Acalabrutinib + Umbralisib + Ublituximab for Mantle Cell Lymphoma

Overseen By Alexey V Danilov

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: City of Hope Medical Center

Must not be taking: Corticosteroids, Proton pump inhibitors

Disqualifiers: Prior malignancy, Cardiovascular disease, 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: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a combination of three treatments—acalabrutinib, umbralisib, and ublituximab—to evaluate their effectiveness against mantle cell lymphoma, a cancer affecting certain white blood cells. The study aims to stop cancer cells from growing and spreading using these drugs. It seeks participants with this specific type of lymphoma who have not received prior treatment and currently require treatment. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take proton pump inhibitors, strong CYP3A4 inhibitors/inducers, or warfarin. If you're on these, you may need to switch to alternatives.

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

Research has shown that the combination of acalabrutinib, umbralisib, and ublituximab has been tested for safety in people with mantle cell lymphoma. These studies indicate that patients generally tolerate this treatment well. The most common side effects are mild to moderate, including tiredness, diarrhea, and nausea. Serious side effects are less common, but they can occur with any treatment.

The FDA has already approved acalabrutinib for certain blood cancers, indicating its safety is well understood. Umbralisib and ublituximab have also been tested in other studies and are generally manageable for many patients. Potential trial participants should discuss any concerns with their healthcare provider to understand the possible risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using the combination of acalabrutinib, ublituximab, and umbralisib for mantle cell lymphoma because it offers a novel multi-target approach. Unlike current treatments that often rely on chemotherapy, this combination includes acalabrutinib, a BTK inhibitor that disrupts cancer cell signaling, and umbralisib, a PI3K inhibitor that can block cancer cell growth pathways. Ublituximab, an anti-CD20 monoclonal antibody, works to target and destroy lymphoma cells directly. This multi-faceted strategy provides a more comprehensive attack on the cancer cells and could potentially improve outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for mantle cell lymphoma?

Research has shown that the combination of acalabrutinib, umbralisib, and ublituximab, which participants in this trial will receive, shows promise for treating mantle cell lymphoma. In one study, every patient improved, resulting in a 100% response rate. Many patients achieved complete responses, with no signs of cancer detected. The treatment also led to undetectable minimal residual disease (MRD), indicating that cancer cells were not found even at very low levels. This suggests the combination effectively stops cancer from growing and spreading. ^{1 3 4 6 7}

Who Is on the Research Team?

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with previously untreated mantle cell lymphoma who are fit enough to undergo treatment and have not had certain other cancers or major surgery recently. They must be able to use effective birth control, have adequate organ function, and cannot be on strong CYP3A4 inhibitors or proton pump inhibitors.

Inclusion Criteria

Documented informed consent of the participant and/or legally authorized representative

With bone marrow involvement: Platelets >= 30,000/mm^3

My kidneys are working well enough, as shown by a test.

Exclusion Criteria

I have chronic hepatitis B, C, or CMV but meet specific testing criteria.

I had cancer before, but it's been treated and inactive for over 2 years, or it was a minor skin cancer or in situ carcinoma without current signs of disease.

I need treatment with a strong medication that affects liver enzymes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive ublituximab IV and acalabrutinib and umbralisib orally for 6 cycles

24 weeks

Multiple visits for IV administration on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2-6

Maintenance

Patients continue treatment with ublituximab IV and acalabrutinib and umbralisib orally for 24 cycles

96 weeks

IV administration on day 1 of every other cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Ublituximab
• Umbralisib

Trial Overview The study tests a combination of acalabrutinib, umbralisib, and ublituximab in treating mantle cell lymphoma. These drugs may block enzymes that cancer cells need to grow and could prevent the spread of cancer by targeting specific proteins on the cells.

How Is the Trial Designed?

Group I: Treatment (ublituximab, acalabrutinib, umbralisib) Experimental Treatment 3 Interventions

Patients receive ublituximab IV over 90 minutes-4 hours on days 1, 8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib PO BID and umbralisib PO QD on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day 1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of unacceptable toxicity.

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?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Acalabrutinib, an oral Bruton tyrosine kinase inhibitor, has shown an impressive overall response rate of 81% in patients with relapsed mantle cell lymphoma (MCL), indicating its efficacy as a treatment option.

