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Study to Evaluate the Safety and Tolerability of Tirabrutinib (ONO/GS-4059) Given as Monotherapy in Participants With Relapsed/Refractory NHL and CLL

Sponsor
Gilead Sciences (Industry)
Overall Status
Completed
CT.gov ID
NCT01659255
Collaborator
Ono Pharmaceutical Co. Ltd (Industry)
90
Enrollment
6
Locations
17
Arms
40.8
Actual Duration (Months)
15
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of the study is to evaluate the safety and tolerability of tirabrutinib (formerly ONO/GS-4059) given as monotherapy to participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
90 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label, Multi-Center, Non-Randomised Phase I Dose-Escalation Study to Investigate the Safety and Tolerability of ONO-4059 (ONO/GS-4059) Given as Monotherapy in Patients With Relapsed/Refractory Non-Hodgkin's Lymphoma (NHL) and Relapsed/Refractory Chronic Lymphocytic Leukaemia (CLL)
Actual Study Start Date :
Aug 17, 2012
Actual Primary Completion Date :
Feb 23, 2015
Actual Study Completion Date :
Jan 11, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Tirabrutinib 20 mg Once Daily (CLL)

Participants with relapsed/refractory chronic lymphocytic leukaemia (CLL) received tirabrutinib 20 mg once daily.

Drug: Tirabrutinib
Capsules administered orally
Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 40 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 80 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 160 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 320 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 400 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 500 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 600 mg Once Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 300 mg Twice Daily (CLL)

    Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 20 mg Once Daily (NHL)

    Participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) received tirabrutinib 20 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 40 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 80 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 160 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 320 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 480 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 600 mg Once Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•
    Experimental: Tirabrutinib 240 mg Twice Daily (NHL)

    Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily.

    Drug: Tirabrutinib
    Capsules administered orally
    Other Names:
  • ONO/GS-4059

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants Experiencing Dose-Limiting Toxicities [Day 1 through Day 28]

      Dose Limiting Toxicities (DLT) were defined as follows: All Common Terminology Criteria (CTC) Grade 4 tirabrutinib related adverse events All CTC Grade 3 tirabrutinib related adverse events, with the exception of the following: CTC Grade 3 lymphocytosis considered an expected outcome of therapy Any toxicity which in the opinion of the Investigator is attributed to a participant's underlying disease was not considered a DLT.

    Secondary Outcome Measures

    1. Overall Response Rate [Up to Cycle 37 (28 days for each cycle) plus 6-month intervals thereafter until disease progression (maximum: up to 39 months)]

      Overall response rate (ORR) was defined as the percentage of participants who achieve a best overall response of complete remission (CR, unconfirmed complete response (CRu), complete response with incomplete marrow recovery (CRi)) or partial remission (PR, nodal PR) during study as assessed by the investigator. ORR assessment was defined per following standardized criteria: NHL: Cheson, 1999 CLL: International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008

    2. Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib [Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28]

      Cmax is defined as the maximum concentration of drug.

    3. PK Parameter: AUCtau of Tirabrutinib [Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28]

      AUCtau is defined as concentration of drug over dosing interval.

    Eligibility Criteria

    Criteria

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

    1. Males or females with a confirmed diagnosis of and documented history of relapsed or refractory malignant disease (B-cell lymphoma and/or CLL) for which no therapy of curative or high priority exists and for whom treatment with a Btk inhibitor may be deemed appropriate.

