Safety and Efficacy of the Combination of Tirabrutinib and Entospletinib With and Without Obinutuzumab in Adults With Chronic Lymphocytic Leukemia (CLL)
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: Tirabrutinib
Administered orally once daily
Other Names:
Drug: Entospletinib
Administered orally once daily
Other Names:
|
| Experimental: 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. |
Drug: Tirabrutinib
Administered orally once daily
Other Names:
Drug: Entospletinib
Administered orally once daily
Other Names:
Drug: Obinutuzumab
Administered intravenously
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 [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 Outcome Measures
- 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/BM MRD at Week 25 was defined as percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved BM MRD negativity 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. MRD response was assessed with four-color-flow cytometry (FACS) and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold.
- 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]
Rate of CR/PB MRD at Week 25 was defined as the percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved PB MRD negativity 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. MRD response was assessed with FACS and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold.
- Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25 [Week 25]
ORR was assessed based on modified IWCLL 2008 criteria and was defined as percentage of participants achieving a CR, CRi, partial remission (PR; including nodular partial response [nPR]), and PR with lymphocytosis (PR-L). CR and CRi: meeting all the criteria that have been defined in Outcome measures 1, 2 and 3. PR: ≥ 2 of these: ≥ 50% decrease in lymphocytes, lymphadenopathy, size of liver, size of spleen, and 50% decrease in bone marrow infiltrates; and ≥ 1 of these: neutrophils > 1500/μL or ≥ 50% increase from Baseline, platelets ≥ 100,000/µL or ≥ 50% increase from Baseline, hemoglobin >11 g/dL or ≥ 50% increase from Baseline. PR-L: meeting PR criteria; however, a lymphocytosis related to treatment may be present. nPR: All criteria for a CR/CRi were fulfilled, but the bone marrow showed lymphoid nodules.
- 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]
A treatment emergent AE is defined as an AE that occurs or worsens in severity on or after the date of the first dose of study drug but no later than 30 days after the permanent discontinuation of study drug or an AE leading to discontinuation of study drug. A SAE is defined as an event that, at any dose, resulted in any of the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically important event or reaction.
Eligibility Criteria
Criteria
Key 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 × 109/liter (L), neutrophil count ≥ 1 × 109/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
Key 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Studienzentrum Aschaffenburg | Aschaffenburg | Germany | 63739 | |
| 2 | Evangelisches Diakoniekrankenhaus Bremen Hämatologie | Bremen | Germany | 28239 | |
| 3 | St.-Johannes-Hospital | Dortmund | Germany | D-44137 | |
| 4 | University Medical Center Freiburg | Freiburg | Germany | 79106 | |
| 5 | Onkologische Schwerpunktpraxis Lerchenfeld | Hamburg | Germany | 22081 | |
| 6 | Universitätsklinikum Heidelberg, Abteilung Innere Medizin V | Heidelberg | Germany | 69120 | |
| 7 | Marienhospital Herne, Dept. of Internal Medicine | Herne | Germany | 44625 | |
