Study Evaluating the Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) (Tugela ) (Tugela)

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia

The primary objective of this study is to evaluate the effect of the addition of idelalisib (formerly GS-1101) to bendamustine + rituximab (BR) on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL)

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Placebo to match idelalisib; Drug: Idelalisib; Drug: Rituximab; Drug: Bendamustine

• Study Type: Interventional
• Enrollment (Actual): 416
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Woolloongabba, Australia, 4102
    • Princess Alexandra Hospital
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital - Sydney
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre - Clayton Campus
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Belgium
  • Antwerpen, Belgium, 2060
    • Ziekenhuisnetwerk Antwerpen - AZ Stuivenberg
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • Cancer Care Manitoba
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Merkur
  • Zagreb, Croatia, 10000
    • Clinical Hospital "Dubrava"
  • Zagreb, Croatia, 10000
    • Klinichki Bolnicki Centar-Zagreb
• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno
  • Hradec Králové, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove
  • Ostrava, Czechia, 708 52
    • Fakultni Nemocnice Ostrava
• France
  • Créteil, France, 94010
    • Hopital Henri Mondor
  • Le Mans cedex, France, 72015
    • Centre Jean Bernard - Clinique Victor Hugo
  • Lille, France, 59045
    • CHRU Lille-Hôpital Claude Huriez
  • Lyon, France, 69373
    • Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes
  • Mulhouse, France, 68100
    • Centre Hospitalier de Mulhouse
  • Nantes, France, 44 093
    • CHU Hôtel-Dieu-Service Hématologie
  • Pierre Bénite, France, Pierre Bénite
    • Centre Hospitalier Lyon Sud
  • Toulouse, France, 31059
    • Hopital Purpan
  • Vandoeuvre-lés-Nancy, France, 54511
    • Hopitaux de Brabois
• Greece
  • Athens, Greece, 11527
    • G. Genimatas Hospital
  • Patras, Greece, 26500
    • University General Hospital of Patras
• Hungary
  • Budapest, Hungary, 1122
    • Orszagos Onkologiai Intezet
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum
  • Kaposvár, Hungary, 7400
    • Tallian Gyula utca 20-32
  • Szeged, Hungary, 6720
    • Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
• Ireland
  • Dublin, Ireland
    • Mater Misericordiae Hospital
• Italy
  • Brescia, Italy, 25123
    • Spedali Civili di Brescia
  • Cagliari, Italy, 9121
    • Ospedale Oncologico Regionale A. Businco
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele
  • Torino, Italy, 10126
    • Azienda Ospedaliera Universitaria San Giovanni Battista-Molinette
• Poland
  • Brzozow, Poland, 36-200
    • Szpital Specjalistyczny w Brzozowie
  • Krakow, Poland, 30-510
    • Malopolskie Centrum Medyczne
  • Lodz, Poland, 93-510
    • Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi
  • Lublin, Poland, 20-081
    • Samodzielny Publiczny Szpital Kliniczny nr 1
  • Opole, Poland, 43-372
    • Wojewodzki Szpital w Opolu
  • Warszawa, Poland, 02-507
    • Centralny Szpital Kliniczny MSW w Warszawie
  • Warszawa, Poland, 02-781
    • Centrum Onkologii Instytut im. Marii Sklodowskiej-Curie
• Portugal
  • Lisboa, Portugal, 1649-035
    • Hospital Santa Maria
  • Porto, Portugal, 4200-072
    • "Instituto Portugues de Oncologia do Porto Francisco Gentil (IPOPFG, EPE)
• Romania
  • Brasov, Romania, 500152
    • Emergency County Clinical Hospital Brasov
  • Bucharest, Romania, 20125
    • "Colentina" Clinical Hospital
  • Bucharest, Romania, 22328
    • "Fundeni" Clinical Institute
