Chronic Lymphocytic Leukemia
Conditions
Keywords
CLL, CAL-101, GS 1101, PI3K, GS-US-312-0117, idelalisib
Brief summary
This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.
Interventions
DRUGIdelalisib
Idelalisib 150 mg tablet administered orally twice daily
DRUGRituximab
Rituximab administered intravenously 8 times through Week 20: Day 1: 375 mg/m\^2, and 500 mg/m\^2 thereafter
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
Inclusion: * Adult subjects with previously treated recurrent CLL who have measurable lymphadenopathy * Require therapy for CLL * Have experienced CLL progression \< 24 months since the completion of the last prior therapy * Currently not sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or comorbidities.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Up to 17 months | Progression-free survival was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was CLL progression based on standard criteria (other than lymphocytosis alone) as defined by the 2008 update of the International Workshop on CLL guidelines, ie, appearance of any new lesion; increase by ≥ 50% in the sum of the products of the perpendicular diameters of measured lymph nodes (SPD); new or ≥ 50% enlargement of liver or spleen; transformation to a more aggressive histology (eg, Richter's or prolymphocytic transformation); reduction in the number of blood cells (cytopenia) attributable to CLL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 17 months | Overall response rate was defined as the percentage of participants who achieved a best overall response of complete response or partial response. Complete response was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. Partial response 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. |
| Lymph Node Response Rate | Up to 17 months | Lymph node response rate was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the SPD of index lymph nodes. |
| Overall Survival | Up to 17 months | Overall survival was defined as the interval from randomization to death from any cause. |
| Complete Response Rate | Up to 17 months | Complete response rate was defined as the percentage of participants who achieved a complete response. |
Countries
France, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at a total of 53 study sites in the United States and Europe. The first participant was screened on 03 April 2012. The last study visit occurred on 20 April 2014.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib + Rituximab Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m\^2, and 500 mg/m\^2 thereafter) | 110 |
| Placebo + Rituximab Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m\^2, and 500 mg/m\^2 thereafter) | 110 |
| Total | 220 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 7 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Richter's Transformation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 5 |
Baseline characteristics
| Characteristic | Total | Placebo + Rituximab | Idelalisib + Rituximab |
|---|---|---|---|
| Age, Continuous | 71 years STANDARD_DEVIATION 7.9 | 70 years STANDARD_DEVIATION 8.1 | 71 years STANDARD_DEVIATION 7.7 |
| Age, Customized < 65 years | 48 participants | 27 participants | 21 participants |
| Age, Customized ≥ 65 years | 172 participants | 83 participants | 89 participants |
| Binet Stage at Screening Binet Stage A | 11 participants | 4 participants | 7 participants |
| Binet Stage at Screening Binet Stage B | 61 participants | 32 participants | 29 participants |
| Binet Stage at Screening Binet Stage C | 123 participants | 60 participants | 63 participants |
| Binet Stage at Screening Missing | 25 participants | 14 participants | 11 participants |
| Karnofsky Performance Status 100 | 28 participants | 13 participants | 15 participants |
| Karnofsky Performance Status 40 | 2 participants | 1 participants | 1 participants |
| Karnofsky Performance Status 50 | 7 participants | 4 participants | 3 participants |
| Karnofsky Performance Status 60 | 11 participants | 5 participants | 6 participants |
| Karnofsky Performance Status 70 | 33 participants | 13 participants | 20 participants |
| Karnofsky Performance Status 80 | 88 participants | 46 participants | 42 participants |
| Karnofsky Performance Status 90 | 51 participants | 28 participants | 23 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 203 participants | 102 participants | 101 participants |
| Race/Ethnicity, Customized Not Permitted | 12 participants | 6 participants | 6 participants |
| Race/Ethnicity, Customized Other | 4 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 198 participants | 98 participants | 100 participants |
| Rai Stage at Screening Missing | 14 participants | 8 participants | 6 participants |
| Rai Stage at Screening Rai Stage 0 | 1 participants | 1 participants | 0 participants |
| Rai Stage at Screening Rai Stage 1 | 37 participants | 19 participants | 18 participants |
| Rai Stage at Screening Rai Stage 2 | 26 participants | 10 participants | 16 participants |
| Rai Stage at Screening Rai Stage 3 | 40 participants | 18 participants | 22 participants |
| Rai Stage at Screening Rai Stage 4 | 102 participants | 54 participants | 48 participants |
| Region of Enrollment France | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Germany | 12 participants | 5 participants | 7 participants |
| Region of Enrollment Italy | 7 participants | 5 participants | 2 participants |
| Region of Enrollment United Kingdom | 32 participants | 14 participants | 18 participants |
| Region of Enrollment United States | 163 participants | 83 participants | 80 participants |
| Sex: Female, Male Female | 76 Participants | 42 Participants | 34 Participants |
| Sex: Female, Male Male | 144 Participants | 68 Participants | 76 Participants |
| Time Since Diagnosis | 107.4 months STANDARD_DEVIATION 57.58 | 106.4 months STANDARD_DEVIATION 52.73 | 108.3 months STANDARD_DEVIATION 62.28 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 103 / 110 | 102 / 108 |
| serious Total, serious adverse events | 65 / 110 | 43 / 108 |
Outcome results
Primary
Progression-Free Survival
Progression-free survival was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was CLL progression based on standard criteria (other than lymphocytosis alone) as defined by the 2008 update of the International Workshop on CLL guidelines, ie, appearance of any new lesion; increase by ≥ 50% in the sum of the products of the perpendicular diameters of measured lymph nodes (SPD); new or ≥ 50% enlargement of liver or spleen; transformation to a more aggressive histology (eg, Richter's or prolymphocytic transformation); reduction in the number of blood cells (cytopenia) attributable to CLL.
Time frame: Up to 17 months
Population: Intent-to-Treat (ITT) Analysis Set: randomized participants with treatment group designated according to initial randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib + Rituximab | Progression-Free Survival | NA months |
| Placebo + Rituximab | Progression-Free Survival | 5.5 months |
p-value: <0.000195% CI: [0.1, 0.32]Log Rank
Secondary
Complete Response Rate
Complete response rate was defined as the percentage of participants who achieved a complete response.
Time frame: Up to 17 months
Population: ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Rituximab | Complete Response Rate | 0 percentage of participants |
| Placebo + Rituximab | Complete Response Rate | 0 percentage of participants |
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 SPD of index lymph nodes.
Time frame: Up to 17 months
Population: ITT Analysis Set: randomized participants with treatment group designated according to initial randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Rituximab | Lymph Node Response Rate | 92.2 percentage of participants |
| Placebo + Rituximab | Lymph Node Response Rate | 5.9 percentage of participants |
Secondary
Overall Response Rate
Overall response rate was defined as the percentage of participants who achieved a best overall response of complete response or partial response. Complete response was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. Partial response 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.
Time frame: Up to 17 months
Population: ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib + Rituximab | Overall Response Rate | 74.5 percentage of participants |
| Placebo + Rituximab | Overall Response Rate | 14.5 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the interval from randomization to death from any cause.
Time frame: Up to 17 months
Population: ITT Analysis Set: randomized participants with treatment group designated according to initial randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib + Rituximab | Overall Survival | NA months |
| Placebo + Rituximab | Overall Survival | NA months |
95% CI: [0.11, 0.69]