 6 cycles (12 infusions). | 209 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 39 | 14 |
| Overall Study | Death | 19 | 15 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Non-Compliance with Study Drug | 6 | 1 |
| Overall Study | Other Anticancer/Experimental Therapy | 2 | 2 |
| Overall Study | Other Reason not Specified | 3 | 5 |
| Overall Study | Physician Decision | 13 | 18 |
| Overall Study | Progressive Disease | 75 | 139 |
| Overall Study | Study Terminated by Sponsor | 24 | 2 |
| Overall Study | Withdrawal by Subject | 25 | 12 |
Baseline characteristics
| Characteristic | Idelalisib + Bendamustine + Rituximab | Placebo + Bendamustine + Rituximab | Total |
|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 9.2 | 63 years STANDARD_DEVIATION 9.8 | 62 years STANDARD_DEVIATION 9.5 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 191 Participants | 188 Participants | 379 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 12 Participants | 15 Participants | 27 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 10 Participants | 12 Participants | 22 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Race White | 187 Participants | 190 Participants | 377 Participants |
| Region of Enrollment Australia | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment Belgium | 3 Participants | 7 Participants | 10 Participants |
| Region of Enrollment Canada | 0 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Croatia | 5 Participants | 9 Participants | 14 Participants |
| Region of Enrollment Czechia | 9 Participants | 5 Participants | 14 Participants |
| Region of Enrollment France | 13 Participants | 14 Participants | 27 Participants |
| Region of Enrollment Greece | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Hungary | 24 Participants | 20 Participants | 44 Participants |
| Region of Enrollment Ireland | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Italy | 10 Participants | 7 Participants | 17 Participants |
| Region of Enrollment New Zealand | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Poland | 17 Participants | 22 Participants | 39 Participants |
| Region of Enrollment Portugal | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Romania | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment Russia | 22 Participants | 14 Participants | 36 Participants |
| Region of Enrollment Spain | 14 Participants | 18 Participants | 32 Participants |
| Region of Enrollment Turkey | 6 Participants | 6 Participants | 12 Participants |
| Region of Enrollment United Kingdom | 27 Participants | 29 Participants | 56 Participants |
| Region of Enrollment United States | 37 Participants | 33 Participants | 70 Participants |
| Sex: Female, Male Female | 47 Participants | 53 Participants | 100 Participants |
| Sex: Female, Male Male | 160 Participants | 156 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 89 / 207 | 106 / 209 |
| other Total, other adverse events | 199 / 207 | 196 / 209 |
| serious Total, serious adverse events | 152 / 207 | 94 / 209 |
Outcome results
Primary
Progression-Free Survival (PFS)
PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. PFS (months) = (minimum (date of disease progression, date of death) - date of randomization + 1)/30.4375.
Time frame: Up to 84 months
Population: The intent-to-treat (ITT) Analysis Set included all participants randomised in the study regardless of whether study drug was administered and with treatment group designated according to initial randomisation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib + Bendamustine + Rituximab | Progression-Free Survival (PFS) | 21.8 months |
| Placebo + Bendamustine + Rituximab | Progression-Free Survival (PFS) | 11.1 months |
p-value: <0.000195% CI: [0.27, 0.45]Stratified log-rank test
Secondary
Complete Response Rate
Complete response (CR) rate was defined as the percentage of participants who achieved a CR.
Time frame: Up to 84 months
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Bendamustine + Rituximab | Complete Response Rate | 4.3 percentage of participants |
| Placebo + Bendamustine + Rituximab | Complete Response Rate | 0.5 percentage of participants |
p-value: 0.01195% CI: [1.19, 76.81]Cochran-Mantel-Haenszel
Secondary
Lymph Node Response Rate
Lymph node response rate was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lesions.
Time frame: Up to 84 months
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Bendamustine + Rituximab | Lymph Node Response Rate | 96.9 percentage of particpants |
| Placebo + Bendamustine + Rituximab | Lymph Node Response Rate | 60.9 percentage of particpants |
p-value: <0.000195% CI: [10.5, 79.02]Cochran-Mantel-Haenszel
Secondary
Overall Response Rate (ORR)
ORR was the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi,) or partial response (PR) and maintained the response for at least 12 weeks. CR was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. PR was defined as \>1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, \> 100000/μL platelets, \> 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors. CRi was defined as all criteria for CR met but with persistent anemia, thrombocytopenia, neutropenia or a hypocellular bone marrow.
Time frame: Up to 84 months
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Bendamustine + Rituximab | Overall Response Rate (ORR) | 70.0 percentage of participants |
| Placebo + Bendamustine + Rituximab | Overall Response Rate (ORR) | 45.5 percentage of participants |
p-value: <0.000195% CI: [1.98, 4.62]Cochran-Mantel-Haenszel
Secondary
Overall Survival
Overall survival (OS) was defined as the interval from randomization to death from any cause. Overall survival (months) = (date of death - date of randomization + 1)/30.4375.
Time frame: Up to 84 months
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib + Bendamustine + Rituximab | Overall Survival | 56.2 months |
| Placebo + Bendamustine + Rituximab | Overall Survival | 42.6 months |
p-value: 0.09895% CI: [0.59, 1.03]Stratified log-rank test