Acalabrutinib + Venetoclax for Chronic Lymphocytic Leukemia/Lymphoma

(MAJIC Trial)

Not currently recruiting at 43 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: PPIs, Warfarin, CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, Active bleeding, Hepatitis, 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: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatment combinations for individuals with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received prior treatment. One group will receive acalabrutinib (a targeted therapy) and venetoclax, while the other group will receive venetoclax and obinutuzumab. The researchers aim to determine which combination more effectively manages the condition. The trial seeks participants diagnosed with CLL or SLL who require treatment according to specific guidelines and have not yet undergone any treatment. This Phase 3 trial, the final step before FDA approval, offers a chance to access potentially effective treatments early.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, such as strong CYP3A4 inhibitors/inducers, warfarin, and proton pump inhibitors. If you are on these, you may need to switch to alternatives. It's best to discuss your current medications with the trial team to see if any changes 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 patients. Most experience mild to moderate side effects, such as headaches and diarrhea, while serious side effects are less common.

For the venetoclax and obinutuzumab combination, studies have shown similar results. Most side effects are mild, like fatigue or nausea, though serious side effects can occur less frequently.

Both treatments have been tested in individuals with chronic lymphocytic leukemia (CLL) and appear safe for most patients. Discussing any concerns with a doctor is important, as individual experiences may vary. ^{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 innovative approaches to tackling the disease. Unlike traditional chemotherapy, which can have widespread effects on the body, Acalabrutinib and Venetoclax work by directly targeting specific proteins that CLL cells need to survive. Acalabrutinib inhibits Bruton's tyrosine kinase (BTK), a protein crucial for cancer cell growth, while Venetoclax blocks BCL-2, a protein that helps cancer cells avoid death. Additionally, the combination of Venetoclax with Obinutuzumab, an antibody that targets the CD20 protein on cancer cells, provides a unique one-two punch by directly attacking the cells and marking them for destruction by the immune system. These targeted therapies not only promise to be more effective but also have the potential for fewer side effects compared to conventional treatments.

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

Research shows that using acalabrutinib and venetoclax together, which participants in Arm A of this trial will receive, may effectively treat chronic lymphocytic leukemia (CLL). Studies found that this combination reduced the risk of disease progression or death by 58% compared to standard treatments. As a result, patients were much less likely to experience disease worsening or face serious health issues. Additionally, participants in Arm B of this trial will receive venetoclax with obinutuzumab, which has also shown positive results. Specifically, it improved survival rates compared to traditional chemoimmunotherapy, offering a more effective initial treatment for CLL. Both treatment combinations in this trial have shown potential in improving outcomes for patients with this type of leukemia. ^{1 2 4 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma who need treatment. Participants must have good bone marrow and liver function, a certain level of kidney function, and be in stable health. They can't join if they've had previous CLL/SLL treatments (except some rituximab), stem cell transplants, significant heart issues within the last 6 months, active infections like HIV or hepatitis B/C, or other conditions that could affect safety.

Inclusion Criteria

Meet specific laboratory parameters

I can swallow pills without any trouble and can follow the study's procedures.

My physical ability hasn't worsened in the last 2 weeks.

Exclusion Criteria

Concurrent participation in another therapeutic clinical trial

Serologic status reflecting active hepatitis B or C infection

Known history of hypersensitivity or anaphylaxis to study intervention(s)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Treatment

Participants receive either Acalabrutinib plus Venetoclax (AV) or Venetoclax plus Obinutuzumab (VO) based on randomization

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6.6 years

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Obinutuzumab
• Venetoclax

Trial Overview The study compares two drug combinations: Acalabrutinib plus Venetoclax (AV) versus Venetoclax plus Obinutuzumab (VO). It aims to determine which combination works better for patients who haven't been treated before for their blood cancer.

How Is the Trial Designed?

Group I: Arm B: Venetoclax plus Obinutuzumab (VO) Experimental Treatment 2 Interventions

Participants will receive Venetoclax orally and Obinutuzumab via IV infusion.

Group II: Arm A: Acalabrutinib plus Venetoclax (AV) Experimental Treatment 2 Interventions

Participants will receive acalabrutinib and venetoclax orally.

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?

AstraZeneca

Lead 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]

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]

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]

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]

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. clinicaltrials.gov clinicaltrials.gov/study/NCT04941716

Study Details | NCT04941716 | Acalabrutinib in ... This phase II trial is to evaluate the effects of acalabrutinib in combination with venetoclax in treating patients with chronic lymphocytic leukemia or ...

7. 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 Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least ...