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Chronic Lymphocytic Leukemia (CLL)Phase 2AVONCT03580928

Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

A Phase 2 study testing Venetoclax, Obinutuzumab and Acalabrutinib in people with Chronic Lymphocytic Leukemia (CLL), run by Dana-Farber Cancer Institute at 4 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab -- as a possible treatment for chronic lymphocytic leukemia (CLL). The drugs involved in this study are: Acalabrutinib Venetoclax Obinutuzmab Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia (CLL)
What is being tested?
Venetoclax, Obinutuzumab and Acalabrutinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
72 participants
Where
4 sitesUnited States
Study dates
7 Aug 2018to 31 Dec 2027
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 26Show fewer
  • 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

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Lifespan Cancer Institute

    Providence, Rhode Island, 02903

  • Stamford Hospital/Bennett Cancer Center

    Stamford, Connecticut, 06904

Other trials in United States

About this study

Official title: A Phase 2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) for Initial Therapy of Chronic Lymphocytic Leukemia

This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab -- as a possible treatment for chronic lymphocytic leukemia (CLL).

The drugs involved in this study are:

  • Acalabrutinib
  • Venetoclax
  • Obinutuzmab
Read the 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.

Being tested
Venetoclax, Obinutuzumab, Acalabrutinib
Keywords
Chronic Lymphocytic Leukemia (CLL)
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VenetoclaxDrug

    Also called Venclexta

    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.

  • ObinutuzumabDrug

    Also called Gazyva

    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

  • AcalabrutinibDrug

    Also called Calquence

    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

Study groups in NCT03580928
Study groupRoleWhat they receive
Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with non-high-risk CLL diseaseExperimental* 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
Receives: Drug: Venetoclax; Drug: Obinutuzumab; Drug: Acalabrutinib
Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with high-risk CLL diseaseExperimental* 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
Receives: Drug: Venetoclax; Drug: Obinutuzumab; Drug: Acalabrutinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

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

Secondary outcomes (6)

  1. 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.

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

  2. Rate of Complete Response ( Including With Incomplete Count Recovery (CRi))

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

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

  3. Median Progression-Free Survival (PFS)

    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.

    Measured: 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.

  4. Median Overall Survival (OS)

    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.

    Measured: Up to 2 years

  5. Rate of Peripheral Blood (PB) MRD

    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.

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

  6. Median Time to BM MRD-positive Disease Recurrence

    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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Jul 2018
  2. Study start7 Aug 2018
  3. Primary completion10 Apr 2024
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
72 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03580928
Sponsor's protocol ID
18-226
Other IDs
1R01CA266298-01A1
Acronym
AVO
Status last verified
Jan 2026
First submitted
25 Jun 2018
Last updated
13 Feb 2026
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 39645236

  • Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. doi: 10.1016/S1470-2045(21)00455-1. Epub 2021 Sep 14.

    PubMed 34534514

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Venetoclax, Obinutuzumab and Acalabrutinib in people with Chronic Lymphocytic Leukemia (CLL), run by Dana-Farber Cancer Institute at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 13 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of Bone Marrow (BM) Minimal Residual Disease (MRD) Negative Complete Response (CR) After 15 Cycles (time frame: BM biopsy evaluated at baseline, cycle 4, 8, 16 on day 1. Relative to this endpoint is after 15 cycles). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03580928, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2026.

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