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Entospletinib in Combination With Idelalisib in Adults With Relapsed or Refractory Hematologic Malignancies

Sponsor
Gilead Sciences (Industry)
Overall Status
Terminated
CT.gov ID
NCT01796470
Collaborator
(none)
66
Enrollment
13
Locations
1
Arm
42.1
Actual Duration (Months)
5.1
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy of the combination entospletinib and idelalisib in participants with relapsed or refractory hematologic malignancies. Participants will be enrolled who have one of the following hematological tumor types: chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), or indolent non-Hodgkin lymphomas (iNHL; including follicular lymphoma (FL) and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia [LPL/WM], small lymphocytic lymphoma [SLL], or marginal zone lymphoma [MZL]).

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
66 participants
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Combination With Idelalisib in Subjects With Relapsed or Refractory Hematologic Malignancies
Actual Study Start Date :
Jun 20, 2013
Actual Primary Completion Date :
Jan 1, 2015
Actual Study Completion Date :
Dec 22, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Entospletinib + idelalisib

Entospletinib plus idelalisib at one of 4 dose combinations (400 mg/100 mg; 600 mg/100 mg; 800 mg/100 mg; 800 mg/150 mg). After discontinuation of entospletinib+idelalisib combination therapy, and following a washout period, participants may continue to receive entospletinib 400 mg monotherapy.

Drug: Entospletinib
Entospletinib tablets administered orally twice daily
Other Names:
  • GS-9973

    • Drug: Idelalisib
    Idelalisib tablets administered orally twice daily
    Other Names:
  • GS-1101
  • GS 1101
  • Cal-101
  • Cal 101
  • Zydelig®

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) [Start of treatment to end of treatment (Up to 18 months)]

      ORR assessed by the Independent Review Committee (IRC), was based on the International Working Group Revised Response Criteria (Cheson, 2012) and investigator's response, defined as the percentage of participants achieving a complete response (CR) or partial response (PR) (or very good partial response [VGPR] or minor response [MR] for participants with LPL/WM). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal immunoglobulin M (IgM) concentration by serum protein electrophoresis (SPEP) respectively.

    Secondary Outcome Measures

    1. Percentage of Participants Experiencing Treatment-Emergent Adverse Events [First dose date up to the last dose date plus 30 days (maximum duration: 19 months)]

      A treatment-emergent Adverse Event (AE) was defined as any AE with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drugs or an AE leading to premature discontinuation of study drug. An AE is any untoward medical occurrence in a clinical investigation where participants administered a medicinal product, and which does not necessarily have a causal relationship with this treatment.

    2. Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [First dose date up to the last dose date plus 30 days (maximum: 18 months)]

      A treatment-emergent laboratory (Hematology, Serum Chemistry and Urinalysis) abnormality was defined as an abnormality that, compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug. Safety as assessed by grading of laboratory values and AEs according to the National Cancer Institutes' Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 0 = none, Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening or disabling. If baseline data are missing, then any graded abnormality (i.e., an abnormality that is Grade ≥ 1 in severity) will be considered treatment-emergent. The percentage of participants in each worst postbaseline grade is reported.

    3. Maximum Tolerated Dose Level [First dose (entospelinib + idelalisib) date up to 6 months]

      Maximum tolerated dose (MTD) is defined as the highest dose level that was consistently well tolerated without dose limiting toxicity (DLT) for the majority of participants time on treatment (ie,> 50%) as determined by the investigator for each participant. DLTs are defined as Grade 4 hematological toxicities persisting for ≥ 14 days or Grade ≥ 3 toxicities of other types.

    4. Progression-free Survival (PFS) [Start of treatment to end of treatment (Up to 18 months)]

      PFS was defined as the interval from the first dose of study drug to the earlier of the first documentation of definitive disease progression or death from any cause.

    5. Duration of Response (DOR) [Start of treatment to end of treatment (Up to 18 months)]

      DOR was defined as the interval from the first-time response (CR or PR [or VGPR or MR for participants with LPL/WM]) is achieved to the earlier of the first documentation of definitive disease progression or death from any cause.CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.