    2. Age ≥ 18 years.

    3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

    Key Exclusion Criteria:

    1. Central nervous system (CNS) lymphoma.

    2. Women who are pregnant or lactating.

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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 CHRU - Hopital Claude HURIEZ Lille France 59037
    2 Centre hospitalier Lyon Sud Lyon France 69495
    3 CHU St Eloi Montpellier France 34295
    4 University Hospital of Wales Cardiff United Kingdom CF14 4XW
    5 Leicester Royal Infirmary Leicester United Kingdom LE1 5WW
    6 Derriford Hospital Plymouth United Kingdom PL6 8DH

    Sponsors and Collaborators

    • Gilead Sciences
    • Ono Pharmaceutical Co. Ltd

    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:
    NCT01659255
    Other Study ID Numbers:
    • ONO-4059POE001
    • 2011-005033-39
    First Posted:
    Aug 7, 2012
    Last Update Posted:
    Mar 16, 2021
    Last Verified:
    Feb 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Lymphoma
    Leukemia
    Lymphoma, Non-Hodgkin
    Leukemia, Lymphoid
    Leukemia, Lymphocytic, Chronic, B-Cell

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at study sites in Europe. The first participant was screened on 17 August 2012. The last study visit occurred on 11 January 2016.
    Pre-assignment Detail 102 participants were screened.
    Arm/Group Title Tirabrutinib 20 mg Once Daily (CLL) Tirabrutinib 40 mg Once Daily (CLL) Tirabrutinib 80 mg Once Daily (CLL) Tirabrutinib 160 mg Once Daily (CLL) Tirabrutinib 320 mg Once Daily (CLL) Tirabrutinib 400 mg Once Daily (CLL) Tirabrutinib 500 mg Once Daily (CLL) Tirabrutinib 600 mg Once Daily (CLL) Tirabrutinib 300 mg Twice Daily (CLL) Tirabrutinib 20 mg Once Daily (NHL) Tirabrutinib 40 mg Once Daily (NHL) Tirabrutinib 80 mg Once Daily (NHL) Tirabrutinib 160 mg Once Daily (NHL) Tirabrutinib 320 mg Once Daily (NHL) Tirabrutinib 480 mg Once Daily (NHL) Tirabrutinib 600 mg Once Daily (NHL) Tirabrutinib 240 mg Twice Daily (NHL)
    Arm/Group Description Participants with relapsed/refractory chronic lymphocytic leukaemia (CLL) received tirabrutinib 20 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily. Participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) received tirabrutinib 20 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily.
    Period Title: Overall Study
    STARTED 3 3 4 3 3 3 3 3 3 3 3 5 8 21 10 9 3
    COMPLETED 1 2 4 3 3 2 1 1 2 0 0 1 0 3 2 4 0
    NOT COMPLETED 2 1 0 0 0 1 2 2 1 3 3 4 8 18 8 5 3

