Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory 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 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: Tirabrutinib
Tablets administered orally
Other Names:
Drug: Idelalisib
Tablets administered orally
Other Names:
|
| Experimental: 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. |
Drug: Tirabrutinib
Tablets administered orally
Other Names:
Drug: Idelalisib
Tablets administered orally
Other Names:
Drug: Obinutuzumab
Administered intravenously
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 [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 weeks) plus 30 days]
Treatment-emergent AEs are defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug Any AEs 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; 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 × 109/L, neutrophil count ≥ 1 × 109/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
-
Able to comply with study procedures and restrictions including mandatory prophylaxis for Pneumocystis jirovecii pneumonia (PJP)
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 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
-
Treatment or prophylaxis for CMV within the past 28 days
-
History of stroke or intracranial hemorrhage within 12 months of randomization; patients requiring therapeutic anticoagulation for any indication should be discussed with the GCLLSG cooperating physician and/or medical monitor prior to screening.
-
Use of a strong CYP3A4 or a strong P-glycoprotein (P-gp) inducer within 2 weeks of first dose of study treatment or anticipated chronic use while on study
-
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 | Ambulante Krebszentrum Schaubstraße | Frankfurt | Brandenburg | Germany | 60596 |
| 2 | Hämatologische-onkologische Gem.-Praxis Dres. Brudler-Heinrich-Bangerter, Augsburg | Augsburg | Germany | 86150 | |
| 3 | Internistische Gemeinschaftspraxis Dres. Schliesser-Käbisch-Weber, Gießen | Gießen | Germany | 35392 | |
| 4 | Uniklinik Koln | Köln | Germany | 50937 | |
| 5 | Uniklinik Leipzig | Leipzig | Germany | 04103 | |
| 6 | Luebecker Onkologische Schwerpunktpraxis | Luebeck | Germany | 23562 | |
| 7 | Universitasmtedizin Mannheim | Mannheim | Germany | 68167 | |
| 8 | Stauferklinikum Schwäbisch Gmünd | Mutlangen | Germany | 73557 | |
| 9 | KH Maria Hilf-Franziskushaus, Mönchengladbach | Mönchengladbach | Germany | 41063 | |
| 10 | Krankenhaus München-Schwabing | München | Germany | 80804 | |
| 11 | Klinikum Rechts der Isar der Technischen Universität München | München | Germany | 81675 | |
| 12 | Studienzentrum Onkologie Ravensburg | Ravensburg | Germany | 88212 | |
| 13 | Facharztzentrum Regensburg | Regensburg | Germany | 93053 | |
| 14 | Universitätsklinikum Ulm | 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
Additional Information:
Publications
None provided.- GS-US-401-1958
- 2015-003909-42
- CLLRUmbrella1
Study Results
Participant Flow
| Recruitment Details | Participants were enrolled at study sites in Germany. The first participant was screened on 13 December 2016. The last study visit occurred on 14 January 2021. |
|---|---|
| Pre-assignment Detail | 35 participants were screened. Randomization was discontinued after implementation of Protocol Amendment 3; all additional participants were enrolled to Arm: Tirabrutinib + Idelalisib + Obinutuzumab. |
