Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Conditions
Keywords
CLL, SLL, GS-1101, CAL-101, Phosphatidylinositol 3-kinase (PI3K), Rituximab, Rituxan
Brief summary
This study is to evaluate the safety and clinical activity of idelalisib alone and in combination with rituximab in patients with CLL or SLL. This Phase 2 study will be the first time that idelalisib is administered to previously untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity, which supports its evaluation in previously untreated patients. The study population is limited to patients over 65 years of age because younger patients are generally appropriate for standard immunochemotherapy regimens that are highly active. Since the mechanism of action of idelalisib is distinct from rituximab, it is hypothesized that the combination will be more active than either agent alone. This study will establish initial safety and clinical activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of this study will establish safety and clinical activity of idelalisib alone in subjects with untreated CLL or SLL.
Interventions
DRUGIdelalisib
Idelalisib 150 mg tablets administered orally twice daily
DRUGRituximab
Rituximab 375 mg/m\^2 administered intravenously once weekly x 8 weeks
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically or cytologically confirmed CLL or SLL. * Age ≥ 65 * Presence of measurable lymphadenopathy (defined as the presence of ≥1 nodal lesion that measures ≥ 1.5 cm in the longest diameter (LD) and ≥ 1.0 cm in the longest perpendicular diameter (LPD) as assessed by physical exam, computed tomography (CT) or magnetic resonance imaging (MRI)). * CLL - Binet Stage C or Rai Stage III or IV or has active disease defined by meeting at least one of the following criteria: * Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia * Massive (ie, \> 6 cm below the left costal margin) or progressive or symptomatic splenomegaly * Massive nodes (ie, \> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time of less than 6 months * Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy * At least one of the following disease-related symptoms: * Unintentional weight loss ≥ 10% within the previous 6 months * Significant fatigue * Fevers \> 100.4 F for ≥ 2 weeks without other evidence of infection * Night sweats for ≥ 1 month without evidence of infection * SLL - has active disease as defined above for CLL, except the lymphocytosis criterion does not apply * World Health Organization (WHO) Performance Status of ≤ 2 * For men of child-bearing potential, willing to use adequate methods of contraception for the entire duration of the study * Able to provide written informed consent Key
Exclusion criteria
* Prior therapy for CLL or SLL, except corticosteroids for symptom relief * Treatment with a short course of corticosteroids for symptom relief within 1-week prior to Visit 1 * Known active central nervous system involvement of the malignancy * Ongoing active, serious infection requiring systemic therapy. Patients may be receiving prophylactic antibiotics and antiviral therapy at the discretion of the treating physician. * Serum creatinine ≥ 2.0 mg/dL * Serum bilirubin ≥ 2 mg/dL (unless due to Gilbert's syndrome) or serum transaminases (ie, aspartate aminotransferase (AST), alanine aminotransferase (ALT)) ≥ 2 x upper limit of normal * Positive test for human immunodeficiency virus (HIV) antibodies * Active hepatitis B or C (confirmed by ribonucleic acid (RNA) test). Patients with serologic evidence of prior exposure are eligible. * History of a non-CLL malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to study entry, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 5 years. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 28 Months | ORR was assessed based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria as specifically modified for this study to reflect current recommendations which consider the mechanism of action of idelalisib and similar drugs, and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. Based on the CLL response definition in the protocol (modified Hallek 2008), the parameters of lymphadenopathy, liver and/or spleen size, constitutional symptoms, polymorphonuclear leukocytes, circulating clonal B-lymphocytes, platelet count, hemoglobin, and marrow were assessed. * CR: meeting all defined criteria * PR: meeting at least 2 of the criteria of circulating lymphocytes, lymphadenopathy, liver, spleen, or bone marrow (or only lymphadenopathy if liver and spleen normal at baseline) and at least 1 of the criteria for polymorphonuclear leukocytes, platelet count, or hemoglobin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lymphadenopathy Response Rate | Baseline and up to 28 Months | Lymphadenopathy response rate was defined as the percentage of participants with a ≥ 50% reduction from baseline in the sum of the perpendicular diameters of all measurable lesions while receiving study therapy. |
| Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | Baseline; Weeks 8, 16, 24, 36, 48, 60, 72, 84, 96, 108, and 120 | — |
| Duration of Response | Up to 28 Months | Duration of response (DOR) was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of disease progression or death from any cause. |
| Progression-Free Survival | Up to 28 Months | Progression-free survival (PFS) was defined as the interval from the first dose date of drug to the earlier of the first documentation of definitive disease progression or death from any cause. Progression was defined using the Standardized IWCLL criteria as specifically modified for this study to consider the mechanism of action of idelalisib and similar drugs. The occurrence of any of the following events indicated progression: 1. Evidence of any new disease 2. Evidence of worsening of index lesions, spleen or liver, or non-index disease 3. Decrease in platelet count or hemoglobin that is attributable to CLL and is confirmed by bone marrow biopsy |
| Overall Safety of Idelalisib | Up to 28 Months | The overall safety of idelalisib was assessed as the percentage of participants experiencing treatment-emergent adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib). |
| Idelalisib Plasma Concentrations (Cohort 2) | Predose and 1.5 hours postdose at Weeks 0 and 4 and predose at Weeks 8 and 20 | — |
| Changes in Potential Pharmacodynamic Markers of Drug Activity in Plasma and Whole Blood | Up to 169 days | Changes in potential pharmacodynamic markers of drug activity will include assessments of chemokine and cytokine concentrations, effects on the activity of PI3K and related pathways, and effect on cell migration and other functional outcomes. This endpoint will be assessed at the following time points: * Idelalisib+Rituximab (Cohort 1): Predose and 1.5 hour postdose on Day 1 and predose on Days 15, 29, 57, 113, and 169 * Idelalisib (Cohort 2): Predose on Days 1, 29, 57, 141 |
| Overall Survival | Up to 28 Months | Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause. |
| Idelalisib Plasma Concentrations (Cohort 1) | Predose and 1.5 hours postdose at Weeks 0, 4, and 24 | — |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 28 September 2010. The last study visit occurred on 07 June 2016.
Pre-assignment details
113 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Idelalisib+Rituximab (Cohort 1) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle for 12 cycles + rituximab 375 mg/m\^2 administered intravenously weekly for 8 doses. Participants who completed 12 cycles of idelalisib were eligible to continue treatment on an extension study (101-99). | 64 |
| Idelalisib (Cohort 2) Idelalisib 150 mg capsules or tablets administered orally twice daily of each 28-day cycle until disease progression or unacceptable toxicity | 41 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 17 | 5 |
| Overall Study | Death | 3 | 1 |
| Overall Study | Disease Progression | 0 | 4 |
| Overall Study | Investigator Request | 0 | 8 |
| Overall Study | Poor tolerance of study drug | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 0 | 12 |
| Overall Study | Withdrew Consent | 1 | 10 |
Baseline characteristics
| Characteristic | Idelalisib+Rituximab (Cohort 1) | Idelalisib (Cohort 2) | Total |
|---|---|---|---|
| Age, Customized < 70 Years | 29 participants | 14 participants | 43 participants |
| Age, Customized ≥ 70 Years | 35 participants | 27 participants | 62 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 40 Participants | 104 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White/Caucasian | 61 participants | 40 participants | 101 participants |
| Sex: Female, Male Female | 24 Participants | 9 Participants | 33 Participants |
| Sex: Female, Male Male | 40 Participants | 32 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 63 / 64 | 40 / 41 |
| serious Total, serious adverse events | 31 / 64 | 28 / 41 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR was assessed based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria as specifically modified for this study to reflect current recommendations which consider the mechanism of action of idelalisib and similar drugs, and was defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as assessed by the investigator. Based on the CLL response definition in the protocol (modified Hallek 2008), the parameters of lymphadenopathy, liver and/or spleen size, constitutional symptoms, polymorphonuclear leukocytes, circulating clonal B-lymphocytes, platelet count, hemoglobin, and marrow were assessed. * CR: meeting all defined criteria * PR: meeting at least 2 of the criteria of circulating lymphocytes, lymphadenopathy, liver, spleen, or bone marrow (or only lymphadenopathy if liver and spleen normal at baseline) and at least 1 of the criteria for polymorphonuclear leukocytes, platelet count, or hemoglobin.
Time frame: Up to 28 Months
Population: Intent-to-treat (ITT) Analysis Set: participants who received at least 1 dose of idelalisib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Overall Response Rate (ORR) | 96.9 percentage of participants |
| Idelalisib (Cohort 2) | Overall Response Rate (ORR) | 87.8 percentage of participants |
Secondary
Changes in Potential Pharmacodynamic Markers of Drug Activity in Plasma and Whole Blood
Changes in potential pharmacodynamic markers of drug activity will include assessments of chemokine and cytokine concentrations, effects on the activity of PI3K and related pathways, and effect on cell migration and other functional outcomes. This endpoint will be assessed at the following time points: * Idelalisib+Rituximab (Cohort 1): Predose and 1.5 hour postdose on Day 1 and predose on Days 15, 29, 57, 113, and 169 * Idelalisib (Cohort 2): Predose on Days 1, 29, 57, 141
Time frame: Up to 169 days
Population: The collection of plasma samples for pharmacodynamic (PD) analysis in this study was planned prior to the availability of results from an identical PD analysis in another idelalisib study with a larger sample size (n = 176 unique subjects with 2085 longitudinal plasma samples). Therefore, PD analysis was not performed in this study (n = 41).
Secondary
Duration of Response
Duration of response (DOR) was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of disease progression or death from any cause.
