Trial Outcomes & Findings for Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL (NCT NCT03580928)

Last Updated: 2025-08-12

Results Overview

The rate of BM MRD was defined as the proportion of participants achieving CR and negative MRD based on 2018 IW-CLL criteria.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE2

Target enrollment

72 participants

Primary outcome timeframe

BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles

Results posted on

2025-08-12

Participant Flow

Participant milestones

Participant milestones
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Overall Study STARTED	37	35
Overall Study COMPLETED	33	30
Overall Study NOT COMPLETED	4	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Overall Study Death	0	3
Overall Study Withdrawal by Subject	2	1
Overall Study Lost to Follow-up	2	0
Overall Study Progressive Disease	0	1

Baseline Characteristics

Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Total n=72 Participants Total of all reporting groups
Age, Continuous	63 years n=5 Participants	65 years n=7 Participants	63 years n=5 Participants
Sex: Female, Male Female	10 Participants n=5 Participants	13 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	22 Participants n=7 Participants	49 Participants n=5 Participants
Race/Ethnicity, Customized White	35 Participants n=5 Participants	34 Participants n=7 Participants	69 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles

The rate of BM MRD was defined as the proportion of participants achieving CR and negative MRD based on 2018 IW-CLL criteria.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Rate of Bone Marrow (BM) Minimal Residual Disease (MRD) Negative Complete Response (CR) After 15 Cycles	0.378 proportion of participants Interval 0.224 to 0.552	0.457 proportion of participants Interval 0.283 to 0.638

SECONDARY outcome

Timeframe: BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles

The PRR was defined as the proportion of participants achieving PR based on 2018 IW-CLL criteria.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Rate of Partial Response (PRR) After 15 Cycles	0.54 proportion of participants Interval 0.37 to 0.698	0.4 proportion of participants Interval 0.236 to 0.582

SECONDARY outcome

Timeframe: BM biopsy evaluated at baseline, cycle 4, 8, 16, 25 on day 1.

The CR+CRi rate was defined as the proportion of participants achieving CR+CRi based on 2018 IW-CLL criteria.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Rate of Complete Response ( Including With Incomplete Count Recovery (CRi)) After cycle 8	0.24 proportion of participants Interval 0.12 to 0.41	0.2 proportion of participants Interval 0.08 to 0.37
Rate of Complete Response ( Including With Incomplete Count Recovery (CRi)) After cycle 16	0.432 proportion of participants Interval 0.267 to 0.609	0.51 proportion of participants Interval 0.336 to 0.689
Rate of Complete Response ( Including With Incomplete Count Recovery (CRi)) After cycle 25	0.46 proportion of participants Interval 0.29 to 0.63	0.62 proportion of participants Interval 0.44 to 0.79

SECONDARY outcome

Timeframe: Disease evaluated at baseline, cycle 4, 8, 16 on day 1, and every 3 months thereafter. Median follow-up for all patients was 55.23 months.

Progression-free survival based on the Kaplan-Meier method is defined as the duration between starting study therapy and documented disease progression (PD) or death, censored at time of last disease assessment.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Median Progression-Free Survival (PFS)	NA months Median and bound of PFS not reached using KM method	49.38 months Interval 49.38 to Upper bound of PFS not reached using KM method

SECONDARY outcome

Timeframe: Up to 2 years

Overall Survival (OS) based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Median Overall Survival (OS)	NA months OS median and bounds not reached using KM method	NA months OS median and bounds not reached using KM method

SECONDARY outcome

Timeframe: PB MRD evaluated on cycle 4, 8, 13, 16, 19, 22, 25, and every 3 cycles thereafter on day 1.

The rate of PB MRD was defined as the proportion of participants achieving negative MRD based on 2018 IW-CLL criteria. PB MRD evaluate by flow cytometry.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Rate of Peripheral Blood (PB) MRD after 8 cycles	0.68 proportion of participants Interval 0.5 to 0.82	0.69 proportion of participants Interval 0.51 to 0.83
Rate of Peripheral Blood (PB) MRD after 16 cycles	0.86 proportion of participants Interval 0.71 to 0.95	0.8 proportion of participants Interval 0.63 to 0.92
Rate of Peripheral Blood (PB) MRD after 25 cycles	0.89 proportion of participants Interval 0.75 to 0.97	0.69 proportion of participants Interval 0.5 to 0.84

SECONDARY outcome

Timeframe: Disease evaluated at baseline, cycle 4, 8, 16 on day 1.

Median Time to BM MRD-positive Disease Recurrence based on the Kaplan-Meier method, is defined as the duration from the date of achieving MRD-negative status in the bone marrow to the date of first documented MRD-positive recurrence in the bone marrow, or death, whichever occurs first.

Outcome measures

Outcome measures
Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 Participants * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Median Time to BM MRD-positive Disease Recurrence	NA years Time of median and bounds cannot be reached using KM method	NA years Time of median and bounds cannot be reached using KM method

Adverse Events

Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease

Serious events: 10 serious events

Other events: 37 other events

Deaths: 0 deaths

Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease

Serious events: 9 serious events

Other events: 34 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Matthew Davids, MD

Dana-Farber Cancer Institute

Phone: 617-632-6331

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With Non-high-risk CLL Disease n=37 participants at risk * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6 Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow	Acalabrutinib/Venetoclax/Obinutuzumab (AVO) With High-risk CLL Disease n=35 participants at risk * Acalabrutinib will be administered orally twice daily at 100 mg bid * Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg * Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6. High-risk CLL disease (cohort 2), defined as 17p deletion and/or TP53 mutation Venetoclax: Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2, venetoclax may kill cancer cells or stop them from growing. Obinutuzumab: Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die Acalabrutinib: Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow
Gastrointestinal disorders Colitis	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
General disorders Non-cardiac chest pain	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Infections and infestations Infections and infestations - Other, specify	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Infections and infestations Lung infection	5.4% 2/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	5.7% 2/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Infections and infestations Upper respiratory infection	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Injury, poisoning and procedural complications Injury, poisoning and procedural complications - Other, specify	2.7% 1/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Investigations Cardiac troponin I increased	2.7% 1/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	0.00% 0/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Investigations Neutrophil count decreased	8.1% 3/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	0.00% 0/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Investigations Platelet count decreased	2.7% 1/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	0.00% 0/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Metabolism and nutrition disorders Hyperkalemia	2.7% 1/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	0.00% 0/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Metabolism and nutrition disorders Tumor lysis syndrome	2.7% 1/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	0.00% 0/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Renal and urinary disorders Acute kidney injury	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).
Renal and urinary disorders Urinary tract obstruction	0.00% 0/37 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).	2.9% 1/35 • AE collection thought entire study, on cycle 1 day 1, cycle 2 day 1, 2, 8, 15, 22, cycle 3 day 1 and 15, cycle 4 day 1, 2, 3, 8, 9, 15, 16, 22, 23, cycle 5 day 1 and 15, then day 1 on each cycle. Median duration of treatment is 25.56 months with range (0.56, 52.2).