    Baseline Characteristics

    Arm/Group Title Tirabrutinib 20 mg Once Daily (CLL) Tirabrutinib 40 mg Once Daily (CLL) Tirabrutinib 80 mg Once Daily (CLL) Tirabrutinib 160 mg Once Daily (CLL) Tirabrutinib 320 mg Once Daily (CLL) Tirabrutinib 400 mg Once Daily (CLL) Tirabrutinib 500 mg Once Daily (CLL) Tirabrutinib 600 mg Once Daily (CLL) Tirabrutinib 300 mg Twice Daily (CLL) Tirabrutinib 20 mg Once Daily (NHL) Tirabrutinib 40 mg Once Daily (NHL) Tirabrutinib 80 mg Once Daily (NHL) Tirabrutinib 160 mg Once Daily (NHL) Tirabrutinib 320 mg Once Daily (NHL) Tirabrutinib 480 mg Once Daily (NHL) Tirabrutinib 600 mg Once Daily (NHL) Tirabrutinib 240 mg Twice Daily (NHL) Total
    Arm/Group Description Participants with relapsed/refractory CLL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily. Participants with relapsed/refractory NHL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily. Total of all reporting groups
    Overall Participants 3 3 4 3 3 3 3 3 3 3 3 5 8 21 10 9 3 90
    Age, Customized (Count of Participants)
    < 65 years
    1
    33.3%
    0
    0%
    3
    75%
    1
    33.3%
    1
    33.3%
    2
    66.7%
    2
    66.7%
    1
    33.3%
    0
    0%
    0
    0%
    2
    66.7%
    3
    60%
    7
    87.5%
    7
    33.3%
    6
    60%
    2
    22.2%
    1
    33.3%
    39
    43.3%
    ≥ 65 years
    2
    66.7%
    3
    100%
    1
    25%
    2
    66.7%
    2
    66.7%
    1
    33.3%
    1
    33.3%
    2
    66.7%
    3
    100%
    3
    100%
    1
    33.3%
    2
    40%
    1
    12.5%
    14
    66.7%
    4
    40%
    7
    77.8%
    2
    66.7%
    51
    56.7%
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    1
    25%
    1
    33.3%
    1
    33.3%
    0
    0%
    0
    0%
    1
    33.3%
    1
    33.3%
    2
    66.7%
    1
    33.3%
    0
    0%
    1
    12.5%
    8
    38.1%
    3
    30%
    3
    33.3%
    2
    66.7%
    25
    27.8%
    Male
    3
    100%
    3
    100%
    3
    75%
    2
    66.7%
    2
    66.7%
    3
    100%
    3
    100%
    2
    66.7%
    2
    66.7%
    1
    33.3%
    2
    66.7%
    5
    100%
    7
    87.5%
    13
    61.9%
    7
    70%
    6
    66.7%
    1
    33.3%
    65
    72.2%
    Race/Ethnicity, Customized (Count of Participants)
    White
    2
    66.7%
    3
    100%
    4
    100%
    1
    33.3%
    3
    100%
    3
    100%
    2
    66.7%
    3
    100%
    2
    66.7%
    3
    100%
    3
    100%
    3
    60%
    7
    87.5%
    16
    76.2%
    9
    90%
    8
    88.9%
    3
    100%
    75
    83.3%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    4.8%
    0
    0%
    1
    11.1%
    0
    0%
    2
    2.2%
    Other
    1
    33.3%
    0
    0%
    0
    0%
    2
    66.7%
    0
    0%
    0
    0%
    1
    33.3%
    0
    0%
    1
    33.3%
    0
    0%
    0
    0%
    2
    40%
    1
    12.5%
    4
    19%
    1
    10%
    0
    0%
    0
    0%
    13
    14.4%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants Experiencing Dose-Limiting Toxicities
    Description Dose Limiting Toxicities (DLT) were defined as follows: All Common Terminology Criteria (CTC) Grade 4 tirabrutinib related adverse events All CTC Grade 3 tirabrutinib related adverse events, with the exception of the following: CTC Grade 3 lymphocytosis considered an expected outcome of therapy Any toxicity which in the opinion of the Investigator is attributed to a participant's underlying disease was not considered a DLT.
    Time Frame Day 1 through Day 28

    Outcome Measure Data

    Analysis Population Description
    The Safety Analysis Set included all the participants who received at least 1 dose of study drug. Per planned analysis, data for DLTs were summarized by dose level received by participants with NHL and CLL.
    Arm/Group Title Tirabrutinib 20 mg Once Daily (CLL) Tirabrutinib 40 mg Once Daily (CLL) Tirabrutinib 80 mg Once Daily (CLL) Tirabrutinib 160 mg Once Daily (CLL) Tirabrutinib 320 mg Once Daily (CLL) Tirabrutinib 400 mg Once Daily (CLL) Tirabrutinib 500 mg Once Daily (CLL) Tirabrutinib 600 mg Once Daily (CLL) Tirabrutinib 300 mg Twice Daily (CLL) Tirabrutinib 20 mg Once Daily (NHL) Tirabrutinib 40 mg Once Daily (NHL) Tirabrutinib 80 mg Once Daily (NHL) Tirabrutinib 160 mg Once Daily (NHL) Tirabrutinib 320 mg Once Daily (NHL) Tirabrutinib 480 mg Once Daily (NHL) Tirabrutinib 600 mg Once Daily (NHL) Tirabrutinib 240 mg Twice Daily (NHL)
    Arm/Group Description Participants with relapsed/refractory CLL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily. Participants with relapsed/refractory NHL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily.
    Measure Participants 3 3 4 3 3 3 3 3 3 3 3 5 8 21 10 9 3
    Number [percentage of participants]
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    33.3
    1110%
    0.0
    0%
    0.0
    0%
    33.3
    1110%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    0.0
    0%
    4.8
    22.9%
    10.0
    100%
    22.2
    246.7%
    0.0
    0%
    2. Secondary Outcome
    Title Overall Response Rate
    Description Overall response rate (ORR) was defined as the percentage of participants who achieve a best overall response of complete remission (CR, unconfirmed complete response (CRu), complete response with incomplete marrow recovery (CRi)) or partial remission (PR, nodal PR) during study as assessed by the investigator. ORR assessment was defined per following standardized criteria: NHL: Cheson, 1999 CLL: International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008
    Time Frame Up to Cycle 37 (28 days for each cycle) plus 6-month intervals thereafter until disease progression (maximum: up to 39 months)

