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

Trial Summary

What is the purpose of this trial?

This phase II trial is to evaluate the effects of acalabrutinib in combination with venetoclax in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that does not respond to treatment (refractory) or that has come back (recurrent). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as venetoclax, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Given acalabrutinib and venetoclax may kill more cancer cells.

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.

What data supports the effectiveness of the drug combination Acalabrutinib and Venetoclax for treating Chronic Lymphocytic Leukemia?

Research shows that Venetoclax, when used with other drugs like obinutuzumab, is effective in treating Chronic Lymphocytic Leukemia (CLL), leading to longer periods without disease progression and higher rates of undetectable cancer cells. Acalabrutinib has also been effective in continuous therapy for CLL, suggesting that the combination of these drugs could be beneficial. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and Venetoclax safe for treating Chronic Lymphocytic Leukemia?

Venetoclax, when used for Chronic Lymphocytic Leukemia, has shown an acceptable safety profile, with manageable side effects like neutropenia (low white blood cell count) and tumor lysis syndrome (a rapid release of cell contents into the blood). Acalabrutinib, when combined with Venetoclax and obinutuzumab, has been studied as a treatment for CLL, suggesting it is generally safe, but specific safety data for the Acalabrutinib and Venetoclax combination alone is limited. ^{1 2 3 4 6}

How is the drug combination of Acalabrutinib and Venetoclax unique for treating chronic lymphocytic leukemia?

The combination of Acalabrutinib and Venetoclax is unique because it offers a time-limited, minimal residual disease (MRD)-guided approach that aims to achieve deep and lasting remissions in patients with chronic lymphocytic leukemia. This approach is different from continuous therapies and focuses on achieving undetectable MRD, which can lead to better long-term outcomes. ^{1 2 3 4 7}

Research Team

Mazyar Shadman

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. [2021]

2. France pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

5. United States 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. [2023]

6. Italy pubmed.ncbi.nlm.nih.gov

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Real-world evidence on venetoclax in chronic lymphocytic leukemia: The Italian experience. [2023]