This novel therapy is not only approved for relapsed MCL but is also being tested as a first-line treatment, highlighting its potential to improve outcomes for patients with this challenging type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib for mantle cell lymphoma. Witzig, TE., Inwards, D.[2021]

In patients with relapsed/refractory mantle cell lymphoma (MCL) who previously failed a Bruton tyrosine kinase inhibitor, brexucabtagene autoleucel (brexu-cel) showed significantly improved overall survival compared to standard of care treatments, with hazard ratios indicating a strong survival benefit.

The analysis used multiple methods to adjust for differences in patient characteristics, consistently showing that brexu-cel led to better outcomes, highlighting its potential as an effective therapy for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Hess, G., Dreyling, M., Oberic, L., et al.[2023]

Acalabrutinib (Calquence®) has received accelerated approval from the US FDA for treating mantle cell lymphoma, based on promising results from a phase II study.

Phase III trials are currently ongoing for acalabrutinib in mantle cell lymphoma and chronic lymphocytic leukaemia, indicating its potential for broader application in treating hematological cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: First Global Approval. Markham, A., Dhillon, S.[2018]

Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, showed improved safety outcomes compared to other targeted therapies for treatment-naïve chronic lymphocytic leukemia (CLL) patients, although it was associated with a higher risk of neutropenia and leukopenia in some cases.

The analysis indicated that acalabrutinib (with or without obinutuzumab) had similar efficacy in terms of progression-free survival compared to other treatments, suggesting it is a safe and effective option for CLL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Davids, MS., Telford, C., Abhyankar, S., et al.[2021]

Acalabrutinib demonstrated significantly higher overall response rates (ORR) and complete response (CR) rates compared to other targeted therapies for relapsed/refractory mantle cell lymphoma (MCL), indicating its efficacy in treating this condition.

The safety profile of acalabrutinib was comparable or better than that of other monotherapies, although it did show increased risks of infection and anemia compared to certain combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma. Telford, C., Kabadi, SM., Abhyankar, S., et al.[2021]

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

Acalabrutinib has been approved in the EU for treating both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL), showing significant improvements in progression-free survival compared to standard therapies in two phase III trials involving adult patients.

The safety profile of acalabrutinib is generally acceptable, with common side effects including headache, diarrhea, and infections, and the overall benefit-risk ratio is considered positive for its use in CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. Delgado, J., Josephson, F., Camarero, J., et al.[2021]

Citations

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Acalabrutinib, Umbralisib and Ublituximab Regimen (AU2 ... Acalabrutinib, Umbralisib and Ublituximab Regimen (AU2) Demonstrates High Response Rate and Undetectable Molecular Minimal Residual Disease (MRD) in Patients ( ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40176303/

A chemotherapy-free regimen of acalabrutinib, umbralisib ... A chemotherapy-free regimen of acalabrutinib, umbralisib and ublituximab achieved high response rates and undetectable minimal residual disease in patients ...

3. onclive.com onclive.com/view/acalabrutinib-regimen-demonstrates-efficacy-in-de-novo-mantle-cell-lymphoma

Acalabrutinib Regimen Demonstrates Efficacy in De Novo ... The AU2 regimen achieved a 100% objective response rate with complete responses in de novo mantle cell lymphoma patients. · At 29 months follow- ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO-25-00690

Acalabrutinib Plus Bendamustine-Rituximab in Untreated ... The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged ...

5. clin.larvol.com clin.larvol.com/trial-detail/NCT04783415

Acalabrutinib, Umbralisib, and Ublituximab for the ... Acalabrutinib, Umbralisib and Ublituximab regimen (AU2) demonstrates high response rate and undetectable molecular minimal residual disease (MRD) in patients.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02793583

NCT02793583 | Study to Assess the Efficacy and Safety of ... The purpose of this study is to evaluate the efficacy and safety of umbralisib monotherapy and the umbralisib + ublituximab (U2) combination in aggressive ...

7. researchgate.net researchgate.net/publication/384856851_Acalabrutinib_umbralisib_and_ublituximab_regimen_AU2_demonstrates_high_response_rate_and_undetectable_molecular_minimal_residual_disease_MRD_in_patients_pts_with_de_novo_mantle_cell_lymphoma_MCL

Acalabrutinib, umbralisib and ublituximab regimen (AU2) ... Acalabrutinib, umbralisib and ublituximab regimen (AU2) demonstrates high response rate and undetectable molecular minimal residual disease (MRD) ...