    6. Time to Response (TTR) [Start of treatment to end of treatment (Up to 18 months)]

      TTR was defined as the interval from the first dose of entospletinib/idelalisib to the time response (CR or PR [or VGPR or MR for participants with LPL/WM]) is first achieved. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    • Diagnosis of B-cell indolent non-Hodgkin lymphoma (iNHL),diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) as documented by medical records and with histology based on criteria established by the World Health Organization

    • For institutions that have Phase 3 or Phase 4 protocols studying idelalisib (Zydelig®; GS-1101); individuals with malignancies being studied in these protocols must have failed screening and be registered as a screen failure in the respective idelalisib protocol

    • Prior treatment for lymphoid malignancy

    • Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy

    • Discontinuation of all therapy for the treatment of cancer ≥ 3 weeks before the start of study drug

    • All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of study drug

    • Karnofsky performance status of ≥ 60

    • Life expectancy of at least 3 months

    Key Exclusion Criteria:

    • Known histological transformation from iNHL or CLL to an aggressive form of NHL (ie, Richter transformation)

    • Known active central nervous system or leptomeningeal lymphoma

    • Presence of known intermediate- or high-grade myelodysplastic syndrome

    • Current therapy with agents that reduce gastric acidity, including but not limited to antacids, H2 inhibitors, and proton pump inhibitors

    • Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study drug

    • Ongoing liver injury

    • Ongoing or recent hepatic encephalopathy

    • Ongoing drug-induced pneumonitis

    • Ongoing inflammatory bowel disease

    • Ongoing alcohol or drug addiction

    • Pregnancy or breastfeeding

    • History of prior allogeneic bone marrow progenitor cell or solid organ transplantation

    • Ongoing immunosuppressive therapy

    • Concurrent participation in an investigational drug trial with therapeutic intent

    Note: Other protocol defined Inclusion/Exclusion criteria may apply.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UC San Diego Moores Cancer Center La Jolla California United States 92093
    2 Pacific Shores Medical Group Long Beach California United States 90813
    3 Ventura County Hematology Oncology Specialists Oxnard California United States 93030
    4 Cancer Center of Santa Barbara Santa Barbara California United States 93105
    5 Georgetown University Medical Center Washington District of Columbia United States 20007
    6 Collaborative Research Group LLC Boynton Beach Florida United States 33435
    7 Weill Cornell Medical College New York New York United States 10021
    8 University of Rochester, James P. Wilmot Cancer Center Rochester New York United States 14642
    9 Signal Point Clinical Research Center, LLC Middletown Ohio United States 45042
    10 Oregon Health and Science University Portland Oregon United States 97239
    11 Charleston Hematology Oncology Charleston South Carolina United States 29414
    12 MD Anderson Cancer Center Houston Texas United States 77030
    13 Northwest Medical Specialties Tacoma Washington United States 98405

    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:
    NCT01796470
    Other Study ID Numbers:
    • GS-US-339-0103
    First Posted:
    Feb 21, 2013
    Last Update Posted:
    Jun 2, 2020
    Last Verified:
    May 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Gilead Sciences
    GS-US-339-0103
    SYK inhibitor
    PI3K inhibitor
    GS-9973
    GS 9973
    GS-1101
    GS 1101
    Cal-101
    Cal 101
    idelalisib
    leukemia
    lymphoma
    CLL
    MCL
    DLBCL
    iNHL
    FL
    MZL
    LPL
    SLL
    WM
    Waldenström's macroglobulinemia
    Additional relevant MeSH terms:
    Lymphoma
    Leukemia, Lymphocytic, Chronic, B-Cell
    Lymphoma, Mantle-Cell
    Lymphoma, Large B-Cell, Diffuse
    Hematologic Neoplasms
    Idelalisib

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at study sites in the United States. The first participant was screened on 20 June 2013. The last study visit occurred on 22 December 2016.
    Pre-assignment Detail 85 participants were screened.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Period Title: Overall Study
    STARTED 35 14 6 3 8
    Entospletinib Monotherapy 4 4 0 0 0
    COMPLETED 0 0 0 0 0
    NOT COMPLETED 35 14 6 3 8

