Indolent Non-Hodgkin's Lymphomas
Conditions
Keywords
iNHL, indolent NHL, follicular lymphoma, CAL-101, rituximab, bendamustine, small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, Waldenstrom macroglobulinemia, LPL, WM, Marginal zone lymphoma, MZL, SLL, FL, GS-1101, PI3K inhibitor, idelalisib
Brief summary
The primary objective of this study is to evaluate the addition of idelalisib to bendamustine/rituximab on progression-free survival (PFS) in adults with previously treated indolent non-Hodgkin lymphoma (iNHL). An increased rate of deaths and serious adverse events (SAEs) among participants with front-line chronic lymphocytic leukemia (CLL) and early-line 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
DRUGRituximab
375 mg/m\^2 single-use vials administered intravenously every 4 weeks (up to a total of 6 infusions)
DRUGBendamustine
90 mg/m\^2 single-use vials administered intravenously for two consecutive days every 4 weeks (up to a total of 4-6 cycles as tolerated)
DRUGPlacebo
Tablet 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: * Histologically confirmed diagnosis of B-cell iNHL, with histological subtype limited to the following 1. Follicular lymphoma (FL) Grade 1, 2, or 3a 2. Small lymphocytic lymphoma (SLL) 3. Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM) 4. Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal) Key
Exclusion criteria
* History of lymphoid malignancy other than those allowed per inclusion criteria. * Ongoing drug-induced liver injury, active hepatitis C, active hepatitis B, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension. * Prior treatment with bendamustine that was not effective. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | — | PFS is defined as the interval from randomization to the earlier of the first documentation of definitive indolent non-Hodgkin lymphomas (iNHL) disease progression or death from any cause. Definitive iNHL disease progression is progression based on standard criteria. PFS was to be assessed by an independent review committee (IRC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR) | — | Complete response rate is defined as the proportion of participants who achieve a complete response. CR rate was to be assessed by an IRC. |
| Overall Response Rate (ORR) | — | Overall response rate is defined as the proportion of participants who achieve a complete response or partial response (or very good partial response (VGPR) or minor response (MR) for participants with Waldenstrom's). ORR was to be assessed by an IRC. |
| Lymph Node Response Rate | — | Lymph node response rate is defined as the proportion of participants who achieve ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Lymph node response rate was to be assessed by an IRC. |
| Overall Survival (OS) | — | Overall survival is defined as the interval from randomization to death from any cause. |
Countries
Australia, Canada, Czechia, France, Germany, Israel, Italy, Poland, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the North America, Europe, and Asia Pacific. The first participant was screened on 02 January 2013. The last study visit occurred on 17 May 2016.
Pre-assignment details
581 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib + Bendamustine + Rituximab Idelalisib 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m\^2 for up to 12 infusions) + rituximab intravenously (375 mg/m\^2 on Day 1 for a total of 6 infusions) | 320 |
| Placebo + Bendamustine + Rituximab Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m\^2 for up to 12 infusions) + rituximab intravenously (375 mg/m\^2 on Day 1 for a total of 6 infusions) | 155 |
| Total | 475 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Blind Broken by Subject or Study Site | 1 | 1 |
| Overall Study | Initiation of Other Anti-Cancer Therapy | 7 | 6 |
| Overall Study | Other Reason | 21 | 4 |
| Overall Study | Physician Decision | 24 | 11 |
| Overall Study | Study Terminated by Sponsor | 168 | 80 |
| Overall Study | Withdrawal by Subject | 46 | 8 |
Baseline characteristics
| Characteristic | Total | Placebo + Bendamustine + Rituximab | Idelalisib + Bendamustine + Rituximab |
|---|---|---|---|
| Age, Continuous | 62 years STANDARD_DEVIATION 10.9 | 62 years STANDARD_DEVIATION 11.1 | 62 years STANDARD_DEVIATION 10.5 |
| Race/Ethnicity, Customized Asian | 34 Participants | 8 Participants | 26 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 24 Participants | 8 Participants | 16 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 391 Participants | 129 Participants | 262 Participants |
| Race/Ethnicity, Customized Not Permitted | 62 Participants | 21 Participants | 41 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 369 Participants | 122 Participants | 247 Participants |
| Region of Enrollment Australia | 67 Participants | 23 Participants | 44 Participants |
| Region of Enrollment Canada | 66 Participants | 19 Participants | 47 Participants |
| Region of Enrollment Czech Republic | 19 Participants | 7 Participants | 12 Participants |
| Region of Enrollment France | 54 Participants | 18 Participants | 36 Participants |
| Region of Enrollment Germany | 3 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Israel | 8 Participants | 2 Participants | 6 Participants |
| Region of Enrollment Italy | 35 Participants | 14 Participants | 21 Participants |
| Region of Enrollment Korea, Republic of | 12 Participants | 2 Participants | 10 Participants |
| Region of Enrollment Poland | 36 Participants | 11 Participants | 25 Participants |
| Region of Enrollment Russian Federation | 27 Participants | 11 Participants | 16 Participants |
| Region of Enrollment Spain | 32 Participants | 11 Participants | 21 Participants |
| Region of Enrollment Sweden | 5 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Taiwan | 9 Participants | 2 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 53 Participants | 20 Participants | 33 Participants |
| Region of Enrollment United States | 49 Participants | 12 Participants | 37 Participants |
| Sex: Female, Male Female | 190 Participants | 58 Participants | 132 Participants |
| Sex: Female, Male Male | 285 Participants | 97 Participants | 188 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 315 / 317 | 147 / 155 |
| serious Total, serious adverse events | 229 / 317 | 58 / 155 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS is defined as the interval from randomization to the earlier of the first documentation of definitive indolent non-Hodgkin lymphomas (iNHL) disease progression or death from any cause. Definitive iNHL disease progression is progression based on standard criteria. PFS was to be assessed by an independent review committee (IRC).
Population: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
Secondary
Complete Response Rate (CR)
Complete response rate is defined as the proportion of participants who achieve a complete response. CR rate was to be assessed by an IRC.
Population: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
Secondary
Lymph Node Response Rate
Lymph node response rate is defined as the proportion of participants who achieve ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Lymph node response rate was to be assessed by an IRC.
Population: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
Secondary
Overall Response Rate (ORR)
Overall response rate is defined as the proportion of participants who achieve a complete response or partial response (or very good partial response (VGPR) or minor response (MR) for participants with Waldenstrom's). ORR was to be assessed by an IRC.
Population: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
Secondary
Overall Survival (OS)
Overall survival is defined as the interval from randomization to death from any cause.
Population: Due to the early termination of the study, efficacy data were not mature for all participants, and therefore the prespecified analyses were not conducted.