| 8 | Universitätsklinikum Schleswig-Holstein Klinik für Innere Medizin II - Hämatologie und Onkologie | Kiel | Germany | 24105 | |
| 9 | Uniklinik Köln Klinik I für Innere Medizin | Köln | Germany | 50937 | |
| 10 | Mannheimer Onkologie Praxis | Manheim | Germany | 68161 | |
| 11 | Gemeinschaftspraxis für Hämatologie und Onkologie | Münster | Germany | 48149 | |
| 12 | Kreiskliniken Reutlingen GmbH Klinikum am Steinenberg | Reutlingen | Germany | 72764 | |
| 13 | Praxis für Hämatologie und Onkologie | Saarbrücken | Germany | 66113 | |
| 14 | Robert-Bosch-Krakenhaus | Stuttgart | Germany | 70376 | |
| 15 | Universitätsklinik Ulm - Klinik für Innere Medizin III | Ulm | Germany | 89081 |
Sponsors and Collaborators
- Gilead Sciences
- German CLL Study Group
Investigators
- Study Director: Gilead Study Director, Gilead Sciences
Study Documents (Full-Text)
More Information
Publications
None provided.- GS-US-401-2076
- 2016-002768-15
- CLLRUmbrella2
Study Results
Participant Flow
| Recruitment Details | Participants were enrolled at study sites in Germany. The first participant was screened on 06 April 2017. The last study visit occurred on 01 October 2020. |
|---|---|
| Pre-assignment Detail | 38 participants were screened. Randomization was discontinued after implementation of Protocol Amendment 3; all additional participants were enrolled to Arm: Tirabrutinib + Entospletinib + Obinutuzumab. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Period Title: Overall Study | ||
| STARTED | 6 | 30 |
| COMPLETED | 6 | 21 |
| NOT COMPLETED | 0 | 9 |
Baseline Characteristics
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab | Total |
|---|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. | Total of all reporting groups |
| Overall Participants | 6 | 30 | 36 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
61
(8.3)
|
67
(9.9)
|
66
(9.8)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
2
33.3%
|
7
23.3%
|
9
25%
|
| Male |
4
66.7%
|
23
76.7%
|
27
75%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
4
66.7%
|
29
96.7%
|
33
91.7%
|
| Not Permitted |
2
33.3%
|
1
3.3%
|
3
8.3%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Black |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| White |
4
66.7%
|
29
96.7%
|
33
91.7%
|
| Other |
0
0%
|
0
0%
|
0
0%
|
| Not Permitted |
2
33.3%
|
1
3.3%
|
3
8.3%
|
Outcome Measures
| Title | 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 |
|---|---|
| Description | 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. |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Measure Participants | 6 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
0
0%
|
6.7
22.3%
|
| Title | 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 |
|---|---|
| Description | Rate of CR/BM MRD at Week 25 was defined as percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved BM MRD negativity 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. MRD response was assessed with four-color-flow cytometry (FACS) and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold. |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Measure Participants | 6 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
0
0%
|
3.3
11%
|
| Title | 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 |
|---|---|
| Description | Rate of CR/PB MRD at Week 25 was defined as the percentage of participants who achieved CR/CRi per modified IWCLL 2008 criteria and also achieved PB MRD negativity 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. MRD response was assessed with FACS and MRD negativity was defined as one CLL cell per 10,000 leukocytes [0.01%], ie,<10^-4 and participants were defined as MRD negative if their disease burden was below this threshold. |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Measure Participants | 6 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