    Baseline Characteristics

    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others Total
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Total of all reporting groups
    Overall Participants 35 14 6 3 8 66
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    68
    (12.9)
    64
    (13.4)
    69
    (17.4)
    62
    (10.8)
    69
    (8.9)
    67
    (12.7)
    Sex: Female, Male (Count of Participants)
    Female
    15
    42.9%
    6
    42.9%
    4
    66.7%
    1
    33.3%
    5
    62.5%
    31
    47%
    Male
    20
    57.1%
    8
    57.1%
    2
    33.3%
    2
    66.7%
    3
    37.5%
    35
    53%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    35
    100%
    12
    85.7%
    6
    100%
    3
    100%
    8
    100%
    64
    97%
    Not Permitted
    0
    0%
    2
    14.3%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Race/Ethnicity, Customized (Count of Participants)
    White/Caucasian
    27
    77.1%
    11
    78.6%
    6
    100%
    3
    100%
    8
    100%
    55
    83.3%
    Black or African American
    5
    14.3%
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    6
    9.1%
    Native Hawaiian or Other Pacific Islander
    1
    2.9%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Asian
    2
    5.7%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    3%
    Other
    0
    0%
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Not Reported
    0
    0%
    1
    7.1%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    Karnofsky Performance Status (Count of Participants)
    40
    1
    2.9%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    50
    1
    2.9%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.5%
    60
    2
    5.7%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    3
    4.5%
    70
    2
    5.7%
    1
    7.1%
    1
    16.7%
    0
    0%
    0
    0%
    4
    6.1%
    80
    9
    25.7%
    7
    50%
    2
    33.3%
    1
    33.3%
    5
    62.5%
    24
    36.4%
    90
    14
    40%
    4
    28.6%
    3
    50%
    1
    33.3%
    3
    37.5%
    25
    37.9%
    100
    6
    17.1%
    2
    14.3%
    0
    0%
    0
    0%
    0
    0%
    8
    12.1%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate (ORR)
    Description ORR assessed by the Independent Review Committee (IRC), was based on the International Working Group Revised Response Criteria (Cheson, 2012) and investigator's response, defined as the percentage of participants achieving a complete response (CR) or partial response (PR) (or very good partial response [VGPR] or minor response [MR] for participants with LPL/WM). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal immunoglobulin M (IgM) concentration by serum protein electrophoresis (SPEP) respectively.
    Time Frame Start of treatment to end of treatment (Up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    The study was terminated due to safety measures. Complete data was not collected for any participant.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 0 0 0 0 0
    2. Secondary Outcome
    Title Percentage of Participants Experiencing Treatment-Emergent Adverse Events
    Description A treatment-emergent Adverse Event (AE) was defined as any AE with an onset date of on or after the study drug start date and no later than 30 days after permanent discontinuation of study drugs or an AE leading to premature discontinuation of study drug. An AE is any untoward medical occurrence in a clinical investigation where participants administered a medicinal product, and which does not necessarily have a causal relationship with this treatment.
    Time Frame First dose date up to the last dose date plus 30 days (maximum duration: 19 months)

    Outcome Measure Data

    Analysis Population Description
    The Safety Analysis Set comprised all participants who received ≥ 1 dose of study drug (entospletinib or idelalisib).
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 35 14 6 3 8
    Number [percentage of participants]
    100
    285.7%
    100
    714.3%
    100
    1666.7%
    100
    3333.3%
    100
    1250%
    3. Secondary Outcome
    Title Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities
    Description A treatment-emergent laboratory (Hematology, Serum Chemistry and Urinalysis) abnormality was defined as an abnormality that, compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug. Safety as assessed by grading of laboratory values and AEs according to the National Cancer Institutes' Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. Grade 0 = none, Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening or disabling. If baseline data are missing, then any graded abnormality (i.e., an abnormality that is Grade ≥ 1 in severity) will be considered treatment-emergent. The percentage of participants in each worst postbaseline grade is reported.
    Time Frame First dose date up to the last dose date plus 30 days (maximum: 18 months)