  • Iasi, Romania, 700483
    • Regional Oncology Institute Iasi
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Russian Oncology Research Center (N.N. Blokhin)
  • Nizhniy Novgorod, Russian Federation, 603126
    • Nizhegorodskaya Regional Clinical Hospital n.a. N.A. Semashko
  • Novosibirsk, Russian Federation
    • Novosibirsk State Regional Clinical Hospital
  • Ryazan, Russian Federation, 390039
    • Ryazan Regional Clinical Hospital
  • Saratov, Russian Federation, 410028
    • Saratov State Medical University
  • St. Petersburg, Russian Federation, 193024
    • Research Institute of Hematology and Blood Transfusion
  • Volgograd, Russian Federation, 400138
    • State Budgetary Healthcare Institution Volgograd Regional Clinical Oncology Dispensary #1
• Spain
  • Madrid, Spain, 28033
    • Hospital Universitario de la Princesa
  • Cataluña
    • Badalona, Cataluña, Spain, 08916
      • Hospital Universitario Germans Trias i Pujol
    • Barcelona, Cataluña, Spain, 8041
      • Hospital de la Santa Creu i Sant Pau
    • Barcelona, Cataluña, Spain, 8036
      • Hospital Clinic de Barcelona
  • Madrid, Communidad De
    • Madrid, Madrid, Communidad De, Spain, 28041
      • Hospital 12 de Octubre
    • Majadahonda, Madrid, Communidad De, Spain, 28222
      • Hospital Universitario Puerta De Hierro
• Turkey
  • Ankara, Turkey, 06500
    • Gazi University Medical Faculty Gazi Hospital
  • Ankara, Turkey, 6590
    • Ankara University Medical Faculty
  • Istanbul, Turkey, 34093
    • Istanbul University Istanbul Medical Faculty
  • Samsun, Turkey, 55239
    • Ondokuz Mayis University Faculty of Medicine
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital
  • Canterbury, United Kingdom, CT1 3NG
    • Kent and Canterbury Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • Dorchester, United Kingdom, DT1 2JY
    • Dorset County Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St. James University Hospital
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, WC1E 6BT
    • University College London
  • London, United Kingdom, W12 0NN
    • Hammersmith Hospital
  • London, United Kingdom, EC1A 7BE
    • St Bartholomews Hospital
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals NHS Trust
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital
  • Truro, United Kingdom, TR1 3LJ
    • Royal Cornwall Hospital
  • Wolverhampton, United Kingdom, WV10 0QP
    • New Cross Hospital
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35805
      • Clearview Cancer Institute
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Palo Alto, California, United States, 94035
      • Stanford Cancer Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center
  • Florida
    • Gainesville, Florida, United States, 32603
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute at Emory University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Summit Medical Group, P.A.
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • 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, 10021
      • Memorial Sloan Kettering Cancer Center
  • Oregon
    • Eugene, Oregon, United States, 97477
      • Willamette Valley Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29414
      • Charleston Hematology Oncology
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Oncology
    • Dallas, Texas, United States, 75246
      • Texas Oncology Pa
    • Fort Worth, Texas, United States, 76104
      • Texas Oncology
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest, US Oncology
    • Vancouver, Washington, United States, 98684
      • Virginia Cancer Specialists, PC
  • 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:

• Previously treated recurrent CLL
• Measurable lymphadenopathy
• Requires therapy for CLL
• Has experienced CLL progression < 36 months since the completion of the last prior therapy

Key Exclusion Criteria:

• Recent history of a major non-CLL malignancy
• Evidence of an ongoing infection
• CLL refractory to bendamustine
• Concurrent participation in another therapeutic clinical trial

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: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Idelalisib+bendamustine+rituximab; Participants will receive idelalisib plus bendamustine and rituximab	Drug: Idelalisib; Idelalisib 150 mg administered orally twice daily; Other Names: Zydelig®; GS-1101; CAL-101; Drug: Rituximab; Rituximab 375 mg/m^2 on Day 1, then 500 mg/m^2 every 28 days administered intravenously for a maximum of 6 infusions; Other Names: MabThera; Rituxan®; Drug: Bendamustine; Bendamustine 70 mg/mg^2/day on 2 consecutive days every 28 days administered intravenously for a maximum of 12 infusions; Other Names: Ribomustin; Treanda®
Placebo Comparator: Placebo to match idelalisib+bendamustine+rituximab; Participants will receive placebo to match idelalisib plus bendamustine and rituximab	Drug: Placebo to match idelalisib; Placebo to match idelalisib administered orally twice daily; Drug: Rituximab; Rituximab 375 mg/m^2 on Day 1, then 500 mg/m^2 every 28 days administered intravenously for a maximum of 6 infusions; Other Names: MabThera; Rituxan®; Drug: Bendamustine; Bendamustine 70 mg/mg^2/day on 2 consecutive days every 28 days administered intravenously for a maximum of 12 infusions; Other Names: Ribomustin; Treanda®

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 randomization to the earlier of the first documentation of definitive disease progression or death from any cause. PFS (months) = (minimum (date of disease progression, date of death) - date of randomization + 1)/30.4375.	Up to 84 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR was the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi,) or partial response (PR) and maintained the response for at least 12 weeks. CR was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. PR was defined as >1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, > 100000/μL platelets, > 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors. CRi was defined as all criteria for CR met but with persistent anemia, thrombocytopenia, neutropenia or a hypocellular bone marrow.	Up to 84 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 lesions.	Up to 84 months
Overall Survival	Overall survival (OS) was defined as the interval from randomization to death from any cause. Overall survival (months) = (date of death - date of randomization + 1)/30.4375.	Up to 84 months
Complete Response Rate	Complete response (CR) rate was defined as the percentage of participants who achieved a CR.	Up to 84 months

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Zelenetz AD, Robak T, et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. American Society ofHematology (ASH) 57th Annual Meeting & Exposition; 5-8 December 2015; Orlando, FL.
• Barrientos JC, Brown JR, et al. Results of a Randomized Double-Blind Placebo-Controlled Phase 3 study Evaluating Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL and Adverse Prognostic Features. American Society of Clinical Oncology (ASCO) 2016 Annual Meeting; 3-7 June 2016; Chicago, IL.
• Hillmen, P, Ferra C, et al. Idelalisib in Combination with Bendamustine and Rituximab Improves Overall Survival in Patients with Relapsed/Refractory CLL: Interim Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. European Hematology Association (EHA) 21st Annual Meeting; 9-12 June 2016; Copenhagen, Denmark.
• Zelenetz AD, Brown JR et al. Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL. American Society of Hematology (ASH) 58th Annual Meeting & Exposition; 3-6 December 2016; San Diego, CA
• Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illes A, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. doi: 10.1016/S1470-2045(16)30671-4. Epub 2017 Jan 28.
• Montillo M, Illes A, Robak T, Pristupa AS, Wach M, Egyed M, Delgado J, Jurczak W, Morschhauser F, Schuh A, Eradat H, Shreay S, Barrientos JC, Zelenetz AD. Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine/rituximab-treated patients: results of a phase 3, randomized, controlled trial. Health Qual Life Outcomes. 2019 Nov 15;17(1):173. doi: 10.1186/s12955-019-1232-8.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2012
• Primary Completion (Actual): June 10, 2019
• Study Completion (Actual): June 10, 2019

Study Registration Dates

• First Submitted: March 27, 2012
• First Submitted That Met QC Criteria: March 30, 2012
• First Posted (Estimate): April 3, 2012

Study Record Updates

• Last Update Posted (Actual): March 10, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Rituxan; Rituximab; Leukemia; CLL; Bendamustine; CAL-101; GS-1101; GS 1101; PI3K; idelalisib; Zydelig
• 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-312-0115; 2011-006292-20 (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 https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy.
• 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