Venetoclax + Obinutuzumab/Acalabrutinib for Chronic Lymphocytic Leukemia

Recruiting at 87 trial locations

Overseen By ABBVIE CALL CENTER

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AbbVie

Must be taking: Venetoclax

Disqualifiers: Active infection, Richter's transformation, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 5 weeks ramp-up, total treatment up to 28 months

170 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of combining two drugs, venetoclax and either obinutuzumab or acalabrutinib (a type of targeted therapy), to treat chronic lymphocytic leukemia (CLL), a common blood cancer. Researchers aim to observe how these drug combinations affect disease activity and identify any side effects. Participants will join one of four groups, each receiving a different combination or dosing schedule of the treatments. The trial seeks individuals with previously untreated CLL or small lymphocytic lymphoma (SLL) who need treatment based on specific criteria. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants access to potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop your current medications. It's best to discuss this with the study doctors to understand how your current medications might interact with the trial treatments.

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

Research has shown that combining venetoclax with either obinutuzumab or acalabrutinib is generally safe for patients with chronic lymphocytic leukemia (CLL). Studies have found that venetoclax with obinutuzumab can lead to long-lasting periods without treatment, indicating effectiveness and manageability for most people.

For the venetoclax and acalabrutinib combination, research is ongoing, but early results suggest it is both effective and safe. The FDA is currently reviewing this treatment, examining data to ensure its safety for use. Patients in everyday settings have experienced safety outcomes similar to those in controlled studies, demonstrating consistent safety results.

Overall, these treatments have shown promise in terms of safety, with manageable side effects. However, participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for chronic lymphocytic leukemia (CLL) because they offer new combinations and mechanisms that could improve patient outcomes. Unlike standard treatments like chemoimmunotherapy, the combinations of Venetoclax with Obinutuzumab or Acalabrutinib target specific proteins that help cancer cells survive. Venetoclax works by inhibiting BCL-2, a protein that prevents cancer cell death, while Acalabrutinib targets the BTK protein to disrupt cancer cell signaling. This targeted approach, especially with the added flexibility in dosing schedules seen in the modified ramp-up strategies, may lead to more effective and potentially less toxic treatment options for CLL patients.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

In this trial, participants will receive different combinations of treatments for chronic lymphocytic leukemia (CLL). Earlier research has shown promising results for the combination of venetoclax and obinutuzumab, which participants in Arm A will receive. One study found that after six years, 53% of patients did not experience disease progression. Another study showed that this combination is more effective than traditional chemoimmunotherapy for patients healthy enough for treatment.

Participants in Arms B, C, and D will receive venetoclax combined with acalabrutinib. Research has shown that this combination reduced the risk of disease progression or death by 58% compared to standard care. It also significantly improved the duration patients remained healthier without disease worsening. These findings suggest both combinations could be effective treatment options for CLL. ^{2 6 7 8 9}

Who Is on the Research Team?

ABBVIE INC.

Principal Investigator

AbbVie

Are You a Good Fit for This Trial?

Adults with previously untreated chronic lymphocytic leukemia (CLL) who need treatment and have a life expectancy over 6 months. They should be able to perform daily activities with ease or some difficulty (ECOG <=2), have good marrow function, and adequate kidney function (CrCl >=30 mL/min). Those with very large lymph nodes (>5 cm) and lower kidney function (CrCl <80 mL/min) can't join.

Inclusion Criteria

I can take care of myself and am up and about more than 50% of my waking hours.

I have untreated small lymphocytic lymphoma that requires treatment.

My blood cell counts are stable without needing extra help, unless it's due to my CLL.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral venetoclax in combination with intravenously infused obinutuzumab or oral acalabrutinib with a ramp-up period

5 weeks ramp-up, total treatment up to 28 months

Regular visits at a hospital or clinic

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The trial is testing the safety of venetoclax combined with obinutuzumab or acalabrutinib in treating CLL. Participants are divided into four groups receiving different combinations and dosing schedules of these drugs orally or through IV infusion. The study will last about 28 months across roughly 80 global sites.

How Is the Trial Designed?

Group I: Arm D: Venetoclax + Acalabrutinib Experimental Treatment 2 Interventions

Participants will receive venetoclax in combination with acalabrutinib, with a modified venetoclax ramp up B.