| Arm/Group Title | Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Period Title: Overall Study | ||
| STARTED | 5 | 30 |
| COMPLETED | 4 | 22 |
| NOT COMPLETED | 1 | 8 |
Baseline Characteristics
| Arm/Group Title | Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. | Total of all reporting groups |
| Overall Participants | 5 | 30 | 35 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
62
(4.7)
|
65
(9.4)
|
65
(8.9)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
3
60%
|
10
33.3%
|
13
37.1%
|
| Male |
2
40%
|
20
66.7%
|
22
62.9%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| White |
5
100%
|
29
96.7%
|
34
97.1%
|
| Not Permitted |
0
0%
|
1
3.3%
|
1
2.9%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| Not Hispanic or Latino |
5
100%
|
29
96.7%
|
34
97.1%
|
| Not Permitted |
0
0%
|
1
3.3%
|
1
2.9%
|
Outcome Measures
| Title | 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 |
|---|---|
| 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 |
|---|
| The Full Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug. |
| Arm/Group Title | Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Measure Participants | 5 | 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 + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Measure Participants | 5 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
0
0%
|
0
0%
|
| 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 + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Measure Participants | 5 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
0
0%
|
0
0%
|
| 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 + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Measure Participants | 5 | 30 |
| Number (90% Confidence Interval) [percentage of participants] |
60.0
1200%
|
93.3
311%
|
| Title | Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) |
|---|---|
| Description | Treatment-emergent AEs are defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug Any AEs 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 weeks) plus 30 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Safety Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug. |
| Arm/Group Title | Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 on Day 1 of Weeks 2, 3, 5, and then every 4 weeks through Week 21. |
| Measure Participants | 5 | 30 |
| Any Treatment-Emergent AEs |
100
2000%
|
100
333.3%
|
| Treatment-Emergent SAEs |
60.0
1200%
|
46.7
155.7%
|
Adverse Events
| Time Frame | Adverse Events: First dose date up to last dose date (maximum: 105 weeks) plus 30 days; All-Cause Mortality: Enrollment up to 31 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse Events: The Safety Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug. All-Cause Mortality: The All Enrolled Analysis Set included all participants who received a study participant identification number in the study after screening. | |||
| Arm/Group Title | Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 + idelalisib 100 mg (1 x 100 mg tablet) 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 over 21 weeks. | ||
All Cause Mortality |
||||
| Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/5 (20%) | 1/30 (3.3%) | ||
Serious Adverse Events |
||||
| Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/5 (60%) | 14/30 (46.7%) | ||
