Acalabrutinib, Venetoclax, and Obinutuzumab for Initial T... | NCT03580928

NCT03580928

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
1R01CA266298-01A1	U.S. NIH Grant/Contract		View source

Status Module

Sponsor/Collaborators Module

Name	Class
AstraZeneca	INDUSTRY
Genentech, Inc.	INDUSTRY
National Institutes of Health (NIH)	NIH
National Cancer Institute (NCI)

Oversight Module

Description Module

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of investigational drugs to learn whether the drugs work in treating a specific disease. "Investigational" means that the drugs are being studied. The FDA (the U.S. Food and Drug Administration) has not approved acalabrutinib for CLL, although it is FDA-approved for patients with relapsed mantle cell lymphoma. The FDA has approved venetoclax and obinutuzumab separately for the treatment of patients with CLL. However, the FDA has not approved the combination of these three drugs together (acalabrutinb, venetoclax, and obinutuzumab) as a treatment for any disease. This combination is investigational. In this research study, the investigators are trying to learn if giving the three drugs together can safely and effectively treat CLL.

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. By blocking BTK, acalabrutinib may kill cancer cells or stop them from growing. As of September 2017, acalabrutinib has been administered to more than 2,000 people including healthy volunteers, patients with cancers, and patients with rheumatoid arthritis. A few hundred patients with CLL have been treated with acalabrutinib as a single drug, and some of these patients had improvement of their cancer with this treatment.

Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein on the surface of the CLL cell, causing it to die. Obintuzumab has already been shown to be safe and effective at treating CLL, and is FDA-approved when given together with chemotherapy.

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. Venetoclax has been shown to be safe and effective when given alone to treat patients with CLL and is FDA-approved for patients with CLL after their disease has worsened after at least 1 prior therapy.

If, after 15 or 24 cycles of this investigational therapy, participants have a complete response to the drugs in this trial -- meaning that the investigators cannot detect any CLL using CT scans, bone marrow biopsy and a sensitive test called minimal residual disease (MRD) testing -- participants will stop therapy with acalabrutinib and venetoclax. The investigators will continue to monitor participants while they are off of therapy, and if the CLL comes back participants will be able to restart acalabrutinib and venetoclax. The use of MRD testing to identify small amounts of CLL is investigational, meaning that it has not been FDA-approved. The use of results from this test to guide the decision to stop and re-start therapy, as is done in the trial here, is also investigational.

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with non-high-risk CLL disease	Experimental	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	Drug: Venetoclax Drug: Obinutuzumab Drug: Acalabrutinib
Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with high-risk CLL disease	Experimental	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	Drug: Venetoclax Drug: Obinutuzumab Drug: Acalabrutinib

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Venetoclax	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Rate of Bone Marrow (BM) Minimal Residual Disease (MRD) Negative Complete Response (CR) 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.	BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles

Secondary Outcomes

Measure	Description	Time Frame
Rate of Partial Response (PRR) After 15 Cycles	The PRR was defined as the proportion of participants achieving PR based on 2018 IW-CLL criteria.	BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles
Rate of Complete Response ( Including With Incomplete Count Recovery (CRi))

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects must have CLL or SLL
In cohort 2, subjects must have TP53-aberrant disease defined as:
- Del(17p) detected on karyotype and/or FISH; OR
- TP53 mutation
Participants must have measurable disease (lymphocytosis > 5,000 / µl, or palpable or CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥30%).
Subjects must not have received any prior systemic therapy for CLL or SLL due to meeting IWCLL 2018 guidelines and must currently have an indication for treatment as defined by the IWCLL 2018 guidelines:
- Massive or progressive or symptomatic splenomegaly; OR
- Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR
- Significant fatigue (i.e. ECOG PS 2 or worse; cannot work or unable to perform usual activities); OR
- Fever ≥ 100.5°F for 2 or more weeks without evidence of infection; OR
- Night sweats for ≥ 1 months without evidence of infection; OR
- Presence of weight loss ≥ 10% over the preceding 6 months; OR
- Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or lymphocyte doubling time of less than 6 months; OR
- Evidence of progressive marrow failure as manifested by the development of or worsening of anemia and/or thrombocytopenia; OR
- Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids and another standard therapy such as rituximab; OR
- Symptomatic or functional extranodal involvement
Age greater than or equal to 18 years.
ECOG performance status ≤2
Participants must have adequate organ and marrow function as defined below:
- total bilirubin ≤1.5 times upper limit of normal, unless there is disease involvement of the liver, hemolysis, or a known history of Gilbert's disease, in which case direct bilirubin must be ≤3 times the upper limit of normal
- AST and ALT ≤ 2.5 times the upper limit of normal. If there is hemolysis or documented disease involvement of the liver, then patients with any AST or ALT abnormalities remain eligible.
- creatinine clearance (CrCl) ≥ 50 mL/min using 24-hour urine collection for creatinine clearance or calculated CrCl
- PT/INR ≤2 times the upper limit of normal and PTT ≤2 times the upper limit of normal
- Absolute neutrophil count ≥750 cells/mm3 or ≥500 cells/mm3 in subjects with documented bone marrow involvement
- Platelet count without transfusional support must be ≥50,000 cells/mm3 or ≥ 30,000 cells/mm3 in subjects with documented bone marrow involvement
Pregnant or lactating