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set included all the participants who received at least 1 dose of study drug. Per planned analysis, data for overall response rate were summarized by overall CLL group and NHL subgroup.
    Arm/Group Title Chronic Lymphocytic Leukaemia NHL Subtype FL NHL Subtype SLL NHL Subtype WM NHL Subtype MZL NHL Subtype DLBCL NHL Subtype MCL
    Arm/Group Description Participants with relapsed/refractory CLL received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype follicular lymphoma (FL) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype small lymphocytic lymphoma (SLL) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype Waldenstrom macroglobulinemia (WM) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype marginal zone lymphoma (MZL) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype diffuse large B-cell lymphoma (DLBCL) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with NHL subtype mantle cell lymphoma (MCL) received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study.
    Measure Participants 28 5 1 3 2 35 16
    Number [percentage of participants]
    85.7
    2856.7%
    0.0
    0%
    0.0
    0%
    33.3
    1110%
    50.0
    1666.7%
    31.4
    1046.7%
    68.8
    2293.3%
    3. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib
    Description Cmax is defined as the maximum concentration of drug.
    Time Frame Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set (all participants who received at least 1 dose of study drug and had at least 1 nonmissing postdose concentration value for the corresponding analyte in plasma) with available data were analyzed. Per planned analysis, data for PK parameters were summarized by dose cohorts.
    Arm/Group Title Tirabrutinib 20 mg Once Daily (CLL or NHL) Tirabrutinib 40 mg Once Daily (CLL or NHL) Tirabrutinib 80 mg Once Daily (CLL or NHL) Tirabrutinib 160 mg Once Daily (CLL or NHL) Tirabrutinib 320 mg Once Daily (CLL or NHL) Tirabrutinib 400 mg Once Daily (CLL) Tirabrutinib 480 mg Once Daily (NHL) Tirabrutinib 500 mg Once Daily (CLL) Tirabrutinib 600 mg Once Daily (CLL or NHL) Tirabrutinib 240 mg Twice Daily (NHL) Tirabrutinib 300 mg Twice Daily (CLL)
    Arm/Group Description Participants with relapsed/refractory CLL or NHL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily. Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily.
    Measure Participants 6 6 5 10 17 2 7 3 6 3 3
    Mean (Standard Deviation) [ng/mL]
    73.4
    (18.26)
    164.5
    (47.22)
    241
    (90.68)
    539.6
    (141.58)
    1181.6
    (380.39)
    826.5
    (499.92)
    1240.3
    (516.99)
    1230
    (285.83)
    1265.2
    (486.21)
    704.3
    (254.51)
    674.3
    (93.78)
    4. Secondary Outcome
    Title PK Parameter: AUCtau of Tirabrutinib
    Description AUCtau is defined as concentration of drug over dosing interval.
    Time Frame Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set with available data were analyzed. Per planned analysis, data for PK parameters were summarized by dose cohorts.
    Arm/Group Title Tirabrutinib 20 mg Once Daily (CLL or NHL) Tirabrutinib 40 mg Once Daily (CLL or NHL) Tirabrutinib 80 mg Once Daily (CLL or NHL) Tirabrutinib 160 mg Once Daily (CLL or NHL) Tirabrutinib 320 mg Once Daily (CLL or NHL) Tirabrutinib 400 mg Once Daily (CLL) Tirabrutinib 480 mg Once Daily (NHL) Tirabrutinib 500 mg Once Daily (CLL) Tirabrutinib 600 mg Once Daily (CLL or NHL) Tirabrutinib 240 mg Twice Daily (NHL) Tirabrutinib 300 mg Twice Daily (CLL)
    Arm/Group Description Participants with relapsed/refractory CLL or NHL received tirabrutinib 20 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 40 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 80 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 160 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 320 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. Participants with relapsed/refractory CLL or NHL received tirabrutinib 600 mg once daily. Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily. Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily.
    Measure Participants 6 6 5 10 17 2 7 3 5 3 2
    Mean (Standard Deviation) [h*ng/mL]
    306.4
    (74.92)
    660.1
    (310.95)
    762
    (374.94)
    2681.8
    (1055.17)
    5664.8
    (1829.07)
    5259.5
    (3166.57)
    7999.8
    (2006.19)
    6766.9
    (1025.64)
    8442.2
    (2499.22)
    3415.5
    (1296.47)
    3297.2
    (1330)

