Non Hodgkins Lymphoma, Chronic Lymphocytic Leukaemia
Conditions
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).
Interventions
DRUGTirabrutinib
Capsules administered orally
Sponsors
Ono Pharmaceutical Co. Ltd
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
France, United Kingdom
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 details
102 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Tirabrutinib 20 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 20 mg once daily. | 3 |
| Tirabrutinib 40 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily. | 3 |
| Tirabrutinib 80 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily. | 4 |
| Tirabrutinib 160 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily. | 3 |
| Tirabrutinib 320 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily. | 3 |
| Tirabrutinib 400 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. | 3 |
| Tirabrutinib 500 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. | 3 |
| Tirabrutinib 600 mg Once Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily. | 3 |
| Tirabrutinib 300 mg Twice Daily (CLL) Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily. | 3 |
| Tirabrutinib 20 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 20 mg once daily. | 3 |
| Tirabrutinib 40 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily. | 3 |
| Tirabrutinib 80 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily. | 5 |
| Tirabrutinib 160 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily. | 8 |
| Tirabrutinib 320 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily. | 21 |
| Tirabrutinib 480 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. | 10 |
| Tirabrutinib 600 mg Once Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily. | 9 |
| Tirabrutinib 240 mg Twice Daily (NHL) Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily. | 3 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 0 | 1 | 0 |
| Overall Study | Completed Treatment Per Protocol at the Time | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 2 | 1 | 0 |
| Overall Study | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Participant Went on to Have an Allograft | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 2 | 3 | 5 | 13 | 6 | 2 | 3 |
| Overall Study | Sponsor's Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 20 mg Once Daily (CLL) | Tirabrutinib 240 mg Twice Daily (NHL) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized < 65 years | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 7 Participants | 7 Participants | 6 Participants | 2 Participants | 1 Participants | 1 Participants | 39 Participants |
| Age, Customized ≥ 65 years | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 14 Participants | 4 Participants | 7 Participants | 2 Participants | 2 Participants | 51 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 13 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 7 Participants | 16 Participants | 9 Participants | 8 Participants | 2 Participants | 3 Participants | 75 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 8 Participants | 3 Participants | 3 Participants | 0 Participants | 2 Participants | 25 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 5 Participants | 7 Participants | 13 Participants | 7 Participants | 6 Participants | 3 Participants | 1 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 28 | 38 / 62 |
| other Total, other adverse events | 28 / 28 | 55 / 62 |
| serious Total, serious adverse events | 17 / 28 | 23 / 62 |
Outcome results
Primary
Percentage of Participants Experiencing Dose-Limiting Toxicities
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tirabrutinib 20 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 40 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 80 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 160 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 320 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 400 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 33.3 percentage of participants |
| Tirabrutinib 500 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 600 mg Once Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 300 mg Twice Daily (CLL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 33.3 percentage of participants |
| Tirabrutinib 20 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 40 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 80 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 160 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
| Tirabrutinib 320 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 4.8 percentage of participants |
| Tirabrutinib 480 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 10.0 percentage of participants |
| Tirabrutinib 600 mg Once Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 22.2 percentage of participants |
| Tirabrutinib 240 mg Twice Daily (NHL) | Percentage of Participants Experiencing Dose-Limiting Toxicities | 0.0 percentage of participants |
Secondary
Overall Response Rate
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tirabrutinib 20 mg Once Daily (CLL) | Overall Response Rate | 85.7 percentage of participants |
| Tirabrutinib 40 mg Once Daily (CLL) | Overall Response Rate | 0.0 percentage of participants |
| Tirabrutinib 80 mg Once Daily (CLL) | Overall Response Rate | 0.0 percentage of participants |
| Tirabrutinib 160 mg Once Daily (CLL) | Overall Response Rate | 33.3 percentage of participants |
| Tirabrutinib 320 mg Once Daily (CLL) | Overall Response Rate | 50.0 percentage of participants |
| Tirabrutinib 400 mg Once Daily (CLL) | Overall Response Rate | 31.4 percentage of participants |
| Tirabrutinib 500 mg Once Daily (CLL) | Overall Response Rate | 68.8 percentage of participants |
Secondary
Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tirabrutinib 20 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 73.4 ng/mL | Standard Deviation 18.26 |
| Tirabrutinib 40 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 164.5 ng/mL | Standard Deviation 47.22 |
| Tirabrutinib 80 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 241 ng/mL | Standard Deviation 90.68 |
| Tirabrutinib 160 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 539.6 ng/mL | Standard Deviation 141.58 |
| Tirabrutinib 320 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 1181.6 ng/mL | Standard Deviation 380.39 |
| Tirabrutinib 400 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 826.5 ng/mL | Standard Deviation 499.92 |
| Tirabrutinib 500 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 1240.3 ng/mL | Standard Deviation 516.99 |
| Tirabrutinib 600 mg Once Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 1230 ng/mL | Standard Deviation 285.83 |
| Tirabrutinib 300 mg Twice Daily (CLL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 1265.2 ng/mL | Standard Deviation 486.21 |
| Tirabrutinib 20 mg Once Daily (NHL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 704.3 ng/mL | Standard Deviation 254.51 |
| Tirabrutinib 40 mg Once Daily (NHL) | Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | 674.3 ng/mL | Standard Deviation 93.78 |
Secondary
PK Parameter: AUCtau of Tirabrutinib
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
Population: Participants in the PK Analysis Set with available data were analyzed. Per planned analysis, data for PK parameters were summarized by dose cohorts.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tirabrutinib 20 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 306.4 h*ng/mL | Standard Deviation 74.92 |
| Tirabrutinib 40 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 660.1 h*ng/mL | Standard Deviation 310.95 |
| Tirabrutinib 80 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 762 h*ng/mL | Standard Deviation 374.94 |
| Tirabrutinib 160 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 2681.8 h*ng/mL | Standard Deviation 1055.17 |
| Tirabrutinib 320 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 5664.8 h*ng/mL | Standard Deviation 1829.07 |
| Tirabrutinib 400 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 5259.5 h*ng/mL | Standard Deviation 3166.57 |
| Tirabrutinib 500 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 7999.8 h*ng/mL | Standard Deviation 2006.19 |
| Tirabrutinib 600 mg Once Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 6766.9 h*ng/mL | Standard Deviation 1025.64 |
| Tirabrutinib 300 mg Twice Daily (CLL) | PK Parameter: AUCtau of Tirabrutinib | 8442.2 h*ng/mL | Standard Deviation 2499.22 |
| Tirabrutinib 20 mg Once Daily (NHL) | PK Parameter: AUCtau of Tirabrutinib | 3415.5 h*ng/mL | Standard Deviation 1296.47 |
| Tirabrutinib 40 mg Once Daily (NHL) | PK Parameter: AUCtau of Tirabrutinib | 3297.2 h*ng/mL | Standard Deviation 1330 |