Chronic Lymphocytic Leukemia
Conditions
Keywords
CLL, Chronic Lymphocytic Leukemia, GS-1101, CAL-101, Ofatumumab
Brief summary
The primary objective of this study is to evaluate the effect of the addition of idelalisib to ofatumumab on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL).
Interventions
DRUGIdelalisib
150 mg tablets administered orally twice daily
DRUGOfatumumab
Administered intravenously
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Adults 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 * Have disease that is not refractory to ofatumumab Note: Other protocol defined Inclusion/
Exclusion criteria
may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Randomization to End of Study (up to 60 months) | Progression-free survival (PFS) 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. PFS was analyzed using Kaplan-Meier (KM) estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Randomization to End of Study (up to 60 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. Overall response rate was analyzed using KM estimates. |
| Lymph Node Response Rate | Randomization to End of Study (up to 60 months) | Lymph node response rate was defined as the proportion of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes. |
| Overall Survival | Randomization to Last Long-Term Follow-Up Visit (up to maximum of 5 years) | Overall survival was defined as the interval from randomization to death from any cause. Overall survival was analyzed using KM estimates. |
| Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation | Randomization to End of Study (up to 60 months) | Progression-free survival in subgroup of participants with chromosome 17p deletion and/or TP53 mutation was analyzed using KM estimates. |
| Complete Response Rate | Randomization to End of Study (up to 60 months) | Complete response rate was defined as the percentage of participants who achieve a complete response and maintain their response for at least 8 weeks (with a 1-week window). |
Countries
Australia, Belgium, Canada, Denmark, France, Ireland, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, and Australia. The first participant was screened on 04 December 2012. The last study visit occurred on 15 August 2018.
Pre-assignment details
310 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib+Ofatumumab Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses)
Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation | 174 |
| Ofatumumab Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)
Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation | 87 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-Term Follow Up | Lost to Follow-up | 3 | 3 |
| Long-Term Follow Up | Withdrawal by Subject | 2 | 1 |
| Main Study | Adverse Event | 2 | 3 |
| Main Study | Lost to Follow-up | 1 | 0 |
| Main Study | Physician Decision | 34 | 16 |
| Main Study | Study Terminated by Sponsor | 16 | 1 |
| Main Study | Unknown Reasons | 2 | 1 |
| Main Study | Withdrawal by Subject | 19 | 16 |
Baseline characteristics
| Characteristic | Idelalisib+Ofatumumab | Total | Ofatumumab |
|---|---|---|---|
| 17p deletion and/or TP53 mutation Either | 70 Participants | 103 Participants | 33 Participants |
| 17p deletion and/or TP53 mutation Neither | 104 Participants | 158 Participants | 54 Participants |
| Age, Continuous | 67 years STANDARD_DEVIATION 9 | 67 years STANDARD_DEVIATION 9.2 | 67 years STANDARD_DEVIATION 9.7 |
| Disease Status Refractory | 82 Participants | 129 Participants | 47 Participants |
| Disease Status Relapsed | 92 Participants | 132 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 10 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 141 Participants | 215 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 26 Participants | 36 Participants | 10 Participants |
| Immunoglobulin heavy chain variable region (IGHV) mutation status Mutated | 37 Participants | 56 Participants | 19 Participants |
| Immunoglobulin heavy chain variable region (IGHV) mutation status Unmutated | 137 Participants | 205 Participants | 68 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Permitted | 20 Participants | 29 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 149 Participants | 220 Participants | 71 Participants |
| Region of Enrollment Australia | 16 Participants | 29 Participants | 13 Participants |
| Region of Enrollment Belgium | 5 Participants | 6 Participants | 1 Participants |
| Region of Enrollment Canada | 13 Participants | 22 Participants | 9 Participants |
| Region of Enrollment Denmark | 4 Participants | 4 Participants | 0 Participants |
| Region of Enrollment France | 15 Participants | 24 Participants | 9 Participants |
| Region of Enrollment Ireland | 7 Participants | 11 Participants | 4 Participants |
| Region of Enrollment Poland | 27 Participants | 36 Participants | 9 Participants |
| Region of Enrollment Spain | 8 Participants | 13 Participants | 5 Participants |
| Region of Enrollment Sweden | 4 Participants | 6 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 11 Participants | 17 Participants | 6 Participants |
| Region of Enrollment United States | 64 Participants | 93 Participants | 29 Participants |
| Sex: Female, Male Female | 50 Participants | 75 Participants | 25 Participants |
| Sex: Female, Male Male | 124 Participants | 186 Participants | 62 Participants |
| Time Since Diagnosis | 101.0 months STANDARD_DEVIATION 60.21 | 98.8 months STANDARD_DEVIATION 57.75 | 94.3 months STANDARD_DEVIATION 52.51 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 87 / 174 | 40 / 87 |
| other Total, other adverse events | 167 / 173 | 79 / 86 |
| serious Total, serious adverse events | 136 / 173 | 36 / 86 |
Outcome results
Primary
Progression-Free Survival
Progression-free survival (PFS) 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. PFS was analyzed using Kaplan-Meier (KM) estimates.
Time frame: Randomization to End of Study (up to 60 months)
Population: Intent-to-Treat (ITT) Analysis Set included participants who were randomized in the study regardless of whether they received any study drug(s), or received a different regimen from that to which they were randomized. Treatment assignment was designated according to randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Ofatumumab | Progression-Free Survival | 16.6 months |
| Ofatumumab | Progression-Free Survival | 8.0 months |
p-value: <0.000195% CI: [0.18, 0.37]Log Rank
Secondary
Complete Response Rate
Complete response rate was defined as the percentage of participants who achieve a complete response and maintain their response for at least 8 weeks (with a 1-week window).
Time frame: Randomization to End of Study (up to 60 months)
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib+Ofatumumab | Complete Response Rate | 1.1 percentage of participants |
| Ofatumumab | Complete Response Rate | 0 percentage of participants |
Secondary
Lymph Node Response Rate
Lymph node response rate was defined as the proportion of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes.
Time frame: Randomization to End of Study (up to 60 months)
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib+Ofatumumab | Lymph Node Response Rate | 92.7 percentage of participants |
| Ofatumumab | Lymph Node Response Rate | 4.9 percentage of participants |
p-value: <0.000195% CI: [94.63, 2467.02]Cochran-Mantel-Haenszel
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. Overall response rate was analyzed using KM estimates.
Time frame: Randomization to End of Study (up to 60 months)
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib+Ofatumumab | Overall Response Rate | 75.3 percentage of participants |
| Ofatumumab | Overall Response Rate | 17.2 percentage of participants |
p-value: <0.000195% CI: [8.17, 34.76]Cochran-Mantel-Haenszel
Secondary
Overall Survival
Overall survival was defined as the interval from randomization to death from any cause. Overall survival was analyzed using KM estimates.
Time frame: Randomization to Last Long-Term Follow-Up Visit (up to maximum of 5 years)
Population: Participants in the ITT Analysis Set were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Ofatumumab | Overall Survival | 45.2 months |
| Ofatumumab | Overall Survival | 39 months |
p-value: 0.24795% CI: [0.54, 1.15]Log Rank
Secondary
Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation
Progression-free survival in subgroup of participants with chromosome 17p deletion and/or TP53 mutation was analyzed using KM estimates.
Time frame: Randomization to End of Study (up to 60 months)
Population: Participants in the ITT Analysis Set with chromosome 17p deletion and/or TP53 mutation were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Ofatumumab | Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation | 16.2 months |
| Ofatumumab | Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation | 5.8 months |
95% CI: [0.17, 0.51]