    Adverse Events

    Time Frame Adverse Events: First dose date up to the last dose date plus 30 days (maximum: 36 months); All-Cause Mortality: First dose date up to 39 months
    Adverse Event Reporting Description The Safety Analysis Set included all the participants who received at least 1 dose of study drug. Per planned analysis, data were summarized by overall groups for NHL and CLL pooling all participants regardless of dose level received.
    Arm/Group Title Chronic Lymphocytic Leukaemia Non-Hodgkin's Lymphoma
    Arm/Group Description Participants with relapsed/refractory CLL received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study. Participants with relapsed/refractory NHL received tirabrutinib until disease progression or until the participant entered into a possible future tirabrutinib study.
    All Cause Mortality
    Chronic Lymphocytic Leukaemia Non-Hodgkin's Lymphoma
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/28 (17.9%) 38/62 (61.3%)
    Serious Adverse Events
    Chronic Lymphocytic Leukaemia Non-Hodgkin's Lymphoma
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 17/28 (60.7%) 23/62 (37.1%)
    Blood and lymphatic system disorders
    Anaemia 0/28 (0%) 1/62 (1.6%)
    Febrile neutropenia 2/28 (7.1%) 1/62 (1.6%)
    Lymphocytic infiltration 1/28 (3.6%) 0/62 (0%)
    Neutropenia 1/28 (3.6%) 0/62 (0%)
    Spontaneous haematoma 1/28 (3.6%) 0/62 (0%)
    Cardiac disorders
    Cardiac arrest 0/28 (0%) 1/62 (1.6%)
    Cardiac failure 0/28 (0%) 1/62 (1.6%)
    Ear and labyrinth disorders
    Ear haemorrhage 0/28 (0%) 1/62 (1.6%)
    Excessive cerumen production 0/28 (0%) 1/62 (1.6%)
    Gastrointestinal disorders
    Constipation 0/28 (0%) 1/62 (1.6%)
    Inguinal hernia strangulated 1/28 (3.6%) 0/62 (0%)
    Oesophageal haemorrhage 0/28 (0%) 1/62 (1.6%)
    Small intestinal haemorrhage 0/28 (0%) 1/62 (1.6%)
    General disorders
    Adverse drug reaction 0/28 (0%) 1/62 (1.6%)
    General physical health deterioration 0/28 (0%) 1/62 (1.6%)
    Ill-defined disorder 0/28 (0%) 1/62 (1.6%)
    Pyrexia 3/28 (10.7%) 1/62 (1.6%)
    Immune system disorders
    Hypersensitivity 0/28 (0%) 1/62 (1.6%)
    Infections and infestations
    Abdominal abscess 1/28 (3.6%) 0/62 (0%)
    Bacteraemia 1/28 (3.6%) 0/62 (0%)
    Bronchiolitis 1/28 (3.6%) 0/62 (0%)
    Bronchitis 1/28 (3.6%) 0/62 (0%)
    Campylobacter gastroenteritis 1/28 (3.6%) 0/62 (0%)
    Device related infection 1/28 (3.6%) 1/62 (1.6%)
