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

12 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Acalabrutinib, Umbralisib, and Ublituximab for treating Mantle Cell Lymphoma?

Acalabrutinib, one of the drugs in the combination, has shown an 81% overall response rate in patients with relapsed Mantle Cell Lymphoma, according to a clinical trial. This suggests it could be a valuable treatment option for this condition. ^{1 2 3 4 5}

How is the drug combination of Acalabrutinib, Umbralisib, and Ublituximab unique for treating Mantle Cell Lymphoma?

This drug combination is unique because it includes Acalabrutinib, a highly selective Bruton tyrosine kinase inhibitor, which has shown promising results in relapsed Mantle Cell Lymphoma, and is combined with Umbralisib and Ublituximab, which may offer a novel approach by targeting different pathways involved in the disease. ^{1 2 5 6 7}

What is the purpose of this trial?

This phase II trial studies the effects of acalabrutinib, umbralisib, and ublituximab in treating previously untreated mantle cell lymphoma. Acalabrutinib and umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Ublituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib and umbralisib with ublituximab may work better in treating mantle cell lymphoma.

Research Team

Alexey V. Danilov

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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, 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 (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 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]

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]

References

1. United States 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. [2021]

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

Acalabrutinib for mantle cell lymphoma. [2021]

3. United States 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. [2023]

4. United States 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. [2021]

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

Acalabrutinib: First Global Approval. [2018]

6. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021]

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

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. [2022]