Chronic Lymphocytic Leukemia
Conditions
Brief summary
The primary objective of this study is to evaluate the effects of idelalisib with obinutuzumab versus the combination of chlorambucil and obinutuzumab on progression-free survival (PFS) in participants with previously untreated chronic lymphocytic leukemia (CLL). 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 those studies in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA). All front-line studies of idelalisib, including this study, were also terminated.
Interventions
DRUGIdelalisib
150 mg tablet administered orally twice daily
DRUGChlorambucil
2 mg tablets administered at a dose of 0.5 mg/kg orally every other week for a total of 12 doses
DRUGObinutuzumab
1000 mg/40 mL single-use vials administered intravenously for a total of 8 doses over 21 weeks
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Safety Run-In Phase: Single Group; Randomized Phase: Parallel
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Not a candidate for fludarabine therapy based on either: 1. creatinine clearance \< 70 mL/min, or 2. Cumulative Illness Rating Scale score \> 6, by assessment of the investigator * 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 * Ongoing drug-induced pneumonitis * Ongoing inflammatory bowel disease * History of prior allogeneic bone marrow progenitor cell or solid organ transplantation * Ongoing immunosuppressive therapy other than corticosteroids * Concurrent participation in another therapeutic clinical trial * Undergone major surgery within 30 days prior to randomization * Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for idelalisib, obinutuzumab, or chlorambucil * History of non-infectious pneumonitis * 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 11 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 11 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 11 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 11 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 11 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 11 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. For participants receiving the final dose of obinutuzumab after the original scheduled date, the MRD assessment was performed no less than 12 weeks after the last dose of obinutuzumab. MRD negativity rate was to be assessed by an IRC. |
Countries
Australia, Belgium, Canada, France, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Australia, Europe, and North America. The first participant was screened on 21 April 2015. The last study visit occurred on 13 May 2016.
Pre-assignment details
80 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Safety Run-In: Idelalisib+Obinutuzumab Idelalisib 150 mg tablet twice daily + obinutuzumab 1000 mg/40 mL intravenously for a total of 8 doses over 21 weeks | 8 |
| Randomized: Idelalisib+Obinutuzumab Idelalisib 150 mg tablet twice daily + obinutuzumab 1000 mg/40 mL intravenously for a total of 8 doses over 21 weeks | 25 |
| Randomized: Obinutuzumab+Chlorambucil Chlorambucil 0.5 mg/kg, as 2 mg tablets every other week for a total of 12 doses + obinutuzumab 1000 mg/40 mL intravenously for a total of 8 doses over 21 weeks | 24 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 7 | 24 | 22 |
| Overall Study | Withdrew Consent | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Safety Run-In: Idelalisib+Obinutuzumab | Randomized: Idelalisib+Obinutuzumab | Randomized: Obinutuzumab+Chlorambucil |
|---|---|---|---|---|
| 17p Deletion in CLL Cells Absent | 51 Participants | 8 Participants | 22 Participants | 21 Participants |
| 17p Deletion in CLL Cells Present | 6 Participants | 0 Participants | 3 Participants | 3 Participants |
| Age, Continuous | 71.1 years STANDARD_DEVIATION 7.7 | 67.1 years STANDARD_DEVIATION 8.1 | 72.2 years STANDARD_DEVIATION 8.23 | 71.1 years STANDARD_DEVIATION 6.84 |
| IgHV Mutation Mutated | 19 Participants | 3 Participants | 9 Participants | 7 Participants |
| IgHV Mutation Unmutated | 38 Participants | 5 Participants | 16 Participants | 17 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Permitted | 5 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 50 Participants | 7 Participants | 22 Participants | 21 Participants |
| Rai Stage Stage I-II | 23 Participants | 3 Participants | 11 Participants | 9 Participants |
| Rai Stage Stage III-IV | 34 Participants | 5 Participants | 14 Participants | 15 Participants |
| Region of Enrollment Australia | 4 participants | 0 participants | 1 participants | 3 participants |
| Region of Enrollment Belgium | 2 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Canada | 2 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment France | 5 participants | 0 participants | 3 participants | 2 participants |
| Region of Enrollment Poland | 28 participants | 2 participants | 14 participants | 12 participants |
| Region of Enrollment Spain | 1 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment United Kingdom | 3 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment United States | 12 participants | 5 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 20 Participants | 3 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 37 Participants | 5 Participants | 17 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 24 | 0 / 23 |
| other Total, other adverse events | 8 / 8 | 19 / 24 | 17 / 23 |
| serious Total, serious adverse events | 2 / 8 | 12 / 24 | 8 / 23 |
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 11 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
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 11 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. For participants receiving the final dose of obinutuzumab after the original scheduled date, the MRD assessment was performed no less than 12 weeks after the last dose of obinutuzumab. MRD negativity rate was to be assessed by an IRC.
Time frame: Up to 11 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 11 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 11 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 11 months
Population: The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.