Triple-Drug Therapy for CLL

(AVO Trial)

Not currently recruiting at 3 trial locations

Overseen By DFCI Clinical Trials Hotline

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Proton pump inhibitors, Strong CYP3A inhibitors

Disqualifiers: Other malignancies, Severe allergies, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three drugs—acalabrutinib, venetoclax, and obinutuzumab—to evaluate their effectiveness in treating chronic lymphocytic leukemia (CLL). The goal is to determine if these drugs can effectively manage CLL, particularly in individuals who have not received prior treatments. Participants are divided into two groups: one for those with typical CLL and another for those with high-risk CLL, characterized by specific genetic changes. This trial may suit individuals diagnosed with CLL who experience noticeable symptoms such as night sweats, weight loss, or significant fatigue affecting daily activities. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to important findings.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain drugs like strong CYP3A inhibitors/inducers or P-gp inhibitors. If you are on these, a 3-day break is needed before starting the trial drugs.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining acalabrutinib, venetoclax, and obinutuzumab can reduce the risk of disease progression or death by 58% compared to standard treatment for chronic lymphocytic leukemia (CLL). This is encouraging news, but safety must also be considered.

Previous studies have examined the safety of using these drugs together. Generally, patients tolerated the treatment well. Some experienced side effects, but they were manageable. The most common side effects were mild to moderate, such as headaches and nausea.

No serious side effects have been reported that would cause concern. Additionally, the FDA has already approved venetoclax and acalabrutinib for other uses, providing extra reassurance about their safety.

Overall, while no treatment is without risk, current research suggests that this drug combination is reasonably safe for most people. ^{1 2 3 4}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple-drug therapy for chronic lymphocytic leukemia (CLL) because it combines three powerful agents: Acalabrutinib, Venetoclax, and Obinutuzumab, each with unique mechanisms of action. Unlike standard CLL treatments that often involve chemotherapy, this combination targets specific cancer growth pathways. Acalabrutinib inhibits a protein called Bruton's tyrosine kinase, which is crucial for cancer cell survival, while Venetoclax disrupts the BCL-2 protein, leading to cancer cell death. Obinutuzumab, an antibody, targets the CD20 protein on cancer cells, enhancing the immune system's ability to attack them. Together, these drugs offer a targeted approach that could be more effective and potentially have fewer side effects compared to traditional therapies.

What evidence suggests that this trial's treatments could be effective for CLL?

Research shows that the combination of three drugs—acalabrutinib, venetoclax, and obinutuzumab (AVO)—yields promising results for treating chronic lymphocytic leukemia (CLL). In this trial, participants will receive the AVO combination, which studies have found reduces the risk of disease progression or death by 58% compared to standard treatments. Specifically, 77% of patients did not experience disease progression after three years. These findings suggest that AVO could be a strong option for managing CLL, offering hope for better outcomes. ^{1 2 3 4 5}

Who Is on the Research Team?

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with chronic lymphocytic leukemia (CLL) who haven't had prior treatment and meet specific health criteria, such as adequate organ function and no severe allergies to the study drugs. They must have symptoms or blood test changes that require treatment for CLL.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My organs and bone marrow are functioning well.

My cancer has a TP53 mutation or Del(17p) detected.

Exclusion Criteria

I have not received any live vaccines in the last 4 weeks.

I am currently on or recently needed IV antibiotics for an infection.

Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of acalabrutinib, venetoclax, and obinutuzumab for CLL treatment

24 months

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with MRD testing to guide therapy decisions

Up to 120 months

Open-label extension (optional)

Participants may restart acalabrutinib and venetoclax if CLL recurs after initial treatment

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing a combination of three drugs: Acalabrutinib, Venetoclax, and Obinutuzumab. It aims to evaluate their effectiveness when used together as an initial therapy for patients with CLL.

How Is the Trial Designed?

Group I: Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with non-high-risk CLL disease Experimental Treatment 3 Interventions

* 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

Group II: Acalabrutinib/Venetoclax/Obinutuzumab (AVO) with high-risk CLL disease Experimental Treatment 3 Interventions

* 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

Acalabrutinib is already approved in United States, European Union for the following indications:

Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Acerta Pharma, LLC

Collaborator

Trials

8

Recruited

390+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The combination of venetoclax and obinutuzumab has been approved as a superior first-line treatment for elderly, unfit patients with chronic lymphocytic leukaemia (CLL), showing better efficacy than chlorambucil/obinutuzumab based on a phase-III trial.

For patients with high-risk features like deletion 17p or TP53 mutations, targeted therapies such as ibrutinib or venetoclax/obinutuzumab are recommended due to their poor response to traditional chemotherapy, highlighting the importance of personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current diagnosis and treatment of chronic lymphocytic leukaemia]. Cramer, P., von Tresckow, J., Eichhorst, B., et al.[2021]

In a phase 2 study involving 37 patients with chronic lymphocytic leukaemia, the combination therapy of acalabrutinib, venetoclax, and obinutuzumab achieved a complete remission with undetectable minimal residual disease (MRD) in 38% of participants by cycle 16, indicating promising efficacy.

The treatment was generally well tolerated, with the most common serious adverse event being neutropenia, affecting 43% of patients, and no deaths reported during the study, suggesting a favorable safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Davids, MS., Lampson, BL., Tyekucheva, S., et al.[2021]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax has been confirmed as an effective and well-tolerated treatment for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in Italy, particularly in those with high-risk disease characteristics, based on three real-world studies.

Combining venetoclax with rituximab resulted in more complete responses in patients, although those with higher disease burden or who progressed while on prior Bruton's tyrosine kinase inhibitors had poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience. Laurenti, L., Scarfò, L., Frustaci, AM., et al.[2023]

Citations

1. astrazeneca.com astrazeneca.com/media-centre/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration Calquence plus venetoclax demonstrated ... Calquence plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03836261

NCT03836261 | Study of Acalabrutinib (ACP-196) in ... This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR)

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-02503

Phase II Study of Acalabrutinib, Venetoclax, and ... This phase II study evaluated acalabrutinib, venetoclax, and obinutuzumab (AVO) with duration guided by measurable residual disease (MRD) in a ...

4. news.abbvie.com news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL

AbbVie Submits for U.S. FDA Approval of Combination ... "This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of VENCLEXTA and ...

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-plus-venetoclax-demonstrated-superior-pfs-vs-standard-care-previously-untreated-cll-with-77-of-patients-progression-free-3-years-amplify-phase-iii-trial.html

Fixed-duration CALQUENCE® (acalabrutinib) plus ... CALQUENCE plus venetoclax with obinutuzumab reduced the risk of disease progression or death by 58% versus standard of care in this setting.