A Prospective, Open-Label, Multicenter, Phase 2 Trial to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib (GS-4059) and Idelalisib With and Without Obinutuzumab in Subjects With Chronic Lymphocytic Leukemia
Overview
- Phase
- Phase 2
- Intervention
- Tirabrutinib
- Conditions
- Chronic Lymphocytic Leukemia
- Sponsor
- Gilead Sciences
- Enrollment
- 35
- Locations
- 14
- Primary Endpoint
- Rate of Complete Response/Complete Remission (CR), as Assessed by Investigator Using Modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria at Week 25
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The primary objective of this study is to determine the preliminary efficacy of the combination of tirabrutinib and idelalisib with obinutuzumab in adults with relapsed or refractory chronic lymphocytic leukemia (CLL).
The study has a 6 participant per arm safety run-in to evaluate safety prior to the enrollment of subsequent participants. The treatment period is adaptive, with a duration of active treatment up to two years and a total follow-up on study for up to 30 days post end of treatment, or up to Week 25 should a participant discontinue treatment prior to Week 25 for reasons other than disease progression.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documentation of relapsed or refractory CLL
- •Requiring treatment per modified International Workshop on CLL (IWCLL) 2008 criteria; individuals without radiographically measurable disease (defined as ≥ 1 lesion \> 1.5 centimetre (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/L, neutrophil count ≥ 1 × 10\^9/L, hemoglobin ≥ 8 grams per decilitre (g/dL) unless lower values are directly attributable to documented bone marrow burden of CLL
- •Creatinine clearance (CrCl) ≥ 50 milliliter 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, hepatitis C virus (HCV) infection, and cytomegalovirus (CMV) 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
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 individuals with prior treatment with agents in these classes should be reviewed by the sponsor or the German CLL Study Group (GCLLSG) study 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
Arms & Interventions
Tirabrutinib + Idelalisib
Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily for up to 104 weeks.
Intervention: Tirabrutinib
Tirabrutinib + Idelalisib
Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily for up to 104 weeks.
Intervention: Idelalisib
Tirabrutinib + Idelalisib + Obinutuzumab
Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily 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, and then every 4 weeks through Week 21.
Intervention: Tirabrutinib
Tirabrutinib + Idelalisib + Obinutuzumab
Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily 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, and then every 4 weeks through Week 21.
Intervention: Idelalisib
Tirabrutinib + Idelalisib + Obinutuzumab
Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) once daily + idelalisib 100 mg (1 x 100 mg tablet) once daily 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, and then every 4 weeks through Week 21.
Intervention: Obinutuzumab
Outcomes
Primary Outcomes
Rate of Complete Response/Complete Remission (CR), 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
- 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 weeks) plus 30 days)
- 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)