Extension Study of Idelalisib in Participants With Chronic Lymphocytic Leukemia (CLL) Who Participated in GS-US-312-0116 (NCT01539512)

Study Overview
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Brief Summary
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The primary objective of this extension study (GS-US-312-0117) that is a companion study to Study GS-US-312-0116 (NCT01539512), is to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control. Randomization was done in study GS-US-312-0116, and carried forward to study GS-US-312-117.

Official Title
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A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated Chronic Lymphocytic Leukemia A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Idelalisib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals in the primary Phase 3 study (Study GS-US-312-0116) who are compliant Tolerating primary study therapy Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose Idelalisib<br>Participants will receive idelalisib 300 mg twice daily (600 mg per day). | Drug: Idelalisib<br>* Idelalisib tablet(s) administered orally twice daily<br>* Other names: CAL 101;|
| Experimental: Standard-dose Idelalisib<br>Participants will receive idelalisib 150 mg twice daily (300 mg per day) | Drug: Idelalisib<br>* Idelalisib tablet(s) administered orally twice daily<br>* Other names: CAL 101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was defined as the interval from the start of study therapy to the earlier of the first documentation of definitive disease progression or death from any cause; definitive disease progression is chronic lymphocytic leukemia (CLL) progression based on standard criteria other than lymphocytosis alone. PFS was analyzed using Kaplan-Meier (KM) estimates. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Safety: Percentage of Participants With Any Treatment-Emergent Adverse Events (TEAE), ≥ Grade 3 TEAE, Study Drug-Related TEAE, ≥ Grade 3 Study Drug-Related TEAE, Serious TEAE, Study Drug-Related Serious TEAE, and TEAE Leading to Study Drug Discontinuation | The TEAEs were defined as events in a given study period that met one of the following criteria: Events with onset dates on or after the start of treatment and up to 30 days after the permanent discontinuation of the study treatment. The continuing adverse events (AEs) diagnosed prior to the start of treatment and worsened in severity grade, or non-serious AEs at baseline which became serious, or AEs resulting in treatment discontinuation after the start of treatment. The severity of AEs was graded by the investigator according to the common terminology criteria for adverse events (CTCAE), Version 4.03, whenever possible. The relationship of an AE to study drug (idelalisib) was assessed using clinical judgment by the investigator, describing the event as either unrelated or related. Events for which the investigator did not record relationship to study drug were considered related to study drug. | First IDL dose date in study GS-US-312-0116 or GS-US-312-0117 to last IDL dose date in study GS-US-312-0117 (maximum: 67.3 months) plus 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved a complete response (CR) or partial response (PR). The determination of CLL response and progression were based on standardized International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, as specifically modified for this study to reflect current recommendations which considered the mechanism of action of idelalisib and similar drugs. CR and PR are defined in Protocol Amendment 9, Sections 7.5.1 and 7.5.2. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Lymph Node Response Rate | Lymph node response rate was defined as the percentage 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. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Complete Response (CR) Rate | CR rate was defined as the percentage of participants who achieved a CR (full definition in Protocol Amendment 9, Section 7.5.1). The determination of CLL response and progression were based on standardized IWCLL criteria, as specifically modified for this study to reflect current recommendations which considered the mechanism of action of idelalisib and similar drugs. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Time to Response (TTR) | TTR was defined as the time interval from start of study therapy to the first documentation of CR or PR. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Duration of Response (DOR) | DOR was defined as the time interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. DOR was analyzed using KM estimates. | From first documentation of CR or PR to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Best Percent Change in Lymph Node Area | The best percent change from baseline in lymph node area (SPD) was defined as the largest decrease in tumor size during the study. The baseline SPD was the last value prior to the baseline reference date. For the participants who only had increases in tumor size from baseline, the smallest increase was considered as the best change from baseline in SPD. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Splenomegaly Response Rate | Splenomegaly response rate was defined as the percentage of participants with baseline splenomegaly who achieved an on-study normalization or a 50% decrease (minimum 2 cm) from baseline in the enlargement of the splenic longest vertical dimension (LVD) (by imaging). | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Hepatomegaly Response Rate | Hepatomegaly response rate was defined as the percentage of participants with baseline hepatomegaly who achieved an on-study normalization or a 50% decrease (minimum 2 cm) from baseline in the hepatic LVD (by imaging). | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Absolute Lymphocyte Count (ALC) Response Rate | ALC response rate was defined as the percentage of participants with baseline lymphocytosis (ALC ≥ 4 x 10^9 cells/L) who achieved an on-study ALC < 4 x 10^9 cells/L or demonstrated a ≥ 50% decrease in ALC from baseline; ALC values within 4 weeks post-baseline were excluded from the ALC response rate evaluation. