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

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ClinicalTrials.gov Identifier: NCT01539291
Recruitment Status : Terminated
First Posted : February 27, 2012
Results First Posted : August 20, 2019
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Idelalisib Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 161 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 3, 2012
Actual Primary Completion Date : May 21, 2018
Actual Study Completion Date : June 29, 2018


Arm Intervention/treatment
Experimental: High-dose Idelalisib
Participants will receive idelalisib 300 mg twice daily (600 mg per day).
Drug: Idelalisib
Idelalisib tablet(s) administered orally twice daily
Other Names:
  • Zydelig®
  • GS-1101
  • CAL 101

Experimental: Standard-dose Idelalisib
Participants will receive idelalisib 150 mg twice daily (300 mg per day)
Drug: Idelalisib
Idelalisib tablet(s) administered orally twice daily
Other Names:
  • Zydelig®
  • GS-1101
  • CAL 101




Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  2. 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 [ Time Frame: 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 ]

    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.



Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  2. Lymph Node Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  3. Complete Response (CR) Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  4. Time to Response (TTR) [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    TTR was defined as the time interval from start of study therapy to the first documentation of CR or PR.

  5. Duration of Response (DOR) [ Time Frame: From first documentation of CR or PR to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  6. Best Percent Change in Lymph Node Area [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  7. Splenomegaly Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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).

  8. Hepatomegaly Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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).

  9. Absolute Lymphocyte Count (ALC) Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  10. Platelet Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  11. Hemoglobin Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  12. Neutrophil Response Rate [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  13. Overall Survival [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  14. 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 [ Time Frame: Study GS-US-312-0116 or GS-US-312-0117 Baseline up to Week 184 ]
    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.

  15. Best Change From Baseline in Karnofsky Performance Status (KPS) [ Time Frame: Study GS-US-312-0116 or GS-US-312-0117 Baseline up to Week 190 ]
    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.

  16. Changes From Baseline in Phosphatidylinositol 3-kinase (PI3Kδ)/Akt/Mammalian Target of Rapamycin (mTOR) Pathway Activation as a Measure of PI3Kδ Pathway Activity [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
  17. Overall Change From Baseline in the Plasma Concentrations of Disease-Associated Chemokines and Cytokines [ Time Frame: GS-US-312-0116 Baseline to end of study GS-US-312-0117 (maximum: up to 67.6 months) ]
    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.

  18. Study Drug Compliance as Assessed by the Percentage of Participants Adhering to Treatment [ Time Frame: 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) ]
    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.

  19. Plasma Trough (Predose) and Peak (1.5 Hours Postdose) Concentrations of Idelalisib [ Time Frame: Weeks 4, 12, and 24 ]
  20. Change in Health Status as Assessed Using the EuroQoL Five-Dimension (EQ-5D) Utility Measure [ Time Frame: Study GS-US-312-0116 or GS-US-312-0117 Baseline; Weeks 24 and 48 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01539291


  Show 45 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Study Protocol: Original  [PDF] January 23, 2012
Study Protocol: Amendment 1  [PDF] January 23, 2013
Study Protocol: Amendment 2  [PDF] September 10, 2013
Study Protocol: Amendment 3  [PDF] December 16, 2013
Study Protocol: Amendment 4  [PDF] May 27, 2014
Study Protocol: Amendment 5  [PDF] October 10, 2014
Study Protocol: Amendment 6  [PDF] March 28, 2016
Study Protocol: Amendment 7  [PDF] August 5, 2016
Statistical Analysis Plan: Blinded  [PDF] November 4, 2013
Statistical Analysis Plan: Open Label  [PDF] January 26, 2015
Study Protocol: Amendment 8  [PDF] October 24, 2016
Study Protocol: Amendment 9  [PDF] September 21, 2017


Publications of Results:
Coutre SE, Furman RR, Sharman, JP, Cheson BD, Pagel JM, Hillmen P, et al. Second Interim Analysis of a Phase 3 Study of Idelalisib (Zydelig®) Plus Rituximab for Relapsed Chronic Lymphocytic Leukemia: Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Blood 2014; 124 (21):330
Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, et al. Efficacy of Idelalisib in CLL Subpopulations Harboring Del(17p) and Other Adverse Prognostic Factors: Results from a Phase 3, Randomized, Double-blind, Placebo-controlled Trial [Poster 7011]. American Society of Clinical Oncology (ASCO) 50th Annual Meeting; 2014 May 30-June 3; Chicago, IL. J Clin Oncol 32:5s, 2014 (suppl; abstr 7011)

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01539291     History of Changes
Other Study ID Numbers: GS-US-312-0117
2011-006293-72 ( EudraCT Number )
First Posted: February 27, 2012    Key Record Dates
Results First Posted: August 20, 2019
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at http://www.gilead.com/research/disclosure-and-transparency.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: 18 months after study completion
Access Criteria: A secured external environment with username, password, and RSA code.
URL: http://www.gilead.com/research/disclosure-and-transparency

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
CLL
CAL-101
CAL 101
GS-1101
GS 1101
PI3K
Leukemia
GS-US-312-0116
idelalisib
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Idelalisib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action