Exclusion Criteria:

Participants who have a history of other malignancies except:
- Malignancy treated with curative intent and with no known active disease present and felt to be at low risk for recurrence by treating physician. Current adjuvant hormonal therapy for disease treated with curative intent is permissible.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- Adequately treated carcinoma in situ without evidence of disease.
- Low-risk prostate cancer on active surveillance
Participants who are receiving any other investigational agents.
History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not excluded.
Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment
Known or suspected Richter's transformation or known CNS involvement
Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., within 28 days of the first dose of study drug or chronic administration of >20 mg/day of prednisone within 7 days of the first dose)
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
Ongoing or recent infection requiring intravenous antimicrobials at time of screening.
Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.
Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
Major surgery within 4 weeks of first dose of study drug. If a subject had major surgery greater than 4 weeks prior to the first dose, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block.
Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed).
Patients who require treatment with proton pump inhibitors (see Appendix F). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment on this study.
Patients who require concurrent treatment with strong CYP3A inhibitors or strong CYP3A inducers are excluded from the study. If patients are receiving strong CYP3A inhibitors/inducers at time of screening but do not require continuous administration of these agents, these patients are eligible if there is a 3-day washout period between discontinuation of the strong CYP3A inhibitor/inducer and initiation of the first study drug, acalabrutinib.
Patients who require concurrent treatment with P-gp inhibitors or narrow therapeutic index P-gp substrates are excluded from the study. If patients are receiving P-gp inhibitors or narrow therapeutic index P-gp substrates at time of screening but do not require continuous administration of these agents, these patients are eligible if there is a 3-day washout period between discontinuation of the P-gp inhibitor and initiation of acalabrutinib.
Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel if thought by the investigator to compromise systemic absorption, active, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection.
Significant co-morbid condition or disease which in the judgment of the Principal Investigator would place the patient at undue risk or interfere with the study
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, compromise the subject's safety, or put the study outcomes at undue risk.

Contacts/Locations Module

Name	Affiliation	Role
Matthew S. Davids, MD, MMSc	Dana-Farber Cancer Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Stamford Hospital/Bennett Cancer Center		Stamford	Connecticut	06904	United States
Beth Israel Deaconess Medical Center

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
39645236	Derived	Davids MS, Ryan CE, Lampson BL, Ren Y, Tyekucheva S, Fernandes SM, Crombie JL, Kim AI, Weinstock M, Montegaard J, Walker HA, Greenman C, Patterson V, Jacobson CA, LaCasce AS, Armand P, Fisher DC, Lo S, Olszewski AJ, Arnason JE, Ahn IE, Brown JR. Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naive Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease. J Clin Oncol. 2025 Mar;43(7):788-799. doi: 10.1200/JCO-24-02503. Epub 2024 Dec 7.
34534514

IPD Sharing Statement Module

Arm/Group Information

ID	Title	Description
FG000	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
FG001	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

Periods

Title

Milestones

Reasons Not Completed

Overall Study

Type	Comment	Milestone Data
STARTED		FG00037 subjects FG00135 subjects
COMPLETED		FG00033 subjects FG00130 subjects
NOT COMPLETED		FG0004 subjects FG0015 subjects

Type	Comment	Reasons
Death		FG0000 subjects FG0013 subjects
Withdrawal by Subject		FG0002 subjects FG001

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Rate of Bone Marrow (BM) Minimal Residual Disease (MRD) Negative Complete Response (CR) 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.

Posted

Number

95% Confidence Interval

proportion of participants

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

ID	Title	Description
OG000	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

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Colitis	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Anemia	Blood and lymphatic system disorders	CTCAE (5.0)	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Matthew Davids, MD	Dana-Farber Cancer Institute	617-632-6331		matthew_davids@dfci.harvard.edu

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jan 18, 2023	May 19, 2025	Prot_SAP_001.pdf

Submission Tracking

Condition Browse Module

ID	Term
D015451	Leukemia, Lymphocytic, Chronic, B-Cell

ID	Term
D015448	Leukemia, B-Cell
D007945	Leukemia, Lymphoid
D007938	Leukemia
D009370	Neoplasms by Histologic Type

Intervention Browse Module

ID	Term
C579720	venetoclax
C543332	obinutuzumab
C000604908	acalabrutinib

Masking Info

Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with high-risk CLL disease
Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with non-high-risk CLL disease

EG0000 affected37 at risk

EG0011 affected35 at risk

EG00023 affected37 at risk

EG00114 affected35 at risk

OG0010.51(0.336 to 0.689)

OG0010.8(0.63 to 0.92)