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/ Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 35 14 6 3 8
    Neutrophils Count Decreased (Grade 1)
    17.1
    48.9%
    21.4
    152.9%
    0
    0%
    66.7
    2223.3%
    25.0
    312.5%
    Neutrophils Count Decreased (Grade 2)
    20.0
    57.1%
    14.3
    102.1%
    0
    0%
    0
    0%
    25.0
    312.5%
    Neutrophils Count Decreased (Grade 3)
    14.3
    40.9%
    7.1
    50.7%
    16.7
    278.3%
    0
    0%
    0
    0%
    Neutrophils Count Decreased (Grade 4)
    11.4
    32.6%
    7.1
    50.7%
    0
    0%
    0
    0%
    25.0
    312.5%
    Anemia (Grade 1)
    20.0
    57.1%
    35.7
    255%
    16.7
    278.3%
    0
    0%
    0
    0%
    Anemia (Grade 2)
    14.3
    40.9%
    7.1
    50.7%
    16.7
    278.3%
    0
    0%
    0
    0%
    Anemia (Grade 3)
    5.7
    16.3%
    0
    0%
    16.7
    278.3%
    0
    0%
    0
    0%
    Anemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Leukocytosis (Grade 1)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Leukocytosis (Grade 2)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Leukocytosis (Grade 3)
    28.6
    81.7%
    0
    0%
    0
    0%
    33.3
    1110%
    0
    0%
    Leukocytosis (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White Blood Cell Count Decreased (Grade 1)
    0
    0%
    21.4
    152.9%
    16.7
    278.3%
    0
    0%
    12.5
    156.3%
    WBC Count Decreased (Grade 2)
    14.3
    40.9%
    0
    0%
    16.7
    278.3%
    33.3
    1110%
    12.5
    156.3%
    WBC Count Decreased (Grade 3)
    5.7
    16.3%
    14.3
    102.1%
    0
    0%
    0
    0%
    12.5
    156.3%
    WBC Count Decreased (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    12.5
    156.3%
    Lymphocyte Count Decreased (Grade 1)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Lymphocyte Count Decreased (Grade 2)
    0
    0%
    0
    0%
    16.7
    278.3%
    33.3
    1110%
    12.5
    156.3%
    Lymphocyte Count Decreased (Grade 3)
    5.7
    16.3%
    21.4
    152.9%
    50.0
    833.3%
    0
    0%
    12.5
    156.3%
    Lymphocyte Count Decreased (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    33.3
    1110%
    0
    0%
    Lymphocyte Count Increased (Grade 1)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Lymphocyte Count Increased (Grade 2)
    8.6
    24.6%
    7.1
    50.7%
    16.7
    278.3%
    0
    0%
    0
    0%
    Lymphocyte Count Increased (Grade 3)
    28.6
    81.7%
    0
    0%
    0
    0%
    0
    0%
    12.5
    156.3%
    Lymphocyte Count Increased (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Platelets Count Decreased (Grade 1)
    11.4
    32.6%
    28.6
    204.3%
    16.7
    278.3%
    33.3
    1110%
    0
    0%
    Platelets Count Decreased (Grade 2)
    2.9
    8.3%
    7.1
    50.7%
    0
    0%
    0
    0%
    0
    0%
    Platelets Count Decreased (Grade 3)
    5.7
    16.3%
    14.3
    102.1%
    0
    0%
    0
    0%
    0
    0%
    Platelets Count Decreased (Grade 4)
    2.9
    8.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alanine Aminotransferase (ALT) Increased (Grade 1)
    22.9
    65.4%
    7.1
    50.7%
    33.3
    555%
    0
    0%
    50.0
    625%
    ALT Increased (Grade 2)
    8.6
    24.6%
    7.1
    50.7%
    0
    0%
    0
    0%
    0
    0%
    ALT Increased (Grade 3)
    0
    0%
    35.7
    255%
    16.7
    278.3%
    33.3
    1110%
    0
    0%
    ALT Increased (Grade 4)
    5.7
    16.3%
    0
    0%
    0
    0%
    0
    0%
    12.5
    156.3%
    Hypoalbuminemia (Grade 1)
    14.3
    40.9%
    28.6
    204.3%
    0
    0%
    0
    0%
    12.5
    156.3%
    Hypoalbuminemia (Grade 2)
    5.7
    16.3%
    0
    0%
    16.7
    278.3%
    33.3
    1110%
    0
    0%
    Hypoalbuminemia (Grade 3)
    0
    0%
    0
    0%
    16.7
    278.3%
    0
    0%
    0
    0%
    Hypoalbuminemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alkaline Phosphatase (ALP) Increased (Grade 1)
    17.1
    48.9%
    28.6
    204.3%
    33.3
    555%
    33.3
    1110%
    12.5
    156.3%
    ALP Increased (Grade 2)
