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

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

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.

Study Overview

• Status: Completed
• Conditions: Relapsed/Refractory B-cell Malignancies
• Intervention / Treatment: Drug: Tirabrutinib

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34295
    • Hopital Saint Eloi
  • Pierre Benite, France, 69310
    • Centre Hospitalier Lyon Sud
  • Nord
    • Lille, Nord, France, 59037
      • CHRU de Lille
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • Plymouth, United Kingdom, PL68DH
    • Derriford Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

12

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirabrutinib 40 mg once daily (CLL); 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; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or capsules administered orally; Other Names: ONO/GS-4059
Experimental: Tirabrutinib 160 mg once daily (NHL); 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; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or 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 for up to 96 months from first dose in the parent study.	Drug: Tirabrutinib; Tablets or capsules administered orally; Other Names: ONO/GS-4059

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Yu H, Truong H, Mitchell SA, Liclican A, Gosink JJ, Li W, Lin J, Feng JY, Jurgensmeier JM, Billin A, Xu R, Patterson S, Pagratis N. Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement. SLAS Discov. 2018 Oct;23(9):919-929. doi: 10.1177/2472555218786165. Epub 2018 Jul 16.
• Rule SA, Cartron G, Fegan C, Morschhauser F, Han L, Mitra S, Salles G, Dyer MJS. Long-term follow-up of patients with mantle cell lymphoma (MCL) treated with the selective Bruton's tyrosine kinase inhibitor tirabrutinib (GS/ONO-4059). Leukemia. 2020 May;34(5):1458-1461. doi: 10.1038/s41375-019-0658-7. Epub 2019 Dec 11. No abstract available.
• Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip S, Karlin L, Jones C, Herbaux C, Quittet P, Shah N, Hutchinson CV, Fegan C, Yang Y, Mitra S, Salles G, Dyer MJS. Long-term follow-up of patients with CLL treated with the selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2017 May 18;129(20):2808-2810. doi: 10.1182/blood-2017-02-765115. Epub 2017 Apr 4. No abstract available.
• Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, Shah N, Hutchinson CV, Honda H, Duffy K, Birkett J, Jamieson V, Courtenay-Luck N, Yoshizawa T, Sharpe J, Ohno T, Abe S, Nishimura A, Cartron G, Morschhauser F, Fegan C, Salles G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov 5.
• Walter HS, Salles GA, Dyer MJ. New Agents to Treat Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jun 2;374(22):2185-6. doi: 10.1056/NEJMc1602674. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2015
• Primary Completion (Actual): December 30, 2020
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: May 27, 2015
• First Submitted That Met QC Criteria: May 27, 2015
• First Posted (Estimate): May 29, 2015

Study Record Updates

• Last Update Posted (Actual): March 24, 2022
• Last Update Submitted That Met QC Criteria: March 23, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: GS-US-401-1787; 2015-001404-58 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes