Trial Outcomes & Findings for Safety and Efficacy of the Combination of Tirabrutinib and Entospletinib With and Without Obinutuzumab in Adults With Chronic Lymphocytic Leukemia (CLL) (NCT NCT02983617)

Last Updated: 2021-12-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

36 participants

Primary outcome timeframe

Week 25

Results posted on

2021-12-21

Participant Flow

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.

38 participants were screened. Randomization was discontinued after implementation of Protocol Amendment 3; all additional participants were enrolled to Arm: Tirabrutinib + Entospletinib + Obinutuzumab.

Participant milestones

Participant milestones
Measure	Tirabrutinib + Entospletinib 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 + Entospletinib + Obinutuzumab 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.
Overall Study STARTED	6	30
Overall Study COMPLETED	6	21
Overall Study NOT COMPLETED	0	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Tirabrutinib + Entospletinib 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 + Entospletinib + Obinutuzumab 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.
Overall Study Adverse Event	0	7
Overall Study Death	0	1
Overall Study Investigator's Discretion	0	1

Baseline Characteristics

Safety and Efficacy of the Combination of Tirabrutinib and Entospletinib With and Without Obinutuzumab in Adults With Chronic Lymphocytic Leukemia (CLL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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 n=36 Participants Total of all reporting groups
Age, Continuous	61 years STANDARD_DEVIATION 8.3 • n=5 Participants	67 years STANDARD_DEVIATION 9.9 • n=7 Participants	66 years STANDARD_DEVIATION 9.8 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	23 Participants n=7 Participants	27 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Not Hispanic or Latino	4 Participants n=5 Participants	29 Participants n=7 Participants	33 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Not Permitted	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	4 Participants n=5 Participants	29 Participants n=7 Participants	33 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · Not Permitted	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 25

Population: Full Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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.
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	0 percentage of participants Interval 0.0 to 39.3	6.7 percentage of participants Interval 1.2 to 19.5

SECONDARY outcome

Timeframe: Week 25

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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.
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	0 percentage of participants Interval 0.0 to 39.3	3.3 percentage of participants Interval 0.2 to 14.9

SECONDARY outcome

Timeframe: Week 25

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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.
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	0 percentage of participants Interval 0.0 to 39.3	3.3 percentage of participants Interval 0.2 to 14.9

SECONDARY outcome

Timeframe: Week 25

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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.
Overall Response Rate (ORR), as Assessed by the Investigator Using the Modified IWCLL 2008 Criteria at Week 25	100.0 percentage of participants Interval 60.7 to 100.0	90.0 percentage of participants Interval 76.1 to 97.2

SECONDARY outcome

Timeframe: First dose date up to the last dose date (maximum: 105.9 weeks) plus 30 days

Population: Safety Analysis Set included all randomized or enrolled participants who received at least 1 dose of any study drug.

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.

Outcome measures

Outcome measures
Measure	Tirabrutinib + Entospletinib n=6 Participants 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 + Entospletinib + Obinutuzumab n=30 Participants 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.
Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) Any Treatment-Emergent AEs	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants Experiencing Any Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs) Treatment-Emergent SAEs	16.7 percentage of participants	50.0 percentage of participants

Adverse Events

Tirabrutinib + Entospletinib

Serious events: 1 serious events

Other events: 6 other events

Deaths: 0 deaths

Tirabrutinib + Entospletinib + Obinutuzumab

Serious events: 15 serious events

Other events: 29 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

Phone: 1-833-445-3230 (GILEAD-0)

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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
Publication restrictions are in place

Restriction type: OTHER