Chronic Lymphocytic Leukemia
Conditions
Brief summary
The primary objective of this study is to evaluate the progression-free survival in participants with previously untreated chronic lymphocytic leukemia (CLL) who would otherwise be suitable for bendamustine and rituximab treatment as standard of care. An increased rate of deaths and serious adverse events (SAEs) among participants with front-line CLL and early-line indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA).
Interventions
DRUGIdelalisib
150 mg tablet administered orally twice daily
DRUGBendamustine
Administered intravenously at a starting dose of 90 mg/m\^2 for up to 6 cycles. Dosing will be based on mg/m\^2 of body surface area.
DRUGRituximab
Single-use vials administered intravenously weekly starting at 375 mg/m\^2 on Day 1 (Week 0) and 500 mg/m\^2 thereafter for a total of 6 infusions
DRUGPlacebo
Placebo to match idelalisib administered orally twice daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Documented diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) * No prior therapy for CLL other than corticosteroids for disease complications * CLL that warrants treatment * Presence of measurable lymphadenopathy * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 Key
Exclusion criteria
* Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation) * Known presence of myelodysplastic syndrome * Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization * Ongoing liver injury * History of non-infectious pneumonitis * Ongoing inflammatory bowel disease * History of prior allogeneic bone marrow progenitor cell or solid organ transplantation * Ongoing immunosuppressive therapy other than corticosteroids * Received last dose of study drug on another therapeutic clinical trial within 30 days prior to randomization Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Up to 22 months | Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Up to 22 months | Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC. |
| Nodal Response Rate | Up to 22 months | Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC. |
| Complete Response Rate | Up to 22 months | Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC. |
| Overall Survival | Up to 22 months | Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC. |
| Minimal Residual Disease Negativity Rate at Week 36 | Up to 22 months | Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD \< 10\^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation or at least 12 weeks after the last dose of rituximab or bendamustine (whichever is later) for participants receiving the final dose of rituximab after the original scheduled date. MRD negativity rate was to be assessed by an IRC. |
Countries
Australia, Belgium, Canada, Croatia, Czechia, France, Hungary, Italy, Poland, Romania, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the North America, Australia, and Europe. The first participant was screened on 05 February 2014. The last study visit occurred on 16 June 2016.
Pre-assignment details
392 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib+Bendamustine+Rituximab Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m\^2 for up to 6 total cycles) + rituximab (375 mg/m\^2 on Day 1 and 500 mg/m\^2 thereafter for at total of 6 infusions) | 157 |
| Placebo+Bendamustine+Rituximab Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m\^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m\^2 on Day 1 and 500 mg/m\^2 thereafter for at total of 6 infusions) | 154 |
| Total | 311 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Investigator's Discretion | 8 | 3 |
| Overall Study | Non-Compliance with Study Drug | 3 | 2 |
| Overall Study | Study Terminated by Sponsor | 116 | 122 |
| Overall Study | Withdrew Consent | 17 | 6 |
Baseline characteristics
| Characteristic | Total | Idelalisib+Bendamustine+Rituximab | Placebo+Bendamustine+Rituximab |
|---|---|---|---|
| 17p Deletion in CLL Cells Absent | 291 Participants | 146 Participants | 145 Participants |
| 17p Deletion in CLL Cells Missing | 1 Participants | 1 Participants | 0 Participants |
| 17p Deletion in CLL Cells Present | 19 Participants | 10 Participants | 9 Participants |
| Age, Continuous | 64 years STANDARD_DEVIATION 9.4 | 64 years STANDARD_DEVIATION 8.7 | 63 years STANDARD_DEVIATION 10 |
| IgHV Mutation Missing | 1 Participants | 1 Participants | 0 Participants |
| IgHV Mutation Mutated | 108 Participants | 54 Participants | 54 Participants |
| IgHV Mutation Unmutated | 202 Participants | 102 Participants | 100 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants | 11 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 295 Participants | 146 Participants | 149 Participants |
| Race/Ethnicity, Customized Not Permitted | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 302 Participants | 152 Participants | 150 Participants |
| Rai Stage at Screening Stage I | 58 Participants | 28 Participants | 30 Participants |
| Rai Stage at Screening Stage II | 124 Participants | 66 Participants | 58 Participants |
| Rai Stage at Screening Stage III | 57 Participants | 25 Participants | 32 Participants |
| Rai Stage at Screening Stage IV | 72 Participants | 38 Participants | 34 Participants |
| Region of Enrollment Australia | 34 participants | 15 participants | 19 participants |
| Region of Enrollment Belgium | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Canada | 19 participants | 11 participants | 8 participants |
| Region of Enrollment Croatia | 11 participants | 5 participants | 6 participants |
| Region of Enrollment Czech Republic | 27 participants | 10 participants | 17 participants |
| Region of Enrollment France | 9 participants | 4 participants | 5 participants |
| Region of Enrollment Hungary | 45 participants | 24 participants | 21 participants |
| Region of Enrollment Italy | 8 participants | 5 participants | 3 participants |
| Region of Enrollment Poland | 33 participants | 15 participants | 18 participants |
| Region of Enrollment Romania | 5 participants | 4 participants | 1 participants |
| Region of Enrollment Spain | 34 participants | 19 participants | 15 participants |
| Region of Enrollment United Kingdom | 20 participants | 7 participants | 13 participants |
| Region of Enrollment United States | 60 participants | 35 participants | 25 participants |
| Sex: Female, Male Female | 105 Participants | 57 Participants | 48 Participants |
| Sex: Female, Male Male | 206 Participants | 100 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 154 / 156 | 150 / 154 |
| serious Total, serious adverse events | 113 / 156 | 68 / 154 |
Outcome results
Primary
Progression-Free Survival
Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC).
Time frame: Up to 22 months
Population: Intent to Treat (ITT) analysis set: all participants who are randomized in the study with treatment group designated according to initial randomization.~Due to early study termination, the prespecified efficacy analyses were not conducted. The PFS data presented are investigator assessments rather than IRC assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Bendamustine+Rituximab | Progression-Free Survival | NA months |
| Placebo+Bendamustine+Rituximab | Progression-Free Survival | NA months |
Secondary
Complete Response Rate
Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC.
Time frame: Up to 22 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
Secondary
Minimal Residual Disease Negativity Rate at Week 36
Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD \< 10\^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation or at least 12 weeks after the last dose of rituximab or bendamustine (whichever is later) for participants receiving the final dose of rituximab after the original scheduled date. MRD negativity rate was to be assessed by an IRC.
Time frame: Up to 22 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
Secondary
Nodal Response Rate
Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC.
Time frame: Up to 22 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
Secondary
Overall Response Rate
Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC.
Time frame: Up to 22 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
Secondary
Overall Survival
Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC.
Time frame: Up to 22 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.