    2.9
    8.3%
    0
    0%
    0
    0%
    0
    0%
    12.5
    156.3%
    ALP Increased (Grade 3)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    ALP Increased (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Aspartate Aminotransferase (AST)Increased(Grade 1)
    20.0
    57.1%
    14.3
    102.1%
    50.0
    833.3%
    0
    0%
    37.5
    468.8%
    AST Increased (Grade 2)
    2.9
    8.3%
    14.3
    102.1%
    0
    0%
    33.3
    1110%
    0
    0%
    AST Increased (Grade 3)
    0
    0%
    28.6
    204.3%
    16.7
    278.3%
    0
    0%
    12.5
    156.3%
    AST Increased (Grade 4)
    5.7
    16.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Chronic Kidney Disease (Grade 1)
    34.3
    98%
    42.9
    306.4%
    50.0
    833.3%
    33.3
    1110%
    37.5
    468.8%
    Chronic Kidney Disease (Grade 2)
    0
    0%
    7.1
    50.7%
    33.3
    555%
    0
    0%
    0
    0%
    Chronic Kidney Disease (Grade 3)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Chronic Kidney Disease (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hyperglycemia (Grade 1)
    11.4
    32.6%
    7.1
    50.7%
    0
    0%
    0
    0%
    12.5
    156.3%
    Hyperglycemia (Grade 2)
    5.7
    16.3%
    7.1
    50.7%
    0
    0%
    0
    0%
    0
    0%
    Hyperglycemia (Grade 3)
    11.4
    32.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hyperglycemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypoglycemia (Grade 1)
    0
    0%
    14.3
    102.1%
    0
    0%
    33.3
    1110%
    25.0
    312.5%
    Hypoglycemia (Grade 2)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypoglycemia (Grade 3)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypoglycemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypophosphatemia (Grade 1)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypophosphatemia (Grade 2)
    2.9
    8.3%
    7.1
    50.7%
    0
    0%
    0
    0%
    0
    0%
    Hypophosphatemia (Grade 3)
    5.7
    16.3%
    0
    0%
    16.7
    278.3%
    0
    0%
    12.5
    156.3%
    Hypophosphatemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypokalemia (Grade 1)
    20.0
    57.1%
    7.1
    50.7%
    33.3
    555%
    0
    0%
    0
    0%
    Hypokalemia (Grade 2)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypokalemia (Grade 3)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hypokalemia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hyponatremia (Grade 1)
    20.0
    57.1%
    0
    0%
    50.0
    833.3%
    0
    0%
    0
    0%
    Hyponatremia (Grade 2)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Hyponatremia (Grade 3)
    5.7
    16.3%
    0
    0%
    0
    0%
    0
    0%
    25.0
    312.5%
    Hyponatremia (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Blood Bilirubin Increased (Grade 1)
    17.1
    48.9%
    14.3
    102.1%
    50.0
    833.3%
    0
    0%
    12.5
    156.3%
    Blood Bilirubin Increased (Grade 2)
    25.7
    73.4%
    14.3
    102.1%
    16.7
    278.3%
    0
    0%
    0
    0%
    Blood Bilirubin Increased (Grade 3)
    2.9
    8.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Blood Bilirubin Increased (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Proteinuria (Grade 1)
    22.9
    65.4%
    7.1
    50.7%
    0
    0%
    0
    0%
    12.5
    156.3%
    Proteinuria (Grade 2)
    2.9
    8.3%
    14.3
    102.1%
    0
    0%
    0
    0%
    0
    0%
    Proteinuria (Grade 3)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Proteinuria (Grade 4)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Secondary Outcome
    Title Maximum Tolerated Dose Level
    Description Maximum tolerated dose (MTD) is defined as the highest dose level that was consistently well tolerated without dose limiting toxicity (DLT) for the majority of participants time on treatment (ie,> 50%) as determined by the investigator for each participant. DLTs are defined as Grade 4 hematological toxicities persisting for ≥ 14 days or Grade ≥ 3 toxicities of other types.
    Time Frame First dose (entospelinib + idelalisib) date up to 6 months

