Study to Assess Change in Disease Activity and Adverse Events of Oral Venetoclax in Combination With Intravenous (IV) Obinutuzumab or Oral Ibrutinib in Adult Participants With Untreated Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

• Venetoclax (Drug), also known as Venclexta, ABT-199, GDC-0199: Oral Tablet
• Ibrutinib (Drug), also known as Imbruvica: Oral Capsule
• Obinutuzumab (Drug), also known as GA101, Gazyva, RO5072759: Intravenous (IV) Infusion

Primary outcomes

• Complete Remission (CR) and CR With an Incomplete Marrow Recovery (CRi) Rate Per Independent Review Committee (IRC) [Up to 46 months]: CR+CRi rate was defined as the percentage of participants achieving a best response of CR or CRi as assessed by an IRC per 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for tumor response. CR required all of the following: * Group A: * Lymphadenopathy: None > 1.5 centimeters * Blood Lymphocytes: <4,000/microliter (μL) * Hepatomegaly: None * Splenomegaly: None * Marrow: Normocellular, < 30% lymphocytes, no B-lymphoid nodules * Group B: * Platelet Count: > 100,000/μL * Hemoglobin: > 11.0 grams per deciliter (g/dL) * Neutrophils: > 1500/μL CRi was defined as a CR with peripheral cytopenia and incomplete recovery of the bone marrow, manifested by persistent cytopenias.

Secondary outcomes

• CR+CRi Rate Per Investigator Assessment [Up to 46 months]: CR+CRi rate was defined as the percentage of participants achieving a best response of CR or CRi as assessed by an IRC per iwCLL criteria for tumor response. CR required all of the following: * Group A: * Lymphadenopathy: None > 1.5 centimeters * Blood Lymphocytes: <4,000/μL * Hepatomegaly: None * Splenomegaly: None * Marrow: Normocellular, < 30% lymphocytes, no B-lymphoid nodules * Group B: * Platelet Count: > 100,000/μL * Hemoglobin: > 11.0 g/dL * Neutrophils: > 1500/μL CRi was defined as a CR with peripheral cytopenia and incomplete recovery of the bone marrow, manifested by persistent cytopenias.
• Overall Response Rate (ORR) Per IRC [Baseline up to 46 months]: ORR was defined as the percentage of participants with a best overall response of CR, CRi, partial remission (PR) or nodular partial remission (nPR) per 2008 iwCLL criteria. PR required at Least 2 Criteria from Group A AND at least 1 Criterion from Group B: * Group A: * Lymphadenopathy: Decrease ≥ 50% * Blood Lymphocytes: Decrease ≥ 50% from baseline * Hepatomegaly: Decrease ≥ 50% * Splenomegaly: Decrease ≥ 50% * Marrow: 50% reduction in marrow infiltrate or B-lymphoid nodules * Group B: * Platelet Count: > 100,000/μL or increase ≥ 50% over baseline * Hemoglobin: > 11.0 g/dL or increase ≥ 50% over baseline * Neutrophils: > 1500/μL or increase ≥ 50% over baseline nPR was a response that met the criteria for CR, but the bone marrow biopsy showed lymphoid nodules, reflecting residual disease.
• ORR Per Investigator Assessment [Baseline up to 46 months]: ORR was defined as the percentage of participants with a best overall response of CR, CRi, PR or nPR per 2008 iwCLL criteria.
• Progression-Free Survival (PFS) Per IRC [Up to 46 months]: PFS was defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurred first, according to iwCLL criteria. PFS was analyzed using Kaplan-Meier methodology.
• PFS Per Investigator Assessment [Up to 46 months]: PFS was defined as the time from the date of first dose of any study drug until the date of disease progression or death due to any cause, whichever occurred first, according to iwCLL criteria. PFS was analyzed using Kaplan-Meier methodology.
• Duration of Response (DOR) as Assessed by IRC [Up to 46 months]: DOR was defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurred first, as determined by an IRC according to iwCLL criteria.
• DOR as Assessed by Investigator [Up to 46 months]: DOR was defined as the time from the first occurrence of overall response (CR, CRi, PR or nPR) until disease progression or death due to any cause, whichever occurred first, as determined by an IRC according to iwCLL criteria.
• Overall Survival (OS) [Up to 46 months]: OS was defined as the time from the date of the first dose of any study drug until death due to any cause.
• Time to Progression (TTP) as Assessed by IRC [Up to 46 months]: TTP was defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an IRC according to iwCLL criteria.
• TTP as Assessed by Investigator [Up to 46 months]: TTP was defined as the time from the date of first dose of any study drug until the date of disease progression, as determined by an investigator according to iwCLL criteria.

Sex: All, ages: 20 Years to any

Inclusion Criteria:

* Adult male or female, at least ≥ 65 years old; or 20 to 64 years old and have at least 1 of the following:

  * Cumulative Illness Rating Scale (CIRS) score > 6.
  * Creatinine clearance (CrCl) estimated < 70 mL/min using Cockcroft-Gault equation.
* Must have measurable nodal disease (by computed tomography \[CT\]), defined as at least one lymph node > 1.5 cm in longest diameter.
* Diagnosed Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) that requires treatment according to the Modified 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.

Exclusion Criteria:

* Transformation of Chronic Lymphocytic Leukemia (CLL) to aggressive non-Hodgkin lymphoma (NHL; Richter's transformation or pro-lymphocytic leukemia).
* Previous treatment history for CLL/SLL.

Participant flow

Outcome results

• Complete Remission (CR) and CR With an Incomplete Marrow Recovery (CRi) Rate Per Independent Review Committee (IRC) (Primary), Number, percentage of participants: Venetoclax + Obinutuzumab 100 (69.2 to 100.0); Venetoclax + Ibrutinib 80.0 (44.4 to 97.5)
• CR+CRi Rate Per Investigator Assessment (Secondary), Number, percentage of participants: Venetoclax + Obinutuzumab 90.0 (55.5 to 99.7); Venetoclax + Ibrutinib 60.0 (26.2 to 87.8)
• Overall Response Rate (ORR) Per IRC (Secondary), Number, percentage of participants: Venetoclax + Obinutuzumab 100 (69.2 to 100.0); Venetoclax + Ibrutinib 100 (69.2 to 100.0)
• ORR Per Investigator Assessment (Secondary), Number, percentage of participants: Venetoclax + Obinutuzumab 100 (69.2 to 100.0); Venetoclax + Ibrutinib 90.0 (55.5 to 99.7)
• Progression-Free Survival (PFS) Per IRC (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib NA (24.6 to NA)
• PFS Per Investigator Assessment (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib 31.0 (16.2 to NA)
• Duration of Response (DOR) as Assessed by IRC (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib NA (17.3 to NA)
• DOR as Assessed by Investigator (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib NA (7.7 to NA)
• Overall Survival (OS) (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib NA (NA to NA)
• Time to Progression (TTP) as Assessed by IRC (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib NA (24.6 to NA)
• TTP as Assessed by Investigator (Secondary), Median, months: Venetoclax + Obinutuzumab NA (NA to NA); Venetoclax + Ibrutinib 31.0 (16.2 to NA)

Adverse events

Time frame: All-cause mortality and adverse event tables include events reported from the start of safety data collection to the end of the study. The median time on follow-up was 1134.5 and 1172.5 days for arms Venetoclax + Obinutuzumab and Venetoclax + Ibrutinib respectively.

Serious adverse events by term

Other adverse events by term

54 more terms not shown.

• Study Protocol (PDF, 2024-03-19)
• Statistical Analysis Plan (PDF, 2024-05-07)

• ABBVIE INC., Study director, AbbVie