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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Non Hodgkins Lymphoma, Chronic Lymphocytic Leukaemia

Intervention / Treatment
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* Drug: Tirabrutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tirabrutinib 20 mg Once Daily (CLL)<br>Participants with relapsed/refractory chronic lymphocytic leukaemia (CLL) received tirabrutinib 20 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 40 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 40 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 80 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 80 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 160 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 160 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 320 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 320 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 400 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 400 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 500 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 500 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 600 mg Once Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 600 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 300 mg Twice Daily (CLL)<br>Participants with relapsed/refractory CLL received tirabrutinib 300 mg twice daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 20 mg Once Daily (NHL)<br>Participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) received tirabrutinib 20 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 40 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 40 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 80 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 80 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 160 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 160 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 320 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 320 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 480 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 480 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 600 mg Once Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 600 mg once daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 240 mg Twice Daily (NHL)<br>Participants with relapsed/refractory NHL received tirabrutinib 240 mg twice daily. | Drug: Tirabrutinib<br>* Capsules administered orally<br>* Other names: ONO/GS-4059;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 through Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Up to Cycle 37 (28 days for each cycle) plus 6-month intervals thereafter until disease progression (maximum: up to 39 months) | 
| Pharmacokinetic (PK) Parameter: Cmax of Tirabrutinib | Cmax is defined as the maximum concentration of drug. | Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28 | 
| PK Parameter: AUCtau of Tirabrutinib | AUCtau is defined as concentration of drug over dosing interval. | Pre-dose, then 30 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose at Cycle 1, Day 28 |