Group II: Arm C: Venetoclax + Acalabrutinib Experimental Treatment 2 Interventions

Participants will receive venetoclax in combination with acalabrutinib, with a modified venetoclax ramp up A.

Group III: Arm B: Venetoclax + Acalabrutinib Experimental Treatment 2 Interventions

Participants will receive venetoclax in combination with acalabrutinib, with a 5 week venetoclax ramp up.

Group IV: Arm A: Venetoclax + Obinutuzumab Experimental Treatment 2 Interventions

Participants will receive venetoclax in combination with obinutuzumab, with a 5 week venetoclax ramp up.

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?

AbbVie

Lead Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

In a phase 2 trial involving 70 patients with chronic lymphocytic leukaemia, both 12 cycles of venetoclax consolidation and minimal residual disease-guided consolidation showed similar effectiveness, with around 50% of patients achieving undetectable minimal residual disease in bone marrow after treatment.

While consolidation treatment did not lead to treatment-related deaths, it was associated with a higher incidence of adverse events, particularly infections, indicating that while it may extend treatment duration, it does not significantly improve disease response or reduce relapse risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Kersting, S., Dubois, J., Nasserinejad, K., et al.[2022]

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 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]

In a phase 3 trial involving 432 patients with untreated chronic lymphocytic leukaemia, the combination of venetoclax plus obinutuzumab resulted in significantly longer progression-free survival compared to chlorambucil plus obinutuzumab, with a hazard ratio of 0.31, indicating a strong treatment advantage.

After a median follow-up of 39.6 months post-treatment, patients receiving venetoclax plus obinutuzumab had not yet reached median progression-free survival, while those on chlorambucil plus obinutuzumab had a median of 35.6 months, highlighting the long-term efficacy of the venetoclax regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Al-Sawaf, O., Zhang, C., Tandon, M., et al.[2020]

In a retrospective study of 14 patients with chronic lymphocytic leukemia (CLL) treated with the venetoclax and obinutuzumab (VenG) regimen, 73% developed grade 3 or 4 neutropenia, indicating a high incidence of this side effect.

The study suggests that the high rate of neutropenia may be linked to patients having more comorbidities and high-risk disease features, highlighting the need for further research on supportive treatments to manage this side effect and allow for optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation and associated risk factors for neutropenia with venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia. Samuels, C., Abbott, D., Niemiec, S., et al.[2022]

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]

Citations

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

Phase II Study of Acalabrutinib, Venetoclax, and ... This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration.

2. ashpublications.org ashpublications.org/thehematologist/article/doi/10.1182/hem.V22.3.2025313/536739/Does-1-1-2-Combining-Targeted-Agents-in-Frontline

Does 1 + 1 = 2? Combining Targeted Agents in Frontline ... , et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study .

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa2409804

Fixed-Duration Acalabrutinib Combinations in Untreated ... Acalabrutinib–venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11899398/

Real-World Effectiveness of Frontline Treatments Among ... We describe the effectiveness of front-line CLL treatments in adult patients with CLL in real-world settings.

5. astrazeneca.com astrazeneca.com/content/astraz/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

6. 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 ... VENCLEXTA is a prescription medicine used: to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). in ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12381400/

Real-World Safety and Efficacy of Venetoclax in Chronic ... In conclusion, patients with CLL treated with venetoclax in a RW clinical setting exhibit similar efficacy and safety outcomes to those observed in RCTs. 1.

8. targetedonc.com targetedonc.com/view/fda-review-underway-for-oral-venetoclax-acalabrutinib-combo-in-untreated-cll

FDA Review Underway for Oral Venetoclax, Acalabrutinib ... AbbVie seeks FDA approval for a groundbreaking oral treatment combining venetoclax and acalabrutinib, promising a new era in CLL care.

9. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1009/530876/Fixed-Duration-Acalabrutinib-Plus-Venetoclax-with

Fixed-Duration Acalabrutinib Plus Venetoclax with or without ... This prespecified interim analysis of AMPLIFY assessed the efficacy and safety of fixed-duration acalabrutinib-venetoclax (±obinutuzumab) vs ...