    Outcome Measure Data

    Analysis Population Description
    The study was terminated due to safety measures. Complete data was not collected for any participant.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 0 0 0 0 0
    5. Secondary Outcome
    Title Progression-free Survival (PFS)
    Description PFS was defined as the interval from the first dose of study drug to the earlier of the first documentation of definitive disease progression or death from any cause.
    Time Frame Start of treatment to end of treatment (Up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    The study was terminated due to safety measures. Complete data was not collected for any participant.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 0 0 0 0 0
    6. Secondary Outcome
    Title Duration of Response (DOR)
    Description DOR was defined as the interval from the first-time response (CR or PR [or VGPR or MR for participants with LPL/WM]) is achieved to the earlier of the first documentation of definitive disease progression or death from any cause.CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.
    Time Frame Start of treatment to end of treatment (Up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    The study was terminated due to safety measures. Complete data was not collected for any participant.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 0 0 0 0 0
    7. Secondary Outcome
    Title Time to Response (TTR)
    Description TTR was defined as the interval from the first dose of entospletinib/idelalisib to the time response (CR or PR [or VGPR or MR for participants with LPL/WM]) is first achieved. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. VGPR and MR were defined as ≥ 90% and ≥ 25% but < 50% decrease from baseline in serum monoclonal IgM concentration by SPEP respectively.
    Time Frame Start of treatment to end of treatment (Up to 18 months)

    Outcome Measure Data

    Analysis Population Description
    The study was terminated due to safety measures. Complete data was not collected for any participant.
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    Measure Participants 0 0 0 0 0

