Acalabrutinib + Venetoclax for Chronic Lymphocytic Leukemia

Overseen By Mazyar Shadman

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Prolymphocytic leukemia, Cardiovascular disease, Gastrointestinal issues, 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: 26

Duration: 24 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of acalabrutinib and venetoclax for chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that resists standard treatments or returns after treatment. The goal is to determine if these drugs can halt the growth and spread of cancer cells. Acalabrutinib blocks certain enzymes necessary for cancer cell growth, while venetoclax aids in killing cancer cells. Individuals with CLL or SLL who have relapsed or shown resistance to at least one prior treatment may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like strong CYP3A4 inhibitors or proton pump inhibitors. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

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

Research has shown that the combination of acalabrutinib and venetoclax is generally safe for people with chronic lymphocytic leukemia (CLL). Studies have examined patient tolerance to this treatment. Some patients reported side effects like low blood cell counts and diarrhea, but these were usually manageable and rarely led to treatment discontinuation.

Other studies have tested this combination and found that many patients could undergo the treatment without serious issues. Most did not experience severe side effects, and the treatment was considered well-tolerated. These findings suggest that this treatment could be a safe option for people with CLL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about acalabrutinib combined with venetoclax for chronic lymphocytic leukemia (CLL) because they bring a novel approach to treatment. Unlike traditional therapies, which often rely on chemotherapy, acalabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor that disrupts cancer cell signaling, while venetoclax targets the BCL-2 protein to promote cancer cell death. This combination has the potential to be more effective and less toxic than standard chemotherapy regimens, offering a targeted therapy option that can be tailored to patients' needs. Additionally, the sequential addition of venetoclax after acalabrutinib may enhance treatment efficacy and manage side effects more effectively.

What evidence suggests that acalabrutinib and venetoclax might be effective for chronic lymphocytic leukemia?

This trial will evaluate the combination of acalabrutinib and venetoclax for treating chronic lymphocytic leukemia (CLL). Studies have shown that this combination effectively treats CLL, reducing the risk of disease progression or death by 58% compared to standard treatments. Most patients did not experience disease progression for three years. Acalabrutinib blocks certain proteins that cancer cells need to grow, while venetoclax helps kill cancer cells or stop them from multiplying. These findings suggest that using both treatments together can be highly effective against CLL. ^{1 2 3 5 6}

Who Is on the Research Team?

Mazyar Shadman

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

Adults diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma that's resistant to treatment or has returned. They must have had night sweats for over a month, relapsed after at least one therapy, and meet specific health criteria like certain blood cell counts and organ function tests. Pregnant women, those with other active cancers, significant heart issues, absorption problems, recent major surgeries, or infections like hepatitis B/C or HIV cannot join.

Inclusion Criteria

Hemoglobin >= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening)

Estimated creatinine clearance of >= 50 mL/min

I have had night sweats for over a month without being sick.

Exclusion Criteria

I have been diagnosed with progressive multifocal leukoencephalopathy.

My condition worsened while I was on venetoclax.

You have had a bad reaction or could not tolerate acalabrutinib or venetoclax in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib orally twice a day and venetoclax once daily. Acalabrutinib is given alone for the first three 28-day cycles, with venetoclax added from Cycle 4. Treatment repeats every 28 days for up to 26 cycles.

24 months

Monthly visits for 26 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 12 weeks and annually for 10 years.

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Venetoclax

Trial Overview The trial is testing the combination of two drugs: Acalabrutinib and Venetoclax in patients whose chronic lymphocytic leukemia or small lymphocytic lymphoma hasn't responded to previous treatments. The goal is to see if this drug combo can better halt cancer growth by blocking enzymes needed for cell growth and killing cancer cells.

How Is the Trial Designed?

Group I: Treatment (acalabrutinib, venetoclax) Experimental Treatment 7 Interventions

Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-28. Patients receive acalabrutinib alone for the first three 28 day cycles. 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. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, and CT or MRI throughout the trial.

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?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

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

Published Research Related to This Trial

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]

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]

In a study of 141 patients with chronic lymphocytic leukemia (CLL) treated with venetoclax, the overall response rate was 72%, indicating that venetoclax is an effective treatment option, especially for patients with mutations that typically resist other therapies like ibrutinib.

The treatment was generally well-tolerated, with 85% of patients reaching the maximum recommended dose of 400 mg daily, although some experienced adverse effects such as neutropenia (47.4%) and tumor lysis syndrome (13.4%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Mato, AR., Thompson, M., Allan, JN., et al.[2020]

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]

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 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 GLOW study, the combination of ibrutinib and venetoclax resulted in significantly higher rates of undetectable minimal residual disease (uMRD) in patients with chronic lymphocytic leukemia (CLL) compared to chlorambucil and obinutuzumab, with 40.6% and 43.4% achieving uMRD in bone marrow and peripheral blood, respectively, at 3 months after treatment.

Patients treated with ibrutinib and venetoclax maintained high progression-free survival (PFS) rates at 12 months, regardless of their MRD status, with rates of 96.3% for uMRD and 93.3% for detectable MRD, indicating that this treatment is effective even for those who do not achieve complete molecular remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study. Munir, T., Moreno, C., Owen, C., et al.[2023]

Citations

1. 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)

2. 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

3. 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.

4. 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.

5. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/ACE-CL-311

Study of Acalabrutinib (ACP-196) in combination with ... The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with ...

6. ema.europa.eu ema.europa.eu/en/documents/variation-report/calquence-h-c-005299-ii-0028-epar-assessment-report-variation_en.pdf

Calquence- INN; Acalabrutinib - European Medicines Agency The AMPLIFY study (also referred to as ACE-CL-311) was designed to assess the efficacy and safety of a fixed-duration therapy of acalabrutinib ...