0
0%
|
3.3
11%
|
| Title | Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25 |
|---|---|
| Description | ORR was assessed based on modified IWCLL 2008 criteria and was defined as percentage of participants achieving a CR, CRi, partial remission (PR; including nodular partial response [nPR]), and PR with lymphocytosis (PR-L). CR and CRi: meeting all the criteria that have been defined in Outcome measures 1, 2 and 3. PR: ≥ 2 of these: ≥ 50% decrease in lymphocytes, lymphadenopathy, size of liver, size of spleen, and 50% decrease in bone marrow infiltrates; and ≥ 1 of these: neutrophils > 1500/μL or ≥ 50% increase from Baseline, platelets ≥ 100,000/µL or ≥ 50% increase from Baseline, hemoglobin >11 g/dL or ≥ 50% increase from Baseline. PR-L: meeting PR criteria; however, a lymphocytosis related to treatment may be present. nPR: All criteria for a CR/CRi were fulfilled, but the bone marrow showed lymphoid nodules. |
| Time Frame | Week 25 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in the Full Analysis Set were analyzed. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Measure Participants | 6 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
100.0
1666.7%
|
90.0
300%
|
| Title | Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) |
|---|---|
| Description | A treatment emergent AE is defined as an AE that occurs or worsens in severity on or after the date of the first dose of study drug but no later than 30 days after the permanent discontinuation of study drug or an AE leading to discontinuation of study drug. A SAE is defined as an event that, at any dose, resulted in any of the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically important event or reaction. |
| Time Frame | First dose date up to the last dose date (maximum: 105.9 weeks) plus 30 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug. |
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab |
|---|---|---|
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. |
| Measure Participants | 6 | 30 |
| Any Treatment-Emergent AEs |
100.0
1666.7%
|
100.0
333.3%
|
| Treatment-Emergent SAEs |
16.7
278.3%
|
50.0
166.7%
|
Adverse Events
| Time Frame | Adverse Events: First dose date up to last dose date (maximum: 105.9 weeks) plus 30 days; All-Cause Mortality: Enrollment up to 42 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse Events: Safety Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug; All-cause mortality: All Enrolled Analysis Set included all participants who received a study participant identification number in the study after screening. | |||
| Arm/Group Title | Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab | ||
| Arm/Group Description | Tirabrutinib 80 mg (4 x 20 mg tablets/2 x 40 mg tablets/1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally once daily for up to 104 weeks. | Tirabrutinib 80 mg (4 x 20 mg tablets/ 2 x 40 mg tablets/ 1 x 80 mg tablet) orally once daily + entospletinib 400 mg (2 x 200 mg tablets) orally 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 administered intravenously on Day 1 of Weeks 2, 3, 5, 9, 13, 17 and 21. | ||
All Cause Mortality |
||||
| Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 4/30 (13.3%) | ||
Serious Adverse Events |
||||
| Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/6 (16.7%) | 15/30 (50%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 0/6 (0%) | 1/30 (3.3%) | ||