    Ear infection 1/28 (3.6%) 0/62 (0%)
    Escherichia sepsis 1/28 (3.6%) 0/62 (0%)
    Escherichia urinary tract infection 0/28 (0%) 1/62 (1.6%)
    H1n1 influenza 0/28 (0%) 1/62 (1.6%)
    Hepatitis E 1/28 (3.6%) 0/62 (0%)
    Herpes simplex 0/28 (0%) 1/62 (1.6%)
    Herpes zoster oticus 0/28 (0%) 1/62 (1.6%)
    Infection 0/28 (0%) 1/62 (1.6%)
    Influenza 0/28 (0%) 1/62 (1.6%)
    Lower respiratory tract infection 4/28 (14.3%) 3/62 (4.8%)
    Lower respiratory tract infection bacterial 1/28 (3.6%) 0/62 (0%)
    Lower respiratory tract infection fungal 1/28 (3.6%) 0/62 (0%)
    Lung infection 1/28 (3.6%) 0/62 (0%)
    Neutropenic infection 1/28 (3.6%) 0/62 (0%)
    Neutropenic sepsis 2/28 (7.1%) 0/62 (0%)
    Pneumocystis jirovecii pneumonia 0/28 (0%) 2/62 (3.2%)
    Pneumonia 1/28 (3.6%) 2/62 (3.2%)
    Pneumonia pneumococcal 1/28 (3.6%) 0/62 (0%)
    Respiratory syncytial virus infection 1/28 (3.6%) 0/62 (0%)
    Respiratory tract infection viral 1/28 (3.6%) 0/62 (0%)
    Sepsis 1/28 (3.6%) 0/62 (0%)
    Upper respiratory tract infection 0/28 (0%) 1/62 (1.6%)
    Injury, poisoning and procedural complications
    Cardiac function disturbance postoperative 1/28 (3.6%) 0/62 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/28 (0%) 1/62 (1.6%)
    International normalised ratio increased 0/28 (0%) 1/62 (1.6%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer 1/28 (3.6%) 0/62 (0%)
    Myelodysplastic syndrome 0/28 (0%) 1/62 (1.6%)
    Squamous cell carcinoma of lung 1/28 (3.6%) 0/62 (0%)
    Squamous cell carcinoma of skin 1/28 (3.6%) 0/62 (0%)
    Nervous system disorders
    Dysarthria 1/28 (3.6%) 0/62 (0%)
    Paraesthesia 1/28 (3.6%) 0/62 (0%)
    Seizure 1/28 (3.6%) 0/62 (0%)
    Syncope 0/28 (0%) 1/62 (1.6%)
    Psychiatric disorders
    Anxiety 1/28 (3.6%) 0/62 (0%)
    Disorientation 1/28 (3.6%) 0/62 (0%)
    Renal and urinary disorders
    Calculus ureteric 1/28 (3.6%) 0/62 (0%)
    Myeloma cast nephropathy 0/28 (0%) 1/62 (1.6%)
    Urinary retention 0/28 (0%) 1/62 (1.6%)
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/28 (0%) 1/62 (1.6%)
    Skin and subcutaneous tissue disorders
    Angioedema 1/28 (3.6%) 0/62 (0%)
    Purpura 1/28 (3.6%) 0/62 (0%)
    Rash 1/28 (3.6%) 0/62 (0%)
    Other (Not Including Serious) Adverse Events
    Chronic Lymphocytic Leukaemia Non-Hodgkin's Lymphoma
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 28/28 (100%) 55/62 (88.7%)
    Blood and lymphatic system disorders
