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

Sponsor
Gilead Sciences (Industry)
Overall Status
Terminated
CT.gov ID
NCT01980888
Collaborator
(none)
311
Enrollment
91
Locations
2
Arms
28.3
Actual Duration (Months)
3.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
311 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Feb 5, 2014
Actual Primary Completion Date :
May 30, 2016
Actual Study Completion Date :
Jun 16, 2016

Arms and Interventions

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

    Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival [Up to 22 months]

      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).

    Secondary Outcome Measures

    1. Overall Response Rate [Up to 22 months]

      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.

    2. Nodal Response Rate [Up to 22 months]

      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.

    3. Complete Response Rate [Up to 22 months]

      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.

    4. Overall Survival [Up to 22 months]

      Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC.

    5. Minimal Residual Disease Negativity Rate at Week 36 [Up to 22 months]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

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

    Sponsors and Collaborators

    • Gilead Sciences

    Investigators

    • Study Director: Gilead Study Director, Gilead Sciences

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Gilead Sciences
    ClinicalTrials.gov Identifier:
    NCT01980888
    Other Study ID Numbers:
    • GS-US-312-0123
    • 2013-003313-17
    First Posted:
    Nov 11, 2013
    Last Update Posted:
    Nov 19, 2018
    Last Verified:
    Sep 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Lymphoid
    Leukemia, Lymphocytic, Chronic, B-Cell
    Rituximab
    Bendamustine Hydrochloride
    Idelalisib

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at study sites in the North America, Australia, and Europe. The first participant was screened on 05 February 2014. The last study visit occurred on 16 June 2016.
    Pre-assignment Detail 392 participants were screened.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Period Title: Overall Study
    STARTED 157 154
    COMPLETED 13 21
    NOT COMPLETED 144 133

    Baseline Characteristics

    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab Total
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Total of all reporting groups
    Overall Participants 157 154 311
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    64
    (8.7)
    63
    (10.0)
    64
    (9.4)
    Sex: Female, Male (Count of Participants)
    Female
    57
    36.3%
    48
    31.2%
    105
    33.8%
    Male
    100
    63.7%
    106
    68.8%
    206
    66.2%
    Race/Ethnicity, Customized (Count of Participants)
    Asian
    1
    0.6%
    0
    0%
    1
    0.3%
    Black or African American
    1
    0.6%
    1
    0.6%
    2
    0.6%
    White
    152
    96.8%
    150
    97.4%
    302
    97.1%
    Other
    3
    1.9%
    1
    0.6%
    4
    1.3%
    Not Permitted
    0
    0%
    2
    1.3%
    2
    0.6%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic or Latino
    11
    7%
    2
    1.3%
    13
    4.2%
    Not Hispanic or Latino
    146
    93%
    149
    96.8%
    295
    94.9%
    Not Permitted
    0
    0%
    3
    1.9%
    3
    1%
    Region of Enrollment (participants) [Number]
    Romania
    4
    2.5%
    1
    0.6%
    5
    1.6%
    Hungary
    24
    15.3%
    21
    13.6%
    45
    14.5%
    United States
    35
    22.3%
    25
    16.2%
    60
    19.3%
    United Kingdom
    7
    4.5%
    13
    8.4%
    20
    6.4%
    Spain
    19
    12.1%
    15
    9.7%
    34
    10.9%
    Canada
    11
    7%
    8
    5.2%
    19
    6.1%
    Czech Republic
    10
    6.4%
    17
    11%
    27
    8.7%
    Belgium
    3
    1.9%
    3
    1.9%
    6
    1.9%
    Poland
    15
    9.6%
    18
    11.7%
    33
    10.6%
    Italy
    5
    3.2%
    3
    1.9%
    8
    2.6%
    Australia
    15
    9.6%
    19
    12.3%
    34
    10.9%
    France
    4
    2.5%
    5
    3.2%
    9
    2.9%
    Croatia
    5
    3.2%
    6
    3.9%
    11
    3.5%
    Rai Stage at Screening (Count of Participants)
    Stage I
    28
    17.8%
    30
    19.5%
    58
    18.6%
    Stage II
    66
    42%
    58
    37.7%
    124
    39.9%
    Stage III
    25
    15.9%
    32
    20.8%
    57
    18.3%
    Stage IV
    38
    24.2%
    34
    22.1%
    72
    23.2%
    IgHV Mutation (Count of Participants)
    Mutated
    54
    34.4%
    54
    35.1%
    108
    34.7%
    Unmutated
    102
    65%
    100
    64.9%
    202
    65%
    Missing
    1
    0.6%
    0
    0%
    1
    0.3%
    17p Deletion in CLL Cells (Count of Participants)
    Absent
    146
    93%
    145
    94.2%
    291
    93.6%
    Present
    10
    6.4%
    9
    5.8%
    19
    6.1%
    Missing
    1
    0.6%
    0
    0%
    1
    0.3%