| Congenital, familial and genetic disorders | ||||
| Hydrocele | 0/6 (0%) | 1/30 (3.3%) | ||
| General disorders | ||||
| Disease progression | 0/6 (0%) | 1/30 (3.3%) | ||
| Pyrexia | 0/6 (0%) | 1/30 (3.3%) | ||
| Infections and infestations | ||||
| Bronchopulmonary aspergillosis | 0/6 (0%) | 1/30 (3.3%) | ||
| Covid-19 pneumonia | 0/6 (0%) | 1/30 (3.3%) | ||
| Nasopharyngitis | 0/6 (0%) | 1/30 (3.3%) | ||
| Peritonsillitis | 0/6 (0%) | 1/30 (3.3%) | ||
| Pneumonia | 0/6 (0%) | 2/30 (6.7%) | ||
| Soft tissue infection | 0/6 (0%) | 1/30 (3.3%) | ||
| Tracheobronchitis | 0/6 (0%) | 1/30 (3.3%) | ||
| Urinary tract infection | 0/6 (0%) | 1/30 (3.3%) | ||
| Injury, poisoning and procedural complications | ||||
| Infusion related reaction | 0/6 (0%) | 2/30 (6.7%) | ||
| Procedural haemorrhage | 1/6 (16.7%) | 0/30 (0%) | ||
| Subdural haematoma | 0/6 (0%) | 1/30 (3.3%) | ||
| Nervous system disorders | ||||
| Syncope | 0/6 (0%) | 2/30 (6.7%) | ||
| Renal and urinary disorders | ||||
| Renal impairment | 0/6 (0%) | 1/30 (3.3%) | ||
| Urethral caruncle | 0/6 (0%) | 1/30 (3.3%) | ||
| Reproductive system and breast disorders | ||||
| Benign prostatic hyperplasia | 0/6 (0%) | 1/30 (3.3%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Pleural effusion | 0/6 (0%) | 1/30 (3.3%) | ||
| Pneumonitis | 0/6 (0%) | 1/30 (3.3%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Pemphigoid | 0/6 (0%) | 1/30 (3.3%) | ||
| Vascular disorders | ||||
| Haematoma | 0/6 (0%) | 1/30 (3.3%) | ||
| Peripheral arterial occlusive disease | 0/6 (0%) | 1/30 (3.3%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Tirabrutinib + Entospletinib | Tirabrutinib + Entospletinib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 29/30 (96.7%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 1/6 (16.7%) | 3/30 (10%) | ||
| Leukopenia | 0/6 (0%) | 2/30 (6.7%) | ||
| Neutropenia | 0/6 (0%) | 14/30 (46.7%) | ||
| Thrombocytopenia | 0/6 (0%) | 2/30 (6.7%) | ||
| Cardiac disorders | ||||
| Aortic valve incompetence | 1/6 (16.7%) | 0/30 (0%) | ||
| Palpitations | 0/6 (0%) | 2/30 (6.7%) | ||
| Tachycardia | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Ear and labyrinth disorders | ||||
| Ear pain | 0/6 (0%) | 2/30 (6.7%) | ||
| Tinnitus | 0/6 (0%) | 2/30 (6.7%) | ||
| Eye disorders | ||||
| Conjunctival haemorrhage | 0/6 (0%) | 2/30 (6.7%) | ||
| Gastrointestinal disorders | ||||
| Abdominal pain | 0/6 (0%) | 3/30 (10%) | ||
| Abdominal pain upper | 0/6 (0%) | 2/30 (6.7%) | ||
| Constipation | 0/6 (0%) | 8/30 (26.7%) | ||
| Diarrhoea | 1/6 (16.7%) | 7/30 (23.3%) | ||
| Dry mouth | 0/6 (0%) | 2/30 (6.7%) | ||
| Dyspepsia | 0/6 (0%) | 2/30 (6.7%) | ||
| Flatulence | 1/6 (16.7%) | 3/30 (10%) | ||
| Gastritis | 0/6 (0%) | 3/30 (10%) | ||
| Gastrointestinal disorder | 1/6 (16.7%) | 0/30 (0%) | ||
| Nausea | 2/6 (33.3%) | 9/30 (30%) | ||
| Stomatitis | 1/6 (16.7%) | 0/30 (0%) | ||
| Vomiting | 0/6 (0%) | 5/30 (16.7%) | ||
| General disorders | ||||
| Asthenia | 0/6 (0%) | 2/30 (6.7%) | ||
| Chest pain | 0/6 (0%) | 2/30 (6.7%) | ||
| Chills | 0/6 (0%) | 7/30 (23.3%) | ||
| Fatigue | 2/6 (33.3%) | 10/30 (33.3%) | ||
| Impaired healing | 1/6 (16.7%) | 0/30 (0%) | ||
| Mucosal inflammation | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Oedema peripheral | 1/6 (16.7%) | 6/30 (20%) | ||
| Pyrexia | 1/6 (16.7%) | 10/30 (33.3%) | ||
| Infections and infestations | ||||
| Bronchitis | 0/6 (0%) | 6/30 (20%) | ||
| Conjunctivitis | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Cystitis | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Folliculitis | 1/6 (16.7%) | 0/30 (0%) | ||