    Anaemia 9/28 (32.1%) 23/62 (37.1%)
    Leukopenia 2/28 (7.1%) 2/62 (3.2%)
    Lymphopenia 2/28 (7.1%) 12/62 (19.4%)
    Neutropenia 9/28 (32.1%) 9/62 (14.5%)
    Thrombocytopenia 4/28 (14.3%) 18/62 (29%)
    Ear and labyrinth disorders
    Ear pain 3/28 (10.7%) 0/62 (0%)
    Eye disorders
    Conjunctival haemorrhage 2/28 (7.1%) 1/62 (1.6%)
    Eye haemorrhage 3/28 (10.7%) 0/62 (0%)
    Eye pruritus 2/28 (7.1%) 2/62 (3.2%)
    Glaucoma 2/28 (7.1%) 0/62 (0%)
    Ocular hyperaemia 2/28 (7.1%) 2/62 (3.2%)
    Gastrointestinal disorders
    Abdominal pain 3/28 (10.7%) 8/62 (12.9%)
    Abdominal pain upper 3/28 (10.7%) 4/62 (6.5%)
    Constipation 6/28 (21.4%) 2/62 (3.2%)
    Diarrhoea 6/28 (21.4%) 18/62 (29%)
    Dry mouth 2/28 (7.1%) 4/62 (6.5%)
    Gastrooesophageal reflux disease 3/28 (10.7%) 1/62 (1.6%)
    Nausea 2/28 (7.1%) 12/62 (19.4%)
    Vomiting 5/28 (17.9%) 9/62 (14.5%)
    General disorders
    Asthenia 3/28 (10.7%) 9/62 (14.5%)
    Fatigue 5/28 (17.9%) 7/62 (11.3%)
    Oedema peripheral 2/28 (7.1%) 8/62 (12.9%)
    Pyrexia 7/28 (25%) 7/62 (11.3%)
    Hepatobiliary disorders
    Cholelithiasis 2/28 (7.1%) 1/62 (1.6%)
    Immune system disorders
    Hypogammaglobulinaemia 2/28 (7.1%) 0/62 (0%)
    Infections and infestations
    Bronchitis 3/28 (10.7%) 4/62 (6.5%)
    Cellulitis 3/28 (10.7%) 0/62 (0%)
    Chronic sinusitis 2/28 (7.1%) 0/62 (0%)
    Ear infection 2/28 (7.1%) 1/62 (1.6%)
    Eye infection 2/28 (7.1%) 0/62 (0%)
    Herpes zoster 4/28 (14.3%) 3/62 (4.8%)
    Influenza 2/28 (7.1%) 2/62 (3.2%)
    Laryngitis 2/28 (7.1%) 1/62 (1.6%)
    Lower respiratory tract infection 5/28 (17.9%) 6/62 (9.7%)
    Lung infection 2/28 (7.1%) 1/62 (1.6%)
    Nasopharyngitis 9/28 (32.1%) 11/62 (17.7%)
    Oral herpes 3/28 (10.7%) 0/62 (0%)
    Pharyngitis 2/28 (7.1%) 0/62 (0%)
    Rhinitis 2/28 (7.1%) 8/62 (12.9%)
    Sinobronchitis 2/28 (7.1%) 0/62 (0%)
    Upper respiratory tract infection 2/28 (7.1%) 5/62 (8.1%)
    Urinary tract infection 3/28 (10.7%) 3/62 (4.8%)
    Injury, poisoning and procedural complications
    Arthropod bite 3/28 (10.7%) 1/62 (1.6%)
    Contusion 10/28 (35.7%) 8/62 (12.9%)
    Fall 8/28 (28.6%) 5/62 (8.1%)
    Laceration 4/28 (14.3%) 0/62 (0%)
    Procedural pain 2/28 (7.1%) 0/62 (0%)
    Tendon rupture 2/28 (7.1%) 0/62 (0%)
    Traumatic haematoma 3/28 (10.7%) 1/62 (1.6%)
    Investigations
    Blood bilirubin increased 1/28 (3.6%) 4/62 (6.5%)
    Metabolism and nutrition disorders
