Venetoclax + Acalabrutinib for Mantle Cell Lymphoma

Overseen By Preetesh Jain, MD,DM, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, 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: Unknown

Duration: 16 weeks

32 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require certain medications like strong CYP3A or CYP1A2 inhibitors, or if you need anticoagulation with warfarin. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Venetoclax and Acalabrutinib for Mantle Cell Lymphoma?

Research shows that Venetoclax is effective in relapsed Mantle Cell Lymphoma (MCL) with a 50% overall response rate, and Acalabrutinib has shown effectiveness in chronic lymphocytic leukemia, suggesting potential benefits when combined for MCL. ^{1 2 3 4 5}

Is the combination of Venetoclax and Acalabrutinib safe for treating Mantle Cell Lymphoma?

Venetoclax has been generally well tolerated in patients with various types of lymphoma, including Mantle Cell Lymphoma, with most side effects being mild to moderate. Common serious side effects include low blood cell counts, which can be managed with dose adjustments and supportive care. ^{1 3 5 6 7}

How does the drug combination of Venetoclax and Acalabrutinib differ from other treatments for mantle cell lymphoma?

The combination of Venetoclax and Acalabrutinib for mantle cell lymphoma is unique because it targets two different pathways: Venetoclax inhibits BCL2, a protein that helps cancer cells survive, while Acalabrutinib inhibits BTK, a protein involved in cancer cell growth. This dual approach may offer a new option for patients, especially those who have relapsed or are resistant to other treatments. ^{3 5 6 7 8}

What is the purpose of this trial?

This phase II trial studies how well venetoclax and acalabrutinib work in treating patients with mantle cell lymphoma that did not respond to previous treatment or has come back. Venetoclax may cause cancer cell death by blocking the mechanism that cancer cells use to stay alive. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving venetoclax and acalabrutinib together may kill more cancer cells in patients with mantle cell lymphoma.

Research Team

Luhua (Michael) Wang

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults over 18 with mantle cell lymphoma that has returned or didn't respond to past treatments. Participants must have measurable disease, be able to swallow pills, and have normal organ function tests. Pregnant women, those with HIV or active hepatitis, and individuals who've had certain other cancers or major surgery recently can't join.

Inclusion Criteria

I can take part in all study activities and can swallow pills without trouble.

I have not had my uterus or both ovaries removed.

Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involved with lymphoma, independent of transfusion support in either situation.

Exclusion Criteria

Pregnant or breast-feeding females.

a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Those who are HbsAg-positive or hepatitis B PCR positive will be excluded. b. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive acalabrutinib orally twice daily on days 1-28. Starting cycle 2 day 1, patients also receive venetoclax daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs within 30 days, then every 4 months for 2 years, every 6 months for the next 2 years, and then annually thereafter.

5 years

Treatment Details

Interventions

• Acalabrutinib
• Venetoclax

Trial Overview The study is testing the combination of two drugs: Venetoclax and Acalabrutinib in patients with relapsed/refractory mantle cell lymphoma. Venetoclax aims to block cancer cells' survival mechanisms while Acalabrutinib may halt their growth by inhibiting necessary enzymes.

Participant Groups

Group I: Treatment (acalabrutinib, venetoclax) Experimental Treatment 2 Interventions

