Study to Evaluate the Safety and Tolerability of Tirabrutinib (ONO/GS-4059) Given as Monotherapy in Participants With Relapsed/Refractory NHL and CLL
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
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
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:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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
- 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.
- 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
Key Inclusion Criteria:
-
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.
-
Age ≥ 18 years.
-
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
Key Exclusion Criteria:
-
Central nervous system (CNS) lymphoma.
-
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.- ONO-4059POE001
- 2011-005033-39
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
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%
|
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%
|
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)
|
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
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) |
GileadClinicalTrials@gilead.com |
- ONO-4059POE001
- 2011-005033-39