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Platelet Response Rate | Platelet response rate was defined as the percentage of participants with baseline thrombocytopenia (platelet count < 100 x 10^9/L) who achieved an on-study platelet count ≥ 100 x 10^9/L or demonstrated a ≥ 50% increase in platelet count from baseline; platelet values within 4 weeks post-baseline or after 8 days post transfusion were excluded from the platelet response rate evaluation. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Hemoglobin Response Rate | Hemoglobin response rate was defined as the percentage of participants with baseline anemia (hemoglobin < 110 g/L [11.0 g/dL]) who achieved an on-study hemoglobin ≥ 110 g/L (11.0 g/dL) or demonstrated a ≥ 50% increase in hemoglobin from baseline; hemoglobin values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood transfusion or after 6 weeks of receiving exogenous growth factors (eg, darbepoetin alfa) were excluded from the hemoglobin response evaluation. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Neutrophil Response Rate | Neutrophil response rate was defined as the percentage of participants with baseline neutropenia (absolute neutrophil count [ANC] ≤ 1.5 x 10^9/L) who achieved an ANC > 1.5 x 10^9/L or demonstrated a ≥ 50% increase in ANC from baseline; ANC values within 4 weeks of post-baseline or after 2 weeks of receiving exogenous growth factors (eg, filgrastim, granulocyte-colony stimulating factor [G-CSF], lenograstim) or after 4 weeks of receiving Neulasta® were excluded from response evaluation. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Overall Survival | Overall survival was defined as the time interval from start of study therapy to death from any cause. Overall survival was analyzed using KM estimates. Data presented includes all available survival information from Study GS-US-312-0116 (including data in long-term follow-up) and Study GS-US-312-0117 (including any data in long-term follow-up) up to the database finalization dates. Data from surviving participants were censored at the last time that the participant was known to be alive on study or long-term follow-up. Data presented includes all participants who were randomized to Study GS-US-312-0116 regardless if they entered Study GS-US-312-0117 or not. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Best Change From Baseline in Health-Related Quality of Life (HRQL) Domain and Symptom Scores Based on the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) Questionnaire | The FACT-Leu questionnaire included subscales for physical well-being (PWB, 7 items), social/family well-being (SWB, 7 items), emotional well-being (EWB, 6 items), functional well-being (FWB, 7 items), and additional concerns or Leukemia-Specific Subscale (LeuS, 17 items). The FACT-Leu scoring guide identified those negatively stated items that must have been reversed before being added to obtain subscale totals. Negatively stated items were reversed by subtracting the response from 4. After reversing proper items, all subscale items were summed to get total subscale scores with the range of 0-28, 0-28, 0-24, 0-28, 0-68 for PWB, SWB, EWB, FWB, and LeuS, respectively. FACT-Leu total score ranged from 0 to 176. Higher scores indicated a better quality of life. Best change from baseline was defined as the highest value of change from baseline among all postbaseline visits. For participants who did not enter Study GS-US-312-0117, baseline values were from Study GS-US-312-0116. | Study GS-US-312-0116 or GS-US-312-0117 Baseline up to Week 184 | 
| Best Change From Baseline in Karnofsky Performance Status (KPS) | KPS is a tool used to measure the ability to perform ordinary tasks. The score ranges from 0 to 100, with a higher score indicating that the participant is better able to carry out daily activities. Best change from baseline was defined as the highest value of change from baseline among all postbaseline visits. For participants who did not enter Study GS-US-312-0117, baseline values were from Study GS-US-312-0116. | Study GS-US-312-0116 or GS-US-312-0117 Baseline up to Week 190 | 
| Changes From Baseline in Phosphatidylinositol 3-kinase (PI3Kδ)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway Activation as a Measure of PI3Kδ Pathway Activity |  | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Overall Change From Baseline in the Plasma Concentrations of Disease-Associated Chemokines and Cytokines | The percent of average on-treatment biomarker concentration of baseline (%Baseline) was used to evaluate the overall pharmacodynamics change on the biomarkers with IDL treatment. The average on-treatment biomarker concentration is calculated using area under curve (AUC) following the trapezoidal rule. The biomarkers with median AUC value of 100 indicated no overall on-treatment biomarker changes compared to the baseline. The biomarkers with median AUC value greater than 100 or less than 100 indicated an increase or decrease, respectively, on-treatment biomarker changes from the baseline. | GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) | 
| Study Drug Compliance as Assessed by the Percentage of Participants Adhering to Treatment | Adherence percentage was calculated as the sum of tablets dispensed - the sum of tablets returned divided by the sum of the overall dosing period (total daily tablets x dosing duration), taking into account investigator-prescribed interruptions. | First IDL dose date in study GS-US-312-0116 or GS-US-312-0117 to last IDL dose date in study GS-US-312-0117 (maximum: 67.3 months) | 
| Plasma Trough (Predose) and Peak (1.5 Hours Postdose) Concentrations of Idelalisib |  | Weeks 4, 12, and 24 | 
| Change in Health Status as Assessed Using the EuroQoL Five-Dimension (EQ-5D) Utility Measure | Change in health status was defined as the change from baseline in overall health and single-item dimension scores as assessed using the EQ-5D utility measure. Percentage of participants with different level of problem were reported. Level 1: indicated no problem; Level 2: indicated some problems; and Level 3: indicated extreme problems. For participants who did not enter Study GS-US-312-0117, baseline values were from Study GS-US-312-0116. | Study GS-US-312-0116 or GS-US-312-0117 Baseline; Weeks 24 and 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLL, CAL-101, CAL 101, GS-1101, GS 1101, PI3K, Leukemia, GS-US-312-0116, idelalisib