Venetoclax + Acalabrutinib for CLL

(ESR-23-22182 Trial)

Overseen By Zulfa Omer, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Zulfa Omer

Must not be taking: Warfarin, Strong CYP3A inhibitors

Disqualifiers: Active disease, CNS lymphoma, 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: 7

Duration: 12 cycles (each cycle is 28 days)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the drugs venetoclax and acalabrutinib work together to treat Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Researchers aim to determine if taking venetoclax intermittently (on and off) or continuously affects its effectiveness. The trial seeks participants with untreated CLL or SLL who may have symptoms like swollen lymph nodes or a high white blood cell count. This opportunity may appeal to those interested in trying new treatment options. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, contributing to important findings.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, like strong CYP3A inhibitors or inducers, within specific timeframes before starting the study drugs. If you are on these medications, you may need to stop or adjust them according to the trial's guidelines.

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

Research has shown that venetoclax and acalabrutinib have been tested for safety in treating Chronic Lymphocytic Leukemia (CLL). Studies indicate that venetoclax, particularly when combined with acalabrutinib, often results in high survival rates. Specifically, several studies found survival rates of about 95% or higher after three years, suggesting the treatment is effective and relatively safe.

However, some side effects require attention. Common issues include changes in blood counts, such as low white blood cells, which can increase infection risk. Other side effects may include diarrhea, tiredness, and headaches. These were noted in studies with both intermittent and continuous use of venetoclax with acalabrutinib.

It is important to remember that these treatments are being tested to determine the safest way to use them. Participants in such trials will be closely monitored, which helps manage any side effects that occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Venetoclax and Acalabrutinib for chronic lymphocytic leukemia (CLL) because these treatments offer a novel approach compared to traditional options like chemotherapy and other targeted therapies like Ibrutinib. Venetoclax works by targeting and blocking the BCL-2 protein, which helps cancer cells survive, leading to their death. Acalabrutinib, on the other hand, is a selective Bruton's tyrosine kinase (BTK) inhibitor that disrupts cancer cell signaling and growth. Together, these drugs are tested in two distinct regimens: one with intermittent Venetoclax, which may reduce side effects and improve quality of life, and another with continuous Venetoclax, which could enhance effectiveness through sustained therapy. This combination aims to provide a more effective and potentially less toxic alternative to existing treatments.

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

Research has shown that the combination of venetoclax and acalabrutinib effectively treats Chronic Lymphocytic Leukemia (CLL). In this trial, participants will join one of two treatment arms: Arm A, with intermittent venetoclax (7 days per cycle) and acalabrutinib, or Arm B, with continuous venetoclax (28 days per cycle) and acalabrutinib. Previous studies demonstrated that this combination kept 94.1% of patients alive after three years and reduced the risk of disease progression or death by 35% compared to standard treatments. Patients, regardless of certain genetic changes, showed good survival rates for up to four years. These findings suggest that this treatment holds promise for individuals with untreated CLL. ^{3 6 7 8 9}

Who Is on the Research Team?

Zulfa Omer

Principal Investigator

University of Cincinnati

Are You a Good Fit for This Trial?

This trial is for individuals with previously untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Specific eligibility criteria are not provided, but typically include factors like age, overall health status, and disease characteristics.

Inclusion Criteria

Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing tablets without difficulty.

Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

My physical health has been stable for the last 2 weeks.

Exclusion Criteria

My body can properly process medications.

Concurrent participation in another therapeutic clinical trial.

Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either intermittent or continuous venetoclax therapy with acalabrutinib for 12 cycles

12 cycles (each cycle is 28 days)

Visits at baseline, cycle 1, cycle 4, cycle 6, cycle 9, and cycle 12

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of BTK mutations and overall survival

Up to 5 years post treatment

Every 6 months from year 2 to year 5

Long-term monitoring

Monitoring for secondary cancer development and disease relapse

3 to 5 years post treatment

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Venetoclax

Trial Overview The study compares two ways of taking Venetoclax—either intermittently or continuously—combined with another drug called Acalabrutinib. It's a Phase II trial which means it focuses on the effectiveness of this treatment combination and further evaluates its safety.

How Is the Trial Designed?

Group I: Arm B: continuous venetoclax Experimental Treatment 2 Interventions

continuous venetoclax (28 days administrations per cycle) + acalabrutinib

Group II: Arm A: intermittent venetoclax Experimental Treatment 2 Interventions

intermittent venetoclax (7days administration per cycle) + acalabrutinib

Who Is Running the Clinical Trial?

Zulfa Omer

Lead Sponsor

Citations

1. ashpublications.org ashpublications.org/ashclinicalnews/news/8558/Fixed-Duration-Acalabrutinib-Combinations

Fixed-Duration Acalabrutinib Combinations Effective for ... At 36 months the estimated OS was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with ...

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

Phase II Study of Acalabrutinib, Venetoclax, and ... Four-year progression-free survival and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively.

3. 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 ... At a median follow up of 41 months, results showed Calquence plus venetoclax reduced the risk of disease progression or death by 35% compared to ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39976417/

Fixed-Duration Acalabrutinib Combinations in Untreated ... Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with ...

5. onclive.com onclive.com/view/acalabrutinib-venetoclax-with-or-without-obinutuzumab-earns-positive-chmp-opinion-for-untreated-cll

Acalabrutinib/Venetoclax With or Without Obinutuzumab ... The estimated 36-month overall survival (OS) rate was 94.1% with acalabrutinib/venetoclax, 87.7% with acalabrutinib/venetoclax with obinutuzumab ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04941716

Study Details | NCT04941716 | Acalabrutinib in ... Venetoclax is added beginning with Cycle 4. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Across all the treatment groups, similar overall survival at 3 years was observed — 95.3%, 96.3%, 96.5%, and 95.0% in the venetoclax– ...

8. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/3257.2/530222/BRAVE-A-Phase-2-Trial-Evaluating-the-Efficacy-and

BRAVE: A Phase 2 Trial Evaluating the Efficacy and Safety of ... Clinical Outcomes with Venetoclax-Based Treatment Regimens in Patients with Chronic Lymphocytic Leukemia (CLL). Paul J. Hampel, Blood, 2023.

9. tandfonline.com tandfonline.com/doi/full/10.2217/fon-2022-0456

MAJIC: A Phase III Trial of Acalabrutinib + Venetoclax ... This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic ...