• Added study flow chart to reflect stratification by mutation, treatment of an early safety cohort, and review of 28-day safety data from the safety cohort by the Safety Review Team (SRT) • Included additional details on sample size determination • Incorporated recommendations from the Summary of Product Characteristics (SmPC) for Gazyvaro® (obinutuzumab) in the event of suspicion of progressive multifocal leukoencephalopathy (PML)

• Updated entospletinib formulation information • Revised the recommendations for concomitant medications with entospletinib • Updated the study procedures for CLL immunophenotyping at disease progression

• Further enrollment into Arm A was discontinued. All additional subjects were enrolled to Arm B. A total of approximately 6 subjects were enrolled in Arm A and 30 subjects in Arm B, thus the total sample size for the study was reduced from 60 subjects to approximately 36 subjects. • As of 07 June 2017, 10 subjects with CLL were treated on Phase 1b Study GS-US-401-1757 with the combination of tirabrutinib and entospletinib with a median exposure of 43 weeks (range: 18-55). All 10 subjects continued on study and treatment however no CLL subjects have achieved a complete remission (CR). Given the lack of CRs seen in the ongoing treatment experience with the combination of tirabrutinib and entospletinib and the primary endpoint of CR in this protocol (GS-US-401-2076), with Amendment 3, enrollment into the doublet combination of tirabrutinib and entospletinib without obinutuzumab was discontinued. Arm B continued enrollment as the safety and preliminary efficacy of the combination with the addition of obinutuzumab retained the potential to be safe and achieve a high rate and depth of response. • The requirement for a bone marrow biopsy at Week 25 was limited to subjects who otherwise would meet criteria for a CR or complete remission with incomplete bone marrow recovery (CRi). For subjects without radiographic evidence of disease at screening, a bone marrow biopsy including aspirate was required at screening. In the presence of systemic disease, the bone marrow result was only a critical study for assessing a complete remission or progressive disease per IWCLL 2008 guidelines. As evaluation of the bone marrow in the case of progressive disease was performed only when clinical progression was suspected, the scheduled bone marrow assessment was only necessary to evaluate subjects who do not have radiographically evident disease. This change did not impact disease response assessment and should decrease the burden of bone marrow biopsies at the cohort level.

• The post treatment follow up period was removed. All subjects completed the study at the End of Treatment visit, or at the Week 25 visit, should treatment have discontinued prior to Week 25. • The primary endpoint of complete remission (CR) and secondary endpoints of rate of CR with bone marrow minimal residual disease (MRD) negativity (CR/BM MRD-) and the rate of CR with MRD negativity (<10-4) in peripheral blood (CR/PB MRD-) at Week 25 were not met, based on data from the ongoing study with the combination of tirabrutinib, entospletinib and obinutuzumab. Therefore, post-treatment disease assessments were no longer conducted. • Based on ongoing study data that indicate MRD negativity may be achieved post Week 25, additional exploratory endpoints were added to allow for analysis at later time points. • The lots of tirabrutinib 20 mg tablets expired in Feb 2020 and it was unknown if the shelf-life was extended, therefore the 20 mg tablets were replaced with 40 mg tablets. Data supporting the tablet formulation was contained within the protocol and supporting documents.