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

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

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Idelalisib

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Rouen, France, 76038
    • Centre Henri Becquerel
• Germany
  • Erlangen, Germany, 91052
    • Hämatologische und Internistische Gemeinschaftspraxis Dres. Eckart / Häcker
  • Köln, Germany, 50937
    • Universitätsklinikum Köln
• Italy
  • Milano, Italy, 20132
    • Ospedale San Raffaele s.r.l.
  • Torino, Italy, 10126
    • Azienda Ospedaliera Citta Della Salute E Della Scienza Di Torino
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • Dorchester, United Kingdom, DT1 2JY
    • Dorset County Hospital
  • Harrow, United Kingdom, HA1 3UJ
    • Northwick Park Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital
  • Orpington, United Kingdom, BR6 8ND
    • Princess Royal University Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Clearview Cancer Institute
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology Associates
  • California
    • La Jolla, California, United States, 92093
      • University of California, San Diego - Moores Cancer Center
    • Oxnard, California, United States, 93030
      • Ventura County Hematology Oncology Specialists
    • Santa Monica, California, United States, 90404
      • UCLA
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Blood and Marrow Transplant Program
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center Lombardi Cancer Center
  • Florida
    • Boynton Beach, Florida, United States, 33435
      • Collaborative Research Group
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists
    • Saint Petersburg, Florida, United States, 33705
      • Florida Cancer Specialists
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New Hyde Park, New York, United States, 11042
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
  • Oregon
    • Springfield, Oregon, United States, 97477
      • Willamette Valley Cancer Center
    • Tualatin, Oregon, United States, 97062
      • Northwest Cancer Specialists, PC
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Cancer Centers of the Carolinas
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology, P.A.
    • Houston, Texas, United States, 77030
      • M.D. Anderson Cancer Center
    • San Antonio, Texas, United States, 78217
      • Cancer Care Network of South Texas
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists, PC
    • Roanoke, Virginia, United States, 24014
      • Oncology and Hematology Associates of Southwest Virginia, Inc.
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Seattle Cancer Care Alliance
    • Yakima, Washington, United States, 98902
      • Yakima Valley Memorial Hospital/North Star Lodge
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• 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)
• Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. doi: 10.1200/JCO.18.01460. Epub 2019 Apr 17.

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2012
• Primary Completion (Actual): May 21, 2018
• Study Completion (Actual): June 29, 2018

Study Registration Dates

• First Submitted: February 12, 2012
• First Submitted That Met QC Criteria: February 21, 2012
• First Posted (Estimate): February 27, 2012

Study Record Updates

• Last Update Posted (Actual): August 20, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Leukemia; CLL; CAL-101; CAL 101; GS-1101; GS 1101; PI3K; GS-US-312-0116; idelalisib
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Idelalisib
• Other Study ID Numbers: GS-US-312-0117; 2011-006293-72 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.
• IPD Sharing Time Frame: 18 months after study completion
• IPD Sharing Access Criteria: A secured external environment with username, password, and RSA code.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No