Study to Assess the Long-term Safety and Efficacy of Tirabrutinib in Adults With Relapsed/Refractory B-cell Malignancies

Study Overview
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Brief Summary
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The primary objective of this study is to determine the long-term safety and tolerability of tirabrutinib in adults with relapsed/refractory B-cell malignancy who have tolerated and achieved stable disease or improved with tirabrutinib treatment while enrolled in a prior (parent study) tirabrutinib study (NCT01659255). The dosing regimen will be based on the prior dosing regimen from the parent study.

Official Title
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An Open-label Study to Assess the Long-term Safety and Efficacy of ONO/GS-4059 in Subjects With Relapsed/Refractory B-cell Malignancies

Conditions
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Relapsed/Refractory B-cell Malignancies

Intervention / Treatment
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* Drug: Tirabrutinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Currently enrolled in a prior tirabrutinib study Did not discontinue treatment with tirabrutinib for any reason other than to enroll in this study Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at enrollment in this study Any Grade 3 or 4 non-hematologic toxicity that the investigator considers related to previous tirabrutinib use must have resolved, reverted to Grade 1, or reverted to the baseline of the prior study prior to Day 1 of this study Negative serum and urine pregnancy test is required for female individuals (unless surgically sterile or greater than 2 years post menopausal) Male and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in the protocol Lactating females must agree to discontinue nursing before the study drug is administered Ability and agreement to attend protocol-specified visits at the study site Able to comprehend and willing to sign the informed consent form Key Exclusion Criteria: Known hypersensitivity to tirabrutinib, its metabolites, or formulation excipients 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 40 mg once daily (CLL)<br>Participants with relapsed/refractory chronic lymphocytic leukemia (CLL) received tirabrutinib 40 mg once daily for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or capsules administered orally<br>* Other names: ONO/GS-4059;|
| Experimental: Tirabrutinib 160 mg once daily (NHL)<br>Participants with relapsed/refractory non-Hodgkin's lymphoma (NHL) received tirabrutinib 160 mg once daily for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 for up to 96 months from first dose in the parent study. | Drug: Tirabrutinib<br>* Tablets or 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 Who Experienced Treatment-Emergent Adverse Events (AEs) | Treatment-emergent AEs were defined as one or both of the following: Any AEs with an onset date on or after the study drug start date of parent study and no later than 30 days after permanent discontinuation of study drug in this rollover study; Any AEs leading to premature discontinuation of study drug. | First dose of tirabrutinib up to 36 months in the parent study and up to 61 months in the rollover study | 
| Percentage of Participants Who Experienced Treatment-Emergent Marked Laboratory Abnormalities | Treatment-emergent marked laboratory abnormalities were defined as values that increase from baseline by at least 3 toxicity grades at any postbaseline time point, up to and including the date of the last dose of study drug plus 30. If the relevant baseline laboratory value is missing, any Grade 3 or 4 values observed within the timeframe specified above will be considered treatment-emergent marked abnormalities. Laboratory assessments included tests for Chemistry, Hematology, Coagulation and Urinalysis. | First dose of tirabrutinib up to 36 months in the parent study and up to 61 months in the rollover study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined per Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for CLL and Cheson, 2007 criteria for NHL as percentage of participants who achieve partial response (PR) or complete response (CR) in either parent or roll-over study. CLL:CR: lymphocytes (Ly) <4*10^9/L, no lymphadenopathy,normal spleen and liver size,absence of disease, absolute neutrophil count (ANC) >1.5*10^9/L,platelets ≥100*10^9/L, hemoglobin (Hb) >110 g/L,bone marrow at least normocellular for age; PR: ≥2 of these: ≥50% decrease in Ly, lymphadenopathy,size of liver and spleen, bone marrow infiltrates;and ≥1 of these: ANC >1500/μL, platelets ≥100,000/µL, Hb >11g/dL. NHL:CR: complete resolution of all disease-related radiological abnormalities; PR: ≥50% reduction in sum of products (SPD) of the longest diameters (LD) of all index lesions,no new lesions;no increase in size of liver or spleen;persistence of bone marrow involvement in participant who meets other criteria for CR. | Up to 39 months in parent study and up to 60 months in rollover study | 
| Duration of Response (DOR) | DOR was defined per IWCLL 2008 criteria for CLL and Cheson, 2007 criteria for NHL as the interval from first documentation of CR or PR to the earlier of the first documentation of definitive disease progression as assessed by the investigator, or death from any cause in subjects who achieve a response. CLL:CR: Ly <4*10^9/L, no lymphadenopathy, normal spleen and liver size, absence of disease, ANC >1.5*10^9/L, platelets ≥100*10^9/L, Hb >110 g/L, bone marrow at least normocellular for age; PR: ≥2 of these: ≥50% decrease in Ly, lymphadenopathy, size of liver and spleen, bone marrow infiltrates; and ≥1 of these: ANC >1500/μL, platelets ≥100,000/µL, Hb >11 g/dL. NHL:CR: complete resolution of all disease-related radiological abnormalities; PR: ≥50% reduction in SPD of the LD of all index lesions, no new lesions; no increase in size of liver or spleen; persistence of bone marrow involvement in participant who meets other criteria for CR. | From first documentation of CR or PR to the first documentation of disease progression or death from any cause up to 39 months in parent study and up to 60 months in the rollover study | 
| Progression-free Survival (PFS) | PFS was defined per IWCLL 2008 criteria for CLL and Cheson 2007 criteria for NHL as the interval from date of the first dose of tirabrutinib on the parent study to the earlier of the first documentation of definitive disease progression as assessed by the investigator, or death from any cause. Progressive disease (PD) in CLL: Lymphadenopathy, or appearance of any new lesion/organomegaly, > 50% increase in the size of the liver and/or spleen, Decrease in platelet count or hemoglobin attributable to CLL per IWCLL, Transformation to a more aggressive histology (eg, Richter syndrome). PD in NHL: Cheson, 2007: Appearance of new lesion or increase by >50% of previously involved sites from nadir, Transformation to a more aggressive NHL histology. | From first dose of tirabrutinib in the parent study (NCT01659255) to the first documentation of disease progression or death from any cause up to 99 months | 
| Overall Survival (OS) | OS is defined as the interval from date of the first dose of tirabrutinib on the parent study until death from any cause. | From first dose of tirabrutinib in the parent study (NCT01659255) until death from any cause up to 99 months |