A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (GS-4059) and Entospletinib With and Without Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Gilead Sciences
- Enrollment
- 36
- Locations
- 15
- Primary Endpoint
- Rate of Complete Remission/Complete Remission With Incomplete Recovery of the Bone Marrow (CR/CRi), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25
Study Overview
Brief Summary
The primary objective of this study is to determine the preliminary efficacy of the combination of tirabrutinib (formerly GS-4059) and entospletinib with obinutuzumab in adults with relapsed or refractory chronic lymphocytic leukemia (CLL).
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Documentation of relapsed or refractory CLL
- •Requiring treatment per modified International Workshop on CLL (IWCLL) 2008 criteria; adults without radiographically measureable disease (defined as ≥ 1 lesion > 1.5 centimetres (cm) in diameter as assessed by computed tomography (CT) or magnetic resonance imaging (MRI)) must have bone marrow evaluation at screening
- •Adequate hematologic function: platelet count ≥ 50 × 10^9/liter (L), neutrophil count ≥ 1 × 10^9/L, hemoglobin ≥ 8 grams per deciliter (g/dL) unless lower values are directly attributable to documented bone marrow burden of CLL
- •Creatinine clearance (CrCl) ≥ 50 milliliters per minute (mL/min)
- •Total bilirubin ≤ 1.5× institutional upper limit of normal (ULN) unless attributed to Gilbert's syndrome and aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5×ULN
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
- •Absence of active human immunodeficiency virus (HIV), hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection
- •Satisfies the following criteria:
- •For females of childbearing potential, willingness to abstain from sexual intercourse or use a protocol-specified method of contraception as described in the study protocol
- •Males of reproductive potential who engage in sexual intercourse must agree to use protocol-specified method(s) of contraception as described in the study protocol
- •Able to comply with study procedures and restrictions
Exclusion Criteria
- •Known transformation of CLL (ie, Richter's transformation, prolymphocytic leukemia)
- •Known central nervous system (CNS) involvement
- •Progression on treatment with any inhibitor of Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), phosphatidylinositol 3-kinase (PI3K), B-cell lymphoma 2 (BCL-2), or obinutuzumab. The treatment and disease response history of participants with prior treatment with agents in these classes should be reviewed by the sponsor or the German CLL Study Group office prior to enrollment to clarify sensitivity to these treatments
- •Any treatment for CLL other than corticosteroids for symptomatic management within 28 days of the start of study treatment
- •Participation on a concurrent therapeutic clinical trial unless all treatment is complete with only ongoing surveillance
- •Diagnosis of or concern for progressive multifocal leukoencephalopathy
- •History of myelodysplastic syndrome or another malignancy other than CLL, except for the following: any malignancy that has been in complete remission for 3 years, adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 year prior to start of study therapy
- •Active infection requiring systemic therapy
- •Pregnant or nursing women (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment and monthly during therapy)
- •Active autoimmune disease or the need for higher than prednisone 10 mg daily unless for management of CLL symptoms
- •History of stroke or intracranial hemorrhage within 12 months of randomization; participants requiring therapeutic anticoagulation for any indication should be discussed with the German CLL Study Group (GCLLSG) cooperating physician and/or medical monitor prior to screening
- •Anticipated chronic use of strong CYP3A4/CYP2C9 inducers, moderate CYP2C9 inducers, or strong P-gp inducers while on study; use within 2 weeks of first dose of study treatment should be avoided
- •Requirement for proton pump inhibitor (PPI) therapy
- •Demonstration of corrected QT (QTc) interval > 450 milliseconds or requirement for ongoing treatment with concomitant medications that prolong the QT interval
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Tirabrutinib + Entospletinib
Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks.
Intervention: Tirabrutinib (Drug)
Tirabrutinib + Entospletinib
Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks.
Intervention: Entospletinib (Drug)
Tirabrutinib + Entospletinib + Obinutuzumab
Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks + obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21.
Intervention: Tirabrutinib (Drug)
Tirabrutinib + Entospletinib + Obinutuzumab
Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks + obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21.
Intervention: Entospletinib (Drug)
Tirabrutinib + Entospletinib + Obinutuzumab
Participants will receive tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) + entospletinib 400 mg (2 x 200 mg tablets) for up to 104 weeks + obinutuzumab 100 mg on Day 1, 900 mg on Day 1 or 2, and 1000 mg subsequently for up to 8 doses on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21.
Intervention: Obinutuzumab (Drug)
Outcomes
Primary Outcomes
Rate of Complete Remission/Complete Remission With Incomplete Recovery of the Bone Marrow (CR/CRi), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25
Time Frame: Week 25
Rate of CR per modified IWCLL 2008 criteria at Week 25 was defined as the percentage of participants who achieved CR/complete remission with incomplete recovery of the bone marrow (CRi) at Week 25. CR: meeting following criteria and no disease related symptoms: no lymphadenopathy \> 1.5 cm/hepatomegaly/splenomegaly; lymphocytes \< 4000/μL; bone marrow sample must be normocellular with 30% lymphocytes and no B-lymphoid nodules; platelets \> 100,000/µL; hemoglobin \> 11 g/dL; and neutrophils \> 1500/µL. CRi: CR criteria (no lymphadenopathy \> 1.5 cm/hepatomegaly/splenomegaly; lymphocytes \< 4000/μL; bone marrow \[hypocellular\] with 30% lymphocytes and no B-lymphoid nodules), persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity.
Secondary Outcomes
- Rate of CR With Bone Marrow Minimal Residual Disease (CR/BM MRD) Negativity, as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25(Week 25)
- Rate of CR With Peripheral Minimal Residual Disease (CR/PB MRD) Negativity, as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25(Week 25)
- Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25(Week 25)
- Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)(First dose date up to the last dose date (maximum: 105.9 weeks) plus 30 days)