    Outcome Measures

    1. Primary Outcome
    Title Progression-Free Survival
    Description 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).
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    Intent to Treat (ITT) analysis set: all participants who are randomized in the study with treatment group designated according to initial randomization. Due to early study termination, the prespecified efficacy analyses were not conducted. The PFS data presented are investigator assessments rather than IRC assessments.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 157 154
    Median (95% Confidence Interval) [months]
    NA
    NA
    2. Secondary Outcome
    Title Overall Response Rate
    Description 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.
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 0 0
    3. Secondary Outcome
    Title Nodal Response Rate
    Description 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.
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 0 0
    4. Secondary Outcome
    Title Complete Response Rate
    Description 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.
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 0 0
    5. Secondary Outcome
    Title Overall Survival
    Description Overall survival is defined as the interval from randomization to death from any cause. Overall survival was to be assessed by an IRC.
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 0 0
    6. Secondary Outcome
    Title Minimal Residual Disease Negativity Rate at Week 36
    Description 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.
    Time Frame Up to 22 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated in agreement with the FDA due to urgent safety measures. Complete data were not collected for any participant.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    Measure Participants 0 0

    Adverse Events

    Time Frame Up to 22 months plus 30 days
    Adverse Event Reporting Description Safety Analysis Set: participants who received at least 1 dose of study treatment, with treatment assignments designated according to the actual treatment received.
    Arm/Group Title Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Arm/Group Description Idelalisib (Zydelig®) 150 mg tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions) Placebo tablet twice daily + bendamustine intravenously (starting dose of 90 mg/m^2 for up to 6 total cycles) + rituximab intravenously (375 mg/m^2 on Day 1 and 500 mg/m^2 thereafter for at total of 6 infusions)
    All Cause Mortality
    Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 113/156 (72.4%) 68/154 (44.2%)
    Blood and lymphatic system disorders
    Anaemia 8/156 (5.1%) 2/154 (1.3%)
    Bone marrow failure 1/156 (0.6%) 0/154 (0%)
    Febrile neutropenia 29/156 (18.6%) 16/154 (10.4%)
    Haemolytic anaemia 1/156 (0.6%) 0/154 (0%)
    Lymphadenopathy mediastinal 0/156 (0%) 1/154 (0.6%)
    Neutropenia 7/156 (4.5%) 1/154 (0.6%)
    Thrombocytopenia 2/156 (1.3%) 1/154 (0.6%)
    Cardiac disorders
    Acute myocardial infarction 0/156 (0%) 2/154 (1.3%)
    Arrhythmia 0/156 (0%) 1/154 (0.6%)
    Atrial fibrillation 4/156 (2.6%) 3/154 (1.9%)
    Cardiac failure 1/156 (0.6%) 2/154 (1.3%)
    Cardiac failure chronic 0/156 (0%) 1/154 (0.6%)
    Cardiac failure congestive 1/156 (0.6%) 0/154 (0%)
    Cardiopulmonary failure 1/156 (0.6%) 1/154 (0.6%)
    Coronary artery disease 1/156 (0.6%) 0/154 (0%)
    Myocardial ischaemia 0/156 (0%) 1/154 (0.6%)
    Supraventricular extrasystoles 0/156 (0%) 1/154 (0.6%)
    Ventricular extrasystoles 0/156 (0%) 1/154 (0.6%)
    Endocrine disorders
    Glucocorticoid deficiency 0/156 (0%) 1/154 (0.6%)
    Eye disorders
    Blindness 1/156 (0.6%) 0/154 (0%)
    Gastrointestinal disorders
    Abdominal pain upper 1/156 (0.6%) 0/154 (0%)
    Colitis ulcerative 1/156 (0.6%) 0/154 (0%)
    Diarrhoea 6/156 (3.8%) 1/154 (0.6%)
    Enterocolitis 2/156 (1.3%) 0/154 (0%)
    Gastritis 0/156 (0%) 1/154 (0.6%)
    Haematochezia 0/156 (0%) 1/154 (0.6%)
    Oesophagitis 1/156 (0.6%) 0/154 (0%)
    Pancreatitis 0/156 (0%) 1/154 (0.6%)
    Pancreatitis acute 0/156 (0%) 1/154 (0.6%)
    Small intestinal obstruction 1/156 (0.6%) 0/154 (0%)
    Vomiting 1/156 (0.6%) 1/154 (0.6%)
    General disorders
    Asthenia 1/156 (0.6%) 0/154 (0%)
    Chest pain 0/156 (0%) 1/154 (0.6%)
    Influenza like illness 1/156 (0.6%) 0/154 (0%)
    Mucosal inflammation 1/156 (0.6%) 0/154 (0%)
    Oedema peripheral 1/156 (0.6%) 0/154 (0%)
    Pyrexia 26/156 (16.7%) 19/154 (12.3%)
    Systemic inflammatory response syndrome 0/156 (0%) 1/154 (0.6%)
    Unevaluable event 0/156 (0%) 1/154 (0.6%)
    Hepatobiliary disorders
    Cholecystitis 1/156 (0.6%) 0/154 (0%)
    Cholecystitis acute 0/156 (0%) 1/154 (0.6%)
    Hepatitis 1/156 (0.6%) 0/154 (0%)
    Immune system disorders
    Anaphylactic reaction 2/156 (1.3%) 0/154 (0%)
    Drug hypersensitivity 0/156 (0%) 3/154 (1.9%)
    Hypersensitivity 0/156 (0%) 1/154 (0.6%)
    Serum sickness 1/156 (0.6%) 0/154 (0%)
    Infections and infestations
    Appendicitis 1/156 (0.6%) 0/154 (0%)
    Bronchitis 1/156 (0.6%) 0/154 (0%)
    Cellulitis 1/156 (0.6%) 1/154 (0.6%)
    Cytomegalovirus gastritis 1/156 (0.6%) 0/154 (0%)
    Cytomegalovirus infection 3/156 (1.9%) 0/154 (0%)
    Cytomegalovirus viraemia 1/156 (0.6%) 0/154 (0%)
    Device related infection 2/156 (1.3%) 0/154 (0%)
    Gastroenteritis 1/156 (0.6%) 0/154 (0%)
    Gastrointestinal bacterial infection 1/156 (0.6%) 0/154 (0%)
    Herpes simplex 1/156 (0.6%) 0/154 (0%)
    Herpes zoster 1/156 (0.6%) 0/154 (0%)
    Infective exacerbation of chronic obstructive airways disease 0/156 (0%) 1/154 (0.6%)
    Influenza 2/156 (1.3%) 0/154 (0%)
    Lower respiratory tract infection 2/156 (1.3%) 1/154 (0.6%)
    Myocarditis infectious 1/156 (0.6%) 0/154 (0%)
    Neutropenic sepsis 5/156 (3.2%) 1/154 (0.6%)
    Pneumocystis jirovecii pneumonia 1/156 (0.6%) 0/154 (0%)
    Pneumonia 11/156 (7.1%) 6/154 (3.9%)
    Pneumonia fungal 1/156 (0.6%) 0/154 (0%)
    Respiratory tract infection 3/156 (1.9%) 1/154 (0.6%)
    Sepsis 9/156 (5.8%) 2/154 (1.3%)
    Septic shock 1/156 (0.6%) 0/154 (0%)
    Staphylococcal sepsis 1/156 (0.6%) 0/154 (0%)
    Strongyloidiasis 0/156 (0%) 1/154 (0.6%)
    Tonsillitis 0/156 (0%) 1/154 (0.6%)
    Upper respiratory tract infection 1/156 (0.6%) 1/154 (0.6%)
    Urinary tract infection 4/156 (2.6%) 1/154 (0.6%)
    Varicella zoster virus infection 1/156 (0.6%) 0/154 (0%)
    Viral infection 0/156 (0%) 1/154 (0.6%)
    Injury, poisoning and procedural complications
    Fall 0/156 (0%) 1/154 (0.6%)
    Hip fracture 0/156 (0%) 1/154 (0.6%)
    Infusion related reaction 3/156 (1.9%) 1/154 (0.6%)
    Procedural complication 0/156 (0%) 1/154 (0.6%)
    Investigations
    Alanine aminotransferase increased 2/156 (1.3%) 0/154 (0%)