Time frame: Up to 28 Months
Population: Participants in the ITT Analysis Set who achieved complete or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Duration of Response | NA months |
| Idelalisib (Cohort 2) | Duration of Response | 14.8 months |
Secondary
Idelalisib Plasma Concentrations (Cohort 1)
Time frame: Predose and 1.5 hours postdose at Weeks 0, 4, and 24
Population: Pharmacokinetic (PK) Analysis Set: participants in the ITT Analysis Set from Cohort 1 who had the necessary baseline and on-study measurements to provide interpretable results for the specific parameters of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 0 predose | 0.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 0 postdose | 1710.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 4 predose | 305.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 4 postdose | 1720.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 24 predose | 256.5 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 1) | Week 24 postdose | 1460.0 ng/mL |
Secondary
Idelalisib Plasma Concentrations (Cohort 2)
Time frame: Predose and 1.5 hours postdose at Weeks 0 and 4 and predose at Weeks 8 and 20
Population: PK Analysis Set: participants in the ITT Analysis Set from Cohort 2 who had the necessary baseline and on-study measurements to provide interpretable results for the specific parameters of interest.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 20 predose | 590.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 0 predose | 0.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 0 postdose | 2190.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 4 predose | 293.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 4 postdose | 2120.0 ng/mL |
| Idelalisib+Rituximab (Cohort 1) | Idelalisib Plasma Concentrations (Cohort 2) | Week 8 predose | 453.0 ng/mL |
Secondary
Lymphadenopathy Response Rate
Lymphadenopathy response rate was defined as the percentage of participants with a ≥ 50% reduction from baseline in the sum of the perpendicular diameters of all measurable lesions while receiving study therapy.
Time frame: Baseline and up to 28 Months
Population: Participants in the ITT Analysis Set with baseline measurable lymph nodes were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Lymphadenopathy Response Rate | 98.0 percentage of participants |
| Idelalisib (Cohort 2) | Lymphadenopathy Response Rate | 86.8 percentage of participants |
Secondary
Overall Safety of Idelalisib
The overall safety of idelalisib was assessed as the percentage of participants experiencing treatment-emergent adverse events (AEs; Serious AEs, Grade ≥ 3 AEs, AEs related to idelalisib, and AEs leading to discontinuation of idelalisib).
Time frame: Up to 28 Months
Population: ITT Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Overall Safety of Idelalisib | Serious AE | 48.4 percentage of participants |
| Idelalisib+Rituximab (Cohort 1) | Overall Safety of Idelalisib | AE related to idelalisib | 81.3 percentage of participants |
| Idelalisib+Rituximab (Cohort 1) | Overall Safety of Idelalisib | Grade ≥ 3 AE | 76.6 percentage of participants |
| Idelalisib+Rituximab (Cohort 1) | Overall Safety of Idelalisib | AE leading to permanent drug discontinuation | 28.1 percentage of participants |
| Idelalisib+Rituximab (Cohort 1) | Overall Safety of Idelalisib | Any AE | 100.0 percentage of participants |
| Idelalisib (Cohort 2) | Overall Safety of Idelalisib | AE leading to permanent drug discontinuation | 56.1 percentage of participants |
| Idelalisib (Cohort 2) | Overall Safety of Idelalisib | Any AE | 100.0 percentage of participants |
| Idelalisib (Cohort 2) | Overall Safety of Idelalisib | Serious AE | 68.3 percentage of participants |
| Idelalisib (Cohort 2) | Overall Safety of Idelalisib | Grade ≥ 3 AE | 85.4 percentage of participants |
| Idelalisib (Cohort 2) | Overall Safety of Idelalisib | AE related to idelalisib | 97.6 percentage of participants |
Secondary
Overall Survival
Overall survival (OS) is defined as the interval from the start of study treatment to death from any cause.
Time frame: Up to 28 Months
Population: Overall survival analysis was not performed because the follow-up period was insufficient to capture enough events.
Secondary
Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions
Time frame: Baseline; Weeks 8, 16, 24, 36, 48, 60, 72, 84, 96, 108, and 120
Population: Participants in the ITT Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 48 | -100.0 percent change |
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 16 | -100.0 percent change |
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 36 | -100.0 percent change |
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 24 | -100.0 percent change |
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | Best % Change | -100.0 percent change |
| Idelalisib+Rituximab (Cohort 1) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 8 | -100.0 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 60 | -69.7 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 72 | -78.0 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 84 | -80.0 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 96 | -81.3 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 108 | -78.1 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 120 | -71.9 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | Best % Change | -81.1 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 8 | -69.8 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 16 | -74.5 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 24 | -76.0 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 36 | -77.5 percent change |
| Idelalisib (Cohort 2) | Percent Change From Baseline in the Sum of the Product of the Greatest Perpendicular Diameters (SPD) of All Measurable Lesions | % Change at Wk 48 | -73.9 percent change |
Secondary
Progression-Free Survival
Progression-free survival (PFS) was defined as the interval from the first dose date of drug to the earlier of the first documentation of definitive disease progression or death from any cause. Progression was defined using the Standardized IWCLL criteria as specifically modified for this study to consider the mechanism of action of idelalisib and similar drugs. The occurrence of any of the following events indicated progression: 1. Evidence of any new disease 2. Evidence of worsening of index lesions, spleen or liver, or non-index disease 3. Decrease in platelet count or hemoglobin that is attributable to CLL and is confirmed by bone marrow biopsy
Time frame: Up to 28 Months
Population: ITT Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Idelalisib+Rituximab (Cohort 1) | Progression-Free Survival | NA months |
| Idelalisib (Cohort 2) | Progression-Free Survival | 26.2 months |