Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab in Adults With Previously Untreated Chronic Lymphocytic Leukemia

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab for Previously Untreated Chronic Lymphocytic Leukemia

The primary objective of this study is to evaluate the progression-free survival in participants with previously untreated chronic lymphocytic leukemia (CLL) who would otherwise be suitable for bendamustine and rituximab treatment as standard of care.

An increased rate of deaths and serious adverse events (SAEs) among participants with front-line CLL and early-line indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA).

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Idelalisib; Drug: Bendamustine; Drug: Rituximab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 311
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital, Sydney
    • North Gosford, New South Wales, Australia, 2250
      • Jarrett Street Specialist Centre
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Haematology and Bone Marrow Transplant Unit, Royal Adelaide Hospital
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre, Department of Haematology, Level 6
    • Kurralta Park, South Australia, Australia, 5037
      • Ashford Cancer Centre Research
    • Woodville South, South Australia, Australia, 5011
      • Queen Elizabeth Hospital
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Frankston Hospital
    • Geelong, Victoria, Australia, 3220
      • Barwon Health, University Hospital Geelong
• Belgium
  • Antwerpen, Belgium, 2060
    • Z N A Stuivenberg
  • Brugge, Belgium, 8000
    • AZ Sint-Jan AV Brugge-Oostende
  • Leuven, Belgium, 3000
    • University Hospital Leuven
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • Cancercare Manitoba - Maccharles Unit
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 2C9
      • Princess Margaret Cancer Centre
  • Quebec
    • Montréal, Quebec, Canada, H4J 1C5
      • Hopital Du Sacre-Coeur de Montreal
    • Quebec City, Quebec, Canada, G1J 1Z4
      • CHU de Quebec - Hopital de l'Enfant-Jesus
• Croatia
  • Zagreb, Croatia, 10000
    • UHC Zagreb
  • Zagreb, Croatia, 10000
    • Klinicka bolnica Dubrava
  • Zagreb, Croatia, 10000
    • Klinicka bolnica Merkur
• Czechia
  • Brno, Czechia, 62500
    • University Hospital
  • Hradec Kralove, Czechia, 500 05
    • Faculty Hospital Hradec Králové
  • Plzen, Czechia, 304 60
    • Faculty Hospital Plzen
  • Prague 10, Czechia, 10034
    • Faculty Hospital Královské Vinohrady
  • Moravian-Silesian
    • Ostrava-Poruba, Moravian-Silesian, Czechia, 70852
      • Faculty Hospital Ostrava
• France
  • Lille, France, 59037
    • CHRU de Lille, Hôpital Claude Huriez
  • Paris, France, 75010
    • Hospital Saint-Louis
  • Tours, France, 37044
    • CHU Bretonneau
• Hungary
  • Budapest, Hungary, 1122
    • National Institute of Oncology
  • Budapest, Hungary, 1083
    • Semmelweis University
  • Debrecen, Hungary, 4032
    • University of Debrecen HSC Institute of internal Medicine, Department of Hematology
  • Gyula, Hungary, 5700
    • Pandy Kalman Hospital
  • Pecs, Hungary, 7624
    • University of Pécs, Medical School
  • Szeged, Hungary, 6725
    • Szegedi Tudomanyegyetem AOK - Szent-Gyorgyi Albert Klinikai Kozpont, II. Belgyógyászati Klinika
  • Komárom - Esztergom
    • Tatabánya, Komárom - Esztergom, Hungary, 2800
      • Szent Borbála Hospital
  • Somogy
    • Kaposvar, Somogy, Hungary, 7400
      • Kaposi Mor Oktato Korhaz, Intezeti Gyogyszertar,
• Italy
  • Cagliari, Italy, 09121
    • Ospedale Oncologico Armando Businco
  • Milan, Italy, 20132
    • Ospedale San Raffaele
  • Modena, Italy, 41124
    • Azienda Ospedaliero Universitaria Policlinico di Modena
  • Novara, Italy, 28100
    • Aou Maggiore Della Carita
  • Puglia
    • Bari, Puglia, Italy, 70024
      • IRCCS Istituto Tumori
• Poland
  • Krakow, Poland, 30-510
    • Malopolskie Centrum Medyczne s.c.
  • Lodz, Poland, 93-510
    • Wojewodzki Szpital Specjalistyczny im. M. Kopernika Klinika Hematologii
  • Warsaw, Poland, 02-507
    • Centralny Szpital Kliniczny MSW w Warszawie Klinika Onkologii i Hematologii
  • Warszawa, Poland, 02-781
    • Centrum Onkologii-Instytut Marii Sklodowskiej -Curie klinika Nowotworow Ukladu Chlonnego
  • Wroclaw, Poland, 53-439
    • Dolnoslakie Centrum Transplantacji Komorkowych z Krajowym Bankiem Dawcow Szpiku
  • Wroclaw, Poland, 50-367
    • Samodzielny Publiczny Szpital Kliniczny nr 1 we Wroclawiu Klinika i Katedra Hematologii,Nowotworow Krwi i Transplantacji Szpiku
  • Pomorskie
    • Gdańsk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne
• Romania
  • Brasov, Romania, 500326
    • Emergency County Clinical Hospital Brasov
  • Bucharest, Romania, 20125
    • Spitalul Clinic Colentina
• Spain
  • Barcelona, Spain, 8041
    • Hospital De La Santa Creu I Sant Pau
  • Barcelona, Spain, 8908
    • ICO, Hospitalet de Llobregat
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital Gregorio Maranon
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro
  • Madrid, Spain, 28033
    • Hospital Universitario Ramon y Cajal
  • Cataluña
    • Barcelona, Cataluña, Spain, 08036
      • Hospital Clinic
    • Barcelona, Cataluña, Spain, 08035
      • Hospital Vall de Hebron
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool & Broadgreen Univ. Hospitals NHS Trust
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospitals NHS Trust
  • Oxford, United Kingdom, OX37LE
    • Oxford University Hospitals
  • Southampton, United Kingdom, SO16 6YD
    • University Hospital Southampton NHS Trust
  • Wolverhampton, United Kingdom, WV10 0QP
    • Royal Wolverhampton Hospital NHS Trust, New Cross Hospital
  • England
    • London, England, United Kingdom, WC1E 6BT
      • University College London
  • Kent
    • Canterbury, Kent, United Kingdom, CT1 3NG
      • East Kent Hospitals University NHS Foundation Trust
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden NHS Trust
• United States
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Heritage Healthcare Virginia K. Crosson Cancer Center
    • La Jolla, California, United States, 92093
      • UCSD Moores Cancer Center
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System
    • Jacksonville, Florida, United States, 32256
      • Cancer Specialists of North Florida
    • Sarasota, Florida, United States, 34236
      • Florida Cancer Specialists-South
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Franciscan Physician Network Oncology & Hematology
  • Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Nevada
    • Las Vegas, Nevada, United States, 89074
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Hematology /Oncology Associates of Northern New Jersey
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Cincinnati, Ohio, United States, 45242
      • Sarah Cannon Research Institute
    • Middletown, Ohio, United States, 45042
      • Signal Point Clinical Research Center
  • South Carolina
    • Greenville, South Carolina, United States, 29601
      • Saint Francis Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Oncology-Austin Midtown
    • Dallas, Texas, United States, 75246
      • Texas Oncology-Baylor Charles A. Sammons Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Utah Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center