    Decreased appetite 0/28 (0%) 6/62 (9.7%)
    Hyperkalaemia 4/28 (14.3%) 2/62 (3.2%)
    Hypoalbuminaemia 2/28 (7.1%) 4/62 (6.5%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 8/28 (28.6%) 5/62 (8.1%)
    Joint stiffness 2/28 (7.1%) 0/62 (0%)
    Joint swelling 2/28 (7.1%) 1/62 (1.6%)
    Muscle spasms 2/28 (7.1%) 2/62 (3.2%)
    Musculoskeletal chest pain 2/28 (7.1%) 0/62 (0%)
    Musculoskeletal pain 4/28 (14.3%) 6/62 (9.7%)
    Musculoskeletal stiffness 2/28 (7.1%) 0/62 (0%)
    Myalgia 2/28 (7.1%) 4/62 (6.5%)
    Neck pain 0/28 (0%) 5/62 (8.1%)
    Pain in extremity 3/28 (10.7%) 2/62 (3.2%)
    Synovial cyst 3/28 (10.7%) 0/62 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 6/28 (21.4%) 1/62 (1.6%)
    Skin papilloma 2/28 (7.1%) 1/62 (1.6%)
    Nervous system disorders
    Carpal tunnel syndrome 2/28 (7.1%) 0/62 (0%)
    Dizziness 4/28 (14.3%) 1/62 (1.6%)
    Dysaesthesia 2/28 (7.1%) 1/62 (1.6%)
    Headache 4/28 (14.3%) 5/62 (8.1%)
    Paraesthesia 4/28 (14.3%) 0/62 (0%)
    Psychiatric disorders
    Anxiety 2/28 (7.1%) 1/62 (1.6%)
    Insomnia 2/28 (7.1%) 5/62 (8.1%)
    Reproductive system and breast disorders
    Prostatomegaly 2/28 (7.1%) 0/62 (0%)
    Respiratory, thoracic and mediastinal disorders
    Catarrh 2/28 (7.1%) 0/62 (0%)
    Cough 8/28 (28.6%) 9/62 (14.5%)
    Dyspnoea 2/28 (7.1%) 6/62 (9.7%)
    Epistaxis 2/28 (7.1%) 4/62 (6.5%)
    Oropharyngeal pain 6/28 (21.4%) 4/62 (6.5%)
    Productive cough 2/28 (7.1%) 5/62 (8.1%)
    Rales 2/28 (7.1%) 4/62 (6.5%)
    Skin and subcutaneous tissue disorders
    Acne 3/28 (10.7%) 1/62 (1.6%)
    Actinic keratosis 3/28 (10.7%) 1/62 (1.6%)
    Dry skin 6/28 (21.4%) 3/62 (4.8%)
    Eczema 2/28 (7.1%) 2/62 (3.2%)
    Erythema 5/28 (17.9%) 2/62 (3.2%)
    Macule 6/28 (21.4%) 1/62 (1.6%)
    Petechiae 6/28 (21.4%) 9/62 (14.5%)
    Pruritus 4/28 (14.3%) 5/62 (8.1%)
    Purpura 5/28 (17.9%) 6/62 (9.7%)
    Rash macular 3/28 (10.7%) 1/62 (1.6%)
    Rash maculo-papular 2/28 (7.1%) 3/62 (4.8%)
    Skin lesion 3/28 (10.7%) 2/62 (3.2%)
    Swelling face 2/28 (7.1%) 1/62 (1.6%)
    Vascular disorders
    Haematoma 7/28 (25%) 3/62 (4.8%)
    Hypertension 0/28 (0%) 4/62 (6.5%)

    Limitations/Caveats

    [Not Specified]

    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:
    NCT01659255
    Other Study ID Numbers:
    • ONO-4059POE001
    • 2011-005033-39
    First Posted:
    Aug 7, 2012
    Last Update Posted:
    Mar 16, 2021
    Last Verified:
    Feb 1, 2021