| Cardiac disorders | ||||
| Cardiac failure acute | 1/5 (20%) | 0/30 (0%) | ||
| Coronary artery stenosis | 0/5 (0%) | 1/30 (3.3%) | ||
| Gastrointestinal disorders | ||||
| Colitis | 0/5 (0%) | 1/30 (3.3%) | ||
| Stomatitis | 0/5 (0%) | 1/30 (3.3%) | ||
| Infections and infestations | ||||
| Atypical pneumonia | 0/5 (0%) | 1/30 (3.3%) | ||
| Cystitis | 0/5 (0%) | 1/30 (3.3%) | ||
| Influenza | 0/5 (0%) | 1/30 (3.3%) | ||
| Large intestine infection | 0/5 (0%) | 1/30 (3.3%) | ||
| Pneumonia | 0/5 (0%) | 1/30 (3.3%) | ||
| Investigations | ||||
| Hepatic enzyme increased | 0/5 (0%) | 1/30 (3.3%) | ||
| Investigation | 0/5 (0%) | 1/30 (3.3%) | ||
| Neutrophil count decreased | 0/5 (0%) | 1/30 (3.3%) | ||
| Metabolism and nutrition disorders | ||||
| Tumour lysis syndrome | 0/5 (0%) | 1/30 (3.3%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Acute myeloid leukaemia | 0/5 (0%) | 1/30 (3.3%) | ||
| Squamous cell carcinoma | 0/5 (0%) | 1/30 (3.3%) | ||
| Nervous system disorders | ||||
| Cerebral infarction | 0/5 (0%) | 1/30 (3.3%) | ||
| Renal and urinary disorders | ||||
| Nephrolithiasis | 1/5 (20%) | 0/30 (0%) | ||
| Ureterolithiasis | 1/5 (20%) | 0/30 (0%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dyspnoea | 0/5 (0%) | 1/30 (3.3%) | ||
| Pleural effusion | 0/5 (0%) | 1/30 (3.3%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Dermatitis allergic | 1/5 (20%) | 0/30 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Tirabrutinib + Idelalisib | Tirabrutinib + Idelalisib + Obinutuzumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | 29/30 (96.7%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 0/5 (0%) | 2/30 (6.7%) | ||
| Leukopenia | 0/5 (0%) | 4/30 (13.3%) | ||
| Lymphopenia | 0/5 (0%) | 2/30 (6.7%) | ||
| Neutropenia | 0/5 (0%) | 11/30 (36.7%) | ||
| Thrombocytopenia | 0/5 (0%) | 8/30 (26.7%) | ||
| Cardiac disorders | ||||
| Tachycardia | 1/5 (20%) | 1/30 (3.3%) | ||
| Ear and labyrinth disorders | ||||
| Vertigo | 0/5 (0%) | 6/30 (20%) | ||
| Eye disorders | ||||
| Lacrimation increased | 1/5 (20%) | 0/30 (0%) | ||
| Vision blurred | 1/5 (20%) | 2/30 (6.7%) | ||
| Visual impairment | 0/5 (0%) | 2/30 (6.7%) | ||
| Gastrointestinal disorders | ||||
| Abdominal distension | 0/5 (0%) | 2/30 (6.7%) | ||
| Abdominal pain | 0/5 (0%) | 2/30 (6.7%) | ||
| Abdominal pain upper | 0/5 (0%) | 2/30 (6.7%) | ||
| Colitis | 0/5 (0%) | 2/30 (6.7%) | ||
| Constipation | 1/5 (20%) | 2/30 (6.7%) | ||
| Diarrhoea | 2/5 (40%) | 10/30 (33.3%) | ||
| Diverticulum intestinal | 1/5 (20%) | 0/30 (0%) | ||
| Flatulence | 0/5 (0%) | 3/30 (10%) | ||
| Gastritis | 0/5 (0%) | 2/30 (6.7%) | ||
| Nausea | 2/5 (40%) | 7/30 (23.3%) | ||
| Vomiting | 1/5 (20%) | 4/30 (13.3%) | ||
| General disorders | ||||
| Chills | 1/5 (20%) | 6/30 (20%) | ||
| Fatigue | 1/5 (20%) | 10/30 (33.3%) | ||
| Feeling cold | 0/5 (0%) | 2/30 (6.7%) | ||
| Influenza like illness | 0/5 (0%) | 2/30 (6.7%) | ||
| Medical device pain | 1/5 (20%) | 0/30 (0%) | ||
| Oedema peripheral | 0/5 (0%) | 2/30 (6.7%) | ||
| Pyrexia | 1/5 (20%) | 7/30 (23.3%) | ||
| Infections and infestations | ||||
| Bronchitis | 0/5 (0%) | 6/30 (20%) | ||
| Conjunctivitis | 0/5 (0%) | 2/30 (6.7%) | ||
| Cystitis | 0/5 (0%) | 2/30 (6.7%) | ||
| Cytomegalovirus infection | 0/5 (0%) | 2/30 (6.7%) | ||