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:

• Documented diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL)
• No prior therapy for CLL other than corticosteroids for disease complications
• CLL that warrants treatment
• Presence of measurable lymphadenopathy
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

Key Exclusion Criteria:

• Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation)
• Known presence of myelodysplastic syndrome
• Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization
• Ongoing liver injury
• History of non-infectious pneumonitis
• Ongoing inflammatory bowel disease
• History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
• Ongoing immunosuppressive therapy other than corticosteroids
• Received last dose of study drug on another therapeutic clinical trial within 30 days prior to randomization

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
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Idelalisib+bendamustine+rituximab; Participants will receive idelalisib for 96 weeks plus bendamustine+rituximab for 21 weeks.	Drug: Idelalisib; 150 mg tablet administered orally twice daily; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Bendamustine; Administered intravenously at a starting dose of 90 mg/m^2 for up to 6 cycles. Dosing will be based on mg/m^2 of body surface area.; Drug: Rituximab; Single-use vials administered intravenously weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 infusions
PLACEBO_COMPARATOR: Placebo+bendamustine+rituximab; Participants will receive placebo to match idelalisib for 96 weeks plus bendamustine+rituximab for 21 weeks.	Drug: Bendamustine; Administered intravenously at a starting dose of 90 mg/m^2 for up to 6 cycles. Dosing will be based on mg/m^2 of body surface area.; Drug: Rituximab; Single-use vials administered intravenously weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 infusions; Drug: Placebo; Placebo to match idelalisib administered orally twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC).	Up to 22 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC.	Up to 22 months
Nodal Response Rate	Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC.	Up to 22 months
Complete Response Rate	Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC.	Up to 22 months
Overall Survival	Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC.	Up to 22 months
Minimal Residual Disease Negativity Rate at Week 36	Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD < 10^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation or at least 12 weeks after the last dose of rituximab or bendamustine (whichever is later) for participants receiving the final dose of rituximab after the original scheduled date. MRD negativity rate was to be assessed by an IRC.	Up to 22 months

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 5, 2014
• Primary Completion (ACTUAL): May 30, 2016
• Study Completion (ACTUAL): June 16, 2016

Study Registration Dates

• First Submitted: November 5, 2013
• First Submitted That Met QC Criteria: November 5, 2013
• First Posted (ESTIMATE): November 11, 2013

Study Record Updates

• Last Update Posted (ACTUAL): November 19, 2018
• Last Update Submitted That Met QC Criteria: October 19, 2018
• Last Verified: September 1, 2017

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Rituximab; Idelalisib
• Other Study ID Numbers: GS-US-312-0123; 2013-003313-17 (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; 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