    Aspartate aminotransferase increased 2/156 (1.3%) 0/154 (0%)
    General physical condition abnormal 1/156 (0.6%) 0/154 (0%)
    Transaminases increased 2/156 (1.3%) 0/154 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 1/156 (0.6%) 0/154 (0%)
    Dehydration 3/156 (1.9%) 1/154 (0.6%)
    Hypokalaemia 0/156 (0%) 1/154 (0.6%)
    Malnutrition 1/156 (0.6%) 0/154 (0%)
    Tumour lysis syndrome 5/156 (3.2%) 4/154 (2.6%)
    Musculoskeletal and connective tissue disorders
    Compartment syndrome 1/156 (0.6%) 0/154 (0%)
    Diabetic amyotrophy 0/156 (0%) 1/154 (0.6%)
    Musculoskeletal chest pain 0/156 (0%) 1/154 (0.6%)
    Spinal column stenosis 0/156 (0%) 1/154 (0.6%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites 0/156 (0%) 1/154 (0.6%)
    Malignant melanoma 1/156 (0.6%) 0/154 (0%)
    Malignant pleural effusion 0/156 (0%) 1/154 (0.6%)
    Meningioma 1/156 (0.6%) 0/154 (0%)
    Metastatic squamous cell carcinoma 1/156 (0.6%) 0/154 (0%)
    Skin cancer 1/156 (0.6%) 0/154 (0%)
    Squamous cell carcinoma 1/156 (0.6%) 0/154 (0%)
    Squamous cell carcinoma of lung 0/156 (0%) 1/154 (0.6%)
    Nervous system disorders
    Dysarthria 0/156 (0%) 1/154 (0.6%)
    Encephalopathy 1/156 (0.6%) 0/154 (0%)
    Facial paralysis 0/156 (0%) 1/154 (0.6%)
    Ischaemic stroke 0/156 (0%) 1/154 (0.6%)
    Syncope 2/156 (1.3%) 0/154 (0%)
    Transient ischaemic attack 2/156 (1.3%) 0/154 (0%)
    Psychiatric disorders
    Anxiety 1/156 (0.6%) 0/154 (0%)
    Confusional state 1/156 (0.6%) 0/154 (0%)
    Depression 1/156 (0.6%) 0/154 (0%)
    Hallucination, auditory 1/156 (0.6%) 0/154 (0%)
    Mental status changes 1/156 (0.6%) 0/154 (0%)
    Renal and urinary disorders
    Acute kidney injury 2/156 (1.3%) 0/154 (0%)
    Prerenal failure 1/156 (0.6%) 0/154 (0%)
    Renal tubular acidosis 1/156 (0.6%) 0/154 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/156 (0.6%) 0/154 (0%)
    Dyspnoea 0/156 (0%) 1/154 (0.6%)
    Pleural effusion 1/156 (0.6%) 0/154 (0%)
    Pneumonitis 5/156 (3.2%) 3/154 (1.9%)
    Procedural pneumothorax 0/156 (0%) 1/154 (0.6%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic 0/156 (0%) 1/154 (0.6%)
    Drug eruption 1/156 (0.6%) 0/154 (0%)
    Generalised erythema 2/156 (1.3%) 1/154 (0.6%)
    Photosensitivity reaction 0/156 (0%) 1/154 (0.6%)
    Rash 4/156 (2.6%) 1/154 (0.6%)
    Rash generalised 1/156 (0.6%) 1/154 (0.6%)
    Rash maculo-papular 2/156 (1.3%) 0/154 (0%)
    Vascular disorders
    Aortitis 1/156 (0.6%) 0/154 (0%)
    Embolism 1/156 (0.6%) 0/154 (0%)
    Haematoma 1/156 (0.6%) 0/154 (0%)
    Peripheral embolism 1/156 (0.6%) 0/154 (0%)
    Thrombophlebitis 0/156 (0%) 1/154 (0.6%)
    Thrombophlebitis superficial 0/156 (0%) 1/154 (0.6%)
    Thrombosis 1/156 (0.6%) 0/154 (0%)
    Other (Not Including Serious) Adverse Events
    Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 154/156 (98.7%) 150/154 (97.4%)
    Blood and lymphatic system disorders
    Anaemia 40/156 (25.6%) 29/154 (18.8%)
    Neutropenia 84/156 (53.8%) 90/154 (58.4%)
    Thrombocytopenia 19/156 (12.2%) 16/154 (10.4%)
    Cardiac disorders
    Atrial fibrillation 8/156 (5.1%) 3/154 (1.9%)
    Gastrointestinal disorders
    Abdominal pain 14/156 (9%) 14/154 (9.1%)
    Constipation 26/156 (16.7%) 34/154 (22.1%)
    Diarrhoea 63/156 (40.4%) 46/154 (29.9%)
    Dry mouth 11/156 (7.1%) 4/154 (2.6%)
    Dyspepsia 15/156 (9.6%) 12/154 (7.8%)
    Gastrooesophageal reflux disease 9/156 (5.8%) 4/154 (2.6%)