| Cytomegalovirus infection reactivation | 0/5 (0%) | 2/30 (6.7%) | ||
| Febrile infection | 1/5 (20%) | 1/30 (3.3%) | ||
| Fungal infection | 0/5 (0%) | 2/30 (6.7%) | ||
| Herpes virus infection | 0/5 (0%) | 2/30 (6.7%) | ||
| Herpes zoster | 1/5 (20%) | 0/30 (0%) | ||
| Influenza | 1/5 (20%) | 2/30 (6.7%) | ||
| Nasopharyngitis | 0/5 (0%) | 10/30 (33.3%) | ||
| Oral pustule | 1/5 (20%) | 0/30 (0%) | ||
| Pneumonia | 0/5 (0%) | 3/30 (10%) | ||
| Sinusitis | 0/5 (0%) | 4/30 (13.3%) | ||
| Upper respiratory tract infection | 2/5 (40%) | 7/30 (23.3%) | ||
| Urinary tract infection | 0/5 (0%) | 3/30 (10%) | ||
| Injury, poisoning and procedural complications | ||||
| Foot fracture | 1/5 (20%) | 1/30 (3.3%) | ||
| Infusion related reaction | 0/5 (0%) | 5/30 (16.7%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 1/5 (20%) | 2/30 (6.7%) | ||
| Aspartate aminotransferase increased | 1/5 (20%) | 2/30 (6.7%) | ||
| C-reactive protein increased | 0/5 (0%) | 3/30 (10%) | ||
| Gamma-glutamyltransferase increased | 0/5 (0%) | 2/30 (6.7%) | ||
| Hepatic enzyme increased | 0/5 (0%) | 3/30 (10%) | ||
| Neutrophil count decreased | 0/5 (0%) | 4/30 (13.3%) | ||
| Platelet count decreased | 0/5 (0%) | 3/30 (10%) | ||
| Weight decreased | 0/5 (0%) | 2/30 (6.7%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 0/5 (0%) | 2/30 (6.7%) | ||
| Hyperkalaemia | 0/5 (0%) | 2/30 (6.7%) | ||
| Hyperuricaemia | 1/5 (20%) | 0/30 (0%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Arthralgia | 0/5 (0%) | 4/30 (13.3%) | ||
| Back pain | 1/5 (20%) | 7/30 (23.3%) | ||
| Flank pain | 1/5 (20%) | 1/30 (3.3%) | ||
| Groin pain | 1/5 (20%) | 0/30 (0%) | ||
| Muscle spasms | 0/5 (0%) | 3/30 (10%) | ||
| Myalgia | 1/5 (20%) | 1/30 (3.3%) | ||
| Osteoarthritis | 0/5 (0%) | 2/30 (6.7%) | ||
| Pain in extremity | 0/5 (0%) | 2/30 (6.7%) | ||
| Spinal pain | 0/5 (0%) | 2/30 (6.7%) | ||
| Nervous system disorders | ||||
| Dizziness | 2/5 (40%) | 3/30 (10%) | ||
| Headache | 1/5 (20%) | 4/30 (13.3%) | ||
| Memory impairment | 0/5 (0%) | 2/30 (6.7%) | ||
| Restless legs syndrome | 0/5 (0%) | 2/30 (6.7%) | ||
| Syncope | 1/5 (20%) | 0/30 (0%) | ||
| Psychiatric disorders | ||||
| Depression | 0/5 (0%) | 2/30 (6.7%) | ||
| Insomnia | 1/5 (20%) | 1/30 (3.3%) | ||
| Sleep disorder | 0/5 (0%) | 2/30 (6.7%) | ||
| Renal and urinary disorders | ||||
| Dysuria | 1/5 (20%) | 1/30 (3.3%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 0/5 (0%) | 8/30 (26.7%) | ||
| Dysphonia | 0/5 (0%) | 2/30 (6.7%) | ||
| Epistaxis | 0/5 (0%) | 4/30 (13.3%) | ||
| Haemoptysis | 0/5 (0%) | 2/30 (6.7%) | ||
| Nasal mucosal disorder | 0/5 (0%) | 2/30 (6.7%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Dermatitis allergic | 1/5 (20%) | 0/30 (0%) | ||
| Dry skin | 0/5 (0%) | 3/30 (10%) | ||
| Ecchymosis | 0/5 (0%) | 3/30 (10%) | ||
| Night sweats | 0/5 (0%) | 3/30 (10%) | ||
| Petechiae | 0/5 (0%) | 2/30 (6.7%) | ||
| Pruritus | 0/5 (0%) | 4/30 (13.3%) | ||
| Rash | 0/5 (0%) | 8/30 (26.7%) | ||
| Rash maculo-papular | 2/5 (40%) | 3/30 (10%) | ||
| Skin exfoliation | 0/5 (0%) | 2/30 (6.7%) | ||
| Skin lesion | 0/5 (0%) | 3/30 (10%) | ||
| Vascular disorders | ||||
| Haematoma | 1/5 (20%) | 6/30 (20%) | ||
| Hypertension | 0/5 (0%) | 5/30 (16.7%) | ||
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-401-1958
- 2015-003909-42
- CLLRUmbrella1