| Gastroenteritis | 2/6 (33.3%) | 1/30 (3.3%) | ||
| Herpes virus infection | 1/6 (16.7%) | 2/30 (6.7%) | ||
| Herpes zoster | 0/6 (0%) | 3/30 (10%) | ||
| Nasopharyngitis | 4/6 (66.7%) | 10/30 (33.3%) | ||
| Oral herpes | 2/6 (33.3%) | 5/30 (16.7%) | ||
| Periodontitis | 0/6 (0%) | 2/30 (6.7%) | ||
| Pneumonia | 0/6 (0%) | 3/30 (10%) | ||
| Respiratory tract infection | 1/6 (16.7%) | 0/30 (0%) | ||
| Rhinitis | 0/6 (0%) | 2/30 (6.7%) | ||
| Root canal infection | 1/6 (16.7%) | 0/30 (0%) | ||
| Sinusitis | 1/6 (16.7%) | 3/30 (10%) | ||
| Upper respiratory tract infection | 1/6 (16.7%) | 3/30 (10%) | ||
| Urinary tract infection | 1/6 (16.7%) | 6/30 (20%) | ||
| Injury, poisoning and procedural complications | ||||
| Arthropod bite | 0/6 (0%) | 3/30 (10%) | ||
| Contusion | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Infusion related reaction | 0/6 (0%) | 4/30 (13.3%) | ||
| Investigations | ||||
| Blood bilirubin increased | 0/6 (0%) | 4/30 (13.3%) | ||
| Blood glucose increased | 1/6 (16.7%) | 0/30 (0%) | ||
| Haemoglobin urine present | 1/6 (16.7%) | 0/30 (0%) | ||
| Immunoglobulins decreased | 0/6 (0%) | 2/30 (6.7%) | ||
| Lipase increased | 0/6 (0%) | 2/30 (6.7%) | ||
| Platelet count decreased | 0/6 (0%) | 2/30 (6.7%) | ||
| Red blood cells urine positive | 1/6 (16.7%) | 0/30 (0%) | ||
| Weight increased | 0/6 (0%) | 2/30 (6.7%) | ||
| Metabolism and nutrition disorders | ||||
| Folate deficiency | 1/6 (16.7%) | 0/30 (0%) | ||
| Hyperkalaemia | 0/6 (0%) | 2/30 (6.7%) | ||
| Hypertriglyceridaemia | 1/6 (16.7%) | 0/30 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 0/6 (0%) | 4/30 (13.3%) | ||
| Back pain | 2/6 (33.3%) | 4/30 (13.3%) | ||
| Muscle spasms | 1/6 (16.7%) | 3/30 (10%) | ||
| Musculoskeletal pain | 0/6 (0%) | 2/30 (6.7%) | ||
| Neck pain | 0/6 (0%) | 3/30 (10%) | ||
| Osteoarthritis | 1/6 (16.7%) | 0/30 (0%) | ||
| Osteoporotic fracture | 1/6 (16.7%) | 0/30 (0%) | ||
| Pain in extremity | 0/6 (0%) | 4/30 (13.3%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Richter's syndrome | 1/6 (16.7%) | 0/30 (0%) | ||
| Nervous system disorders | ||||
| Dizziness | 1/6 (16.7%) | 3/30 (10%) | ||
| Headache | 1/6 (16.7%) | 6/30 (20%) | ||
| Paraesthesia | 0/6 (0%) | 2/30 (6.7%) | ||
| Polyneuropathy | 0/6 (0%) | 2/30 (6.7%) | ||
| Psychiatric disorders | ||||
| Insomnia | 0/6 (0%) | 2/30 (6.7%) | ||
| Renal and urinary disorders | ||||
| Haematuria | 0/6 (0%) | 2/30 (6.7%) | ||
| Reproductive system and breast disorders | ||||
| Benign prostatic hyperplasia | 0/6 (0%) | 2/30 (6.7%) | ||
| Erectile dysfunction | 1/6 (16.7%) | 0/30 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 1/6 (16.7%) | 9/30 (30%) | ||
| Oropharyngeal pain | 1/6 (16.7%) | 1/30 (3.3%) | ||
| Pleural effusion | 0/6 (0%) | 2/30 (6.7%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Eczema | 0/6 (0%) | 2/30 (6.7%) | ||
| Night sweats | 0/6 (0%) | 3/30 (10%) | ||
| Petechiae | 0/6 (0%) | 3/30 (10%) | ||
| Pruritus | 1/6 (16.7%) | 5/30 (16.7%) | ||
| Purpura | 0/6 (0%) | 2/30 (6.7%) | ||
| Rash | 2/6 (33.3%) | 5/30 (16.7%) | ||
| Rash papular | 1/6 (16.7%) | 0/30 (0%) | ||
| Urticaria | 0/6 (0%) | 3/30 (10%) | ||
| Vascular disorders | ||||
| Haematoma | 2/6 (33.3%) | 6/30 (20%) | ||
| Hypotension | 0/6 (0%) | 2/30 (6.7%) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years
Results Point of Contact
| Name/Title | Gilead Clinical Study Information Center |
|---|---|
| Organization | Gilead Sciences |
| Phone | 1-833-445-3230 (GILEAD-0) |
| GileadClinicalTrials@gilead.com |
- GS-US-401-2076
- 2016-002768-15
- CLLRUmbrella2