Acalabrutinib + Venetoclax for Chronic Lymphocytic Leukemia/Lymphoma

(MAJIC Trial)

Recruiting at 40 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

607 Participants Needed

Trial Summary

What is the purpose of this trial?

A study of acalabrutinib plus venetoclax (AV) versus venetoclax plus obinutuzumab (VO) in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

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.

What makes the drug combination of Acalabrutinib, Venetoclax, and Obinutuzumab unique for treating chronic lymphocytic leukemia?

This drug combination is unique because it uses a time-limited, minimal residual disease (MRD)-guided approach, aiming to achieve deep and lasting remissions by combining the continuous therapy benefits of Acalabrutinib with the fixed-duration effectiveness of Venetoclax and Obinutuzumab. ^{1 2 3 4 5}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

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]

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 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]

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

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

3. France pubmed.ncbi.nlm.nih.gov

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

A Probabilistic Cost-Effectiveness Analysis of Venetoclax and Obinutuzumab as a First-Line Therapy in Chronic Lymphocytic Leukemia in Canada. [2023]

5. England 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. [2020]