    Adverse Events

    Time Frame First dose date up to the last dose date plus 30 days (maximum duration: 19 months); All-Cause Mortality: Baseline to Last Follow-Up Visit (Up to 3.6 years)
    Adverse Event Reporting Description The Safety Analysis Set comprised all participants who received ≥ 1 dose of study drug (entospletinib or idelalisib).
    Arm/Group Title Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Arm/Group Description Participants with a documented diagnosis of chronic lymphocytic leukemia (CLL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of indolent non-Hodgkin lymphoma (iNHL) with follicular lymphoma (FL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of diffuse large B-cell lymphoma (DLBCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred ,increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of mantle cell lymphoma (MCL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) occurred, increased dose to 600 mg/100 mg for 2 weeks, if no DLT occurred, increased dose to 800 mg/100 mg for 4 weeks, if no DLT occurred, increased dose to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months. Participants with a documented diagnosis of iNHL with other subtypes lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM), small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL) were included in this arm. Participants were administered 4 dose combinations of entospletinib plus idelalisib tablets orally twice daily under fasted conditions (400 mg/100 mg for 2 weeks, if no dose limiting toxicity (DLT) increased to 600 mg/100 mg for 2 weeks, if no DLT increased to 800 mg/100 mg for 4 weeks, if no DLT increased to 800 mg/150 mg) for up to 6 months. After discontinuation of combination therapy and a washout period of 14-28 days, participants could continue to receive entospletinib 400 mg monotherapy for up to 18 months.
    All Cause Mortality
    Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/35 (8.6%) 1/14 (7.1%) 2/6 (33.3%) 2/3 (66.7%) 2/8 (25%)
    Serious Adverse Events
    Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 24/35 (68.6%) 2/14 (14.3%) 4/6 (66.7%) 2/3 (66.7%) 5/8 (62.5%)
    Blood and lymphatic system disorders
    Febrile neutropenia 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 2/8 (25%)
    Gastrointestinal disorders
    Abdominal pain 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Abdominal pain upper 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Diarrhoea 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    General disorders
    Drug interaction 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Pyrexia 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Infections and infestations
    Bacteraemia 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Bronchopulmonary aspergillosis 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Fungal infection 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Lung infection 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 1/3 (33.3%) 1/8 (12.5%)
    Pneumonia 5/35 (14.3%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Sepsis 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 2/8 (25%)
    Investigations
    Alanine aminotransferase increased 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Aspartate aminotransferase increased 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Blood bilirubin increased 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    International normalised ratio increased 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Lymphocyte count increased 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Nervous system disorders
    Altered state of consciousness 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Cerebrovascular accident 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Psychiatric disorders
    Confusional state 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Renal and urinary disorders
    Hydronephrosis 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 1/3 (33.3%) 0/8 (0%)
    Hypoxia 1/35 (2.9%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Pneumonitis 8/35 (22.9%) 0/14 (0%) 2/6 (33.3%) 0/3 (0%) 1/8 (12.5%)
    Pulmonary embolism 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Respiratory failure 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Skin and subcutaneous tissue disorders
    Erythema multiforme 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Vascular disorders
    Deep vein thrombosis 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Other (Not Including Serious) Adverse Events
    Entospletinib + Idelalisib CLL Entospletinib + Idelalisib iNHL: FL Entospletinib + Idelalisib DLBCL Entospletinib + Idelalisib MCL Entospletinib + Idelalisib iNHL: Others
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 34/35 (97.1%) 14/14 (100%) 6/6 (100%) 3/3 (100%) 8/8 (100%)
    Blood and lymphatic system disorders
    Anaemia 5/35 (14.3%) 0/14 (0%) 2/6 (33.3%) 0/3 (0%) 0/8 (0%)
    Increased tendency to bruise 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Leukopenia 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Lymphadenopathy 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Lymphopenia 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Neutropenia 4/35 (11.4%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Pancytopenia 0/35 (0%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Thrombocytopenia 3/35 (8.6%) 2/14 (14.3%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Cardiac disorders
    Atrial fibrillation 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Palpitations 3/35 (8.6%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Supraventricular tachycardia 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Tachycardia 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Ear and labyrinth disorders
    Ear pain 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Gastrointestinal disorders
    Abdominal pain 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Abdominal pain upper 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Abdominal tenderness 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Chapped lips 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Constipation 11/35 (31.4%) 2/14 (14.3%) 2/6 (33.3%) 0/3 (0%) 0/8 (0%)
    Diarrhoea 14/35 (40%) 2/14 (14.3%) 2/6 (33.3%) 0/3 (0%) 1/8 (12.5%)
    Dyschezia 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Dyspepsia 3/35 (8.6%) 4/14 (28.6%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Dysphagia 1/35 (2.9%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Faeces soft 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Flatulence 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Gastritis 1/35 (2.9%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Gastrooesophageal reflux disease 8/35 (22.9%) 0/14 (0%) 2/6 (33.3%) 1/3 (33.3%) 2/8 (25%)
    Gingival pain 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Mouth ulceration 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Nausea 14/35 (40%) 7/14 (50%) 4/6 (66.7%) 1/3 (33.3%) 1/8 (12.5%)
    Oral discomfort 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Stomatitis 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 2/8 (25%)
    Vomiting 5/35 (14.3%) 2/14 (14.3%) 2/6 (33.3%) 0/3 (0%) 1/8 (12.5%)
    General disorders
    Asthenia 3/35 (8.6%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Catheter site pain 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Chest discomfort 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Chest pain 1/35 (2.9%) 2/14 (14.3%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Chills 7/35 (20%) 1/14 (7.1%) 3/6 (50%) 0/3 (0%) 1/8 (12.5%)
    Discomfort 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Fatigue 15/35 (42.9%) 6/14 (42.9%) 4/6 (66.7%) 0/3 (0%) 3/8 (37.5%)
    Malaise 3/35 (8.6%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Mucosal inflammation 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Oedema peripheral 5/35 (14.3%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Pain 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Peripheral swelling 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Pyrexia 10/35 (28.6%) 5/14 (35.7%) 5/6 (83.3%) 1/3 (33.3%) 1/8 (12.5%)
    Hepatobiliary disorders
    Cholelithiasis 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Hyperbilirubinaemia 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Jaundice 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Immune system disorders
    Hypogammaglobulinaemia 4/35 (11.4%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Infections and infestations
    Cellulitis 2/35 (5.7%) 0/14 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/8 (0%)
    Conjunctivitis 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Herpes zoster 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Localised infection 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Mucosal infection 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Nasopharyngitis 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Oesophageal candidiasis 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Oral candidiasis 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Pharyngitis streptococcal 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Pyelonephritis 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Respiratory tract infection 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Sinusitis 5/35 (14.3%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Upper respiratory tract infection 6/35 (17.1%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Injury, poisoning and procedural complications
    Contusion 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Periorbital haematoma 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Investigations
    Alanine aminotransferase increased 6/35 (17.1%) 4/14 (28.6%) 1/6 (16.7%) 1/3 (33.3%) 2/8 (25%)
    Aspartate aminotransferase increased 7/35 (20%) 4/14 (28.6%) 1/6 (16.7%) 0/3 (0%) 2/8 (25%)
    Blood alkaline phosphatase increased 0/35 (0%) 0/14 (0%) 2/6 (33.3%) 0/3 (0%) 0/8 (0%)
    Blood bilirubin increased 1/35 (2.9%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Blood creatinine increased 4/35 (11.4%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Blood glucose increased 1/35 (2.9%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    International normalised ratio abnormal 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Neutrophil count decreased 4/35 (11.4%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Urine output decreased 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Weight decreased 1/35 (2.9%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    White blood cell count decreased 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 5/35 (14.3%) 1/14 (7.1%) 4/6 (66.7%) 0/3 (0%) 1/8 (12.5%)
    Hyperuricaemia 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Hypoalbuminaemia 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Hypocalcaemia 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Hypokalaemia 2/35 (5.7%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Hypomagnesaemia 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Hyponatraemia 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 2/8 (25%)
    Hypophosphataemia 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Back pain 0/35 (0%) 3/14 (21.4%) 1/6 (16.7%) 1/3 (33.3%) 0/8 (0%)
    Joint swelling 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Muscle spasms 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Muscular weakness 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Musculoskeletal discomfort 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Myalgia 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Neck pain 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Osteopenia 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Pain in extremity 4/35 (11.4%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Nervous system disorders
    Dizziness 5/35 (14.3%) 2/14 (14.3%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Dysgeusia 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Headache 9/35 (25.7%) 4/14 (28.6%) 1/6 (16.7%) 2/3 (66.7%) 1/8 (12.5%)
    Hypoaesthesia 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Neuropathy peripheral 2/35 (5.7%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Paraesthesia 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Peripheral sensory neuropathy 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Presyncope 0/35 (0%) 0/14 (0%) 0/6 (0%) 1/3 (33.3%) 0/8 (0%)
    Syncope 1/35 (2.9%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Psychiatric disorders
    Anxiety 2/35 (5.7%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Confusional state 0/35 (0%) 2/14 (14.3%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Depression 1/35 (2.9%) 1/14 (7.1%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Insomnia 6/35 (17.1%) 1/14 (7.1%) 2/6 (33.3%) 0/3 (0%) 0/8 (0%)
    Restlessness 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Suicidal ideation 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Renal and urinary disorders
    Chromaturia 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Haematuria 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Nephrolithiasis 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 10/35 (28.6%) 2/14 (14.3%) 1/6 (16.7%) 1/3 (33.3%) 2/8 (25%)
    Dysphonia 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Dyspnoea 4/35 (11.4%) 2/14 (14.3%) 1/6 (16.7%) 2/3 (66.7%) 1/8 (12.5%)
    Epistaxis 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 2/8 (25%)
    Lung infiltration 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Nasal congestion 1/35 (2.9%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Oropharyngeal pain 2/35 (5.7%) 2/14 (14.3%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Pleural effusion 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 1/3 (33.3%) 0/8 (0%)
    Productive cough 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Rhinitis allergic 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Sinus congestion 2/35 (5.7%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Sneezing 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Throat irritation 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Throat tightness 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Upper respiratory tract congestion 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Skin and subcutaneous tissue disorders
    Drug eruption 0/35 (0%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 0/8 (0%)
    Dry skin 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Eczema 0/35 (0%) 0/14 (0%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Erythema 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 1/8 (12.5%)
    Hyperhidrosis 1/35 (2.9%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Night sweats 6/35 (17.1%) 1/14 (7.1%) 2/6 (33.3%) 0/3 (0%) 0/8 (0%)
    Pruritus 2/35 (5.7%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Rash 7/35 (20%) 1/14 (7.1%) 2/6 (33.3%) 0/3 (0%) 1/8 (12.5%)
    Rash generalised 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Rash maculo-papular 2/35 (5.7%) 1/14 (7.1%) 1/6 (16.7%) 1/3 (33.3%) 2/8 (25%)
    Rash pruritic 0/35 (0%) 2/14 (14.3%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Vascular disorders
    Flushing 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Hypertension 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)
    Hypotension 3/35 (8.6%) 0/14 (0%) 1/6 (16.7%) 0/3 (0%) 1/8 (12.5%)
    Thrombophlebitis superficial 0/35 (0%) 1/14 (7.1%) 0/6 (0%) 0/3 (0%) 0/8 (0%)

    Limitations/Caveats

    As a result of the early termination of the trial for safety, the efficacy endpoints were not evaluable due to insufficient treatment exposure.

    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 Gilead Clinical Study Information Center
    Organization Gilead Sciences
    Phone 1-833-445-3230 (GILEAD-0)
    Email GileadClinicalTrials@gilead.com
    Responsible Party:
    Gilead Sciences
    ClinicalTrials.gov Identifier:
    NCT01796470
    Other Study ID Numbers:
    • GS-US-339-0103
    First Posted:
    Feb 21, 2013
    Last Update Posted:
    Jun 2, 2020
    Last Verified:
    May 1, 2020