    Nausea 61/156 (39.1%) 63/154 (40.9%)
    Stomatitis 10/156 (6.4%) 4/154 (2.6%)
    Vomiting 37/156 (23.7%) 23/154 (14.9%)
    General disorders
    Asthenia 21/156 (13.5%) 9/154 (5.8%)
    Chills 21/156 (13.5%) 14/154 (9.1%)
    Fatigue 43/156 (27.6%) 44/154 (28.6%)
    Mucosal inflammation 14/156 (9%) 1/154 (0.6%)
    Oedema peripheral 19/156 (12.2%) 16/154 (10.4%)
    Pyrexia 71/156 (45.5%) 38/154 (24.7%)
    Immune system disorders
    Drug hypersensitivity 8/156 (5.1%) 2/154 (1.3%)
    Infections and infestations
    Bronchitis 5/156 (3.2%) 8/154 (5.2%)
    Influenza 6/156 (3.8%) 8/154 (5.2%)
    Nasopharyngitis 8/156 (5.1%) 14/154 (9.1%)
    Oral candidiasis 8/156 (5.1%) 4/154 (2.6%)
    Oral herpes 5/156 (3.2%) 8/154 (5.2%)
    Pneumonia 10/156 (6.4%) 3/154 (1.9%)
    Respiratory tract infection 9/156 (5.8%) 4/154 (2.6%)
    Sinusitis 9/156 (5.8%) 4/154 (2.6%)
    Upper respiratory tract infection 25/156 (16%) 21/154 (13.6%)
    Urinary tract infection 15/156 (9.6%) 6/154 (3.9%)
    Injury, poisoning and procedural complications
    Infusion related reaction 21/156 (13.5%) 33/154 (21.4%)
    Investigations
    Alanine aminotransferase increased 22/156 (14.1%) 3/154 (1.9%)
    Aspartate aminotransferase increased 18/156 (11.5%) 2/154 (1.3%)
    Neutrophil count decreased 8/156 (5.1%) 2/154 (1.3%)
    Weight decreased 19/156 (12.2%) 4/154 (2.6%)
    Metabolism and nutrition disorders
    Decreased appetite 26/156 (16.7%) 21/154 (13.6%)
    Dehydration 12/156 (7.7%) 2/154 (1.3%)
    Hypokalaemia 25/156 (16%) 4/154 (2.6%)
    Hypophosphataemia 9/156 (5.8%) 0/154 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 16/156 (10.3%) 12/154 (7.8%)
    Back pain 11/156 (7.1%) 18/154 (11.7%)
    Nervous system disorders
    Dizziness 13/156 (8.3%) 13/154 (8.4%)
    Dysgeusia 10/156 (6.4%) 11/154 (7.1%)
    Headache 16/156 (10.3%) 25/154 (16.2%)
    Psychiatric disorders
    Anxiety 11/156 (7.1%) 9/154 (5.8%)
    Depression 8/156 (5.1%) 2/154 (1.3%)
    Insomnia 17/156 (10.9%) 12/154 (7.8%)
    Renal and urinary disorders
    Dysuria 9/156 (5.8%) 3/154 (1.9%)
    Respiratory, thoracic and mediastinal disorders
    Cough 34/156 (21.8%) 29/154 (18.8%)
    Dyspnoea 24/156 (15.4%) 12/154 (7.8%)
    Oropharyngeal pain 8/156 (5.1%) 9/154 (5.8%)
    Skin and subcutaneous tissue disorders
    Dry skin 14/156 (9%) 4/154 (2.6%)
    Erythema 12/156 (7.7%) 8/154 (5.2%)
    Pruritus 24/156 (15.4%) 32/154 (20.8%)
    Rash 63/156 (40.4%) 34/154 (22.1%)
    Rash macular 8/156 (5.1%) 2/154 (1.3%)
    Rash maculo-papular 29/156 (18.6%) 12/154 (7.8%)
    Vascular disorders
    Hypotension 11/156 (7.1%) 10/154 (6.5%)

    Limitations/Caveats

    The study was terminated in agreement with the FDA due to urgent safety measures. Due to early study termination, the prespecified efficacy analyses were not conducted. The PFS data presented are investigator assessments rather than IRC assessments.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years

    Results Point of Contact

    Name/Title Clinical Trial Disclosures
    Organization Gilead Sciences
    Phone
    Email ClinicalTrialDisclosures@gilead.com
    Responsible Party:
    Gilead Sciences
    ClinicalTrials.gov Identifier:
    NCT01980888
    Other Study ID Numbers:
    • GS-US-312-0123
    • 2013-003313-17
    First Posted:
    Nov 11, 2013
    Last Update Posted:
    Nov 19, 2018
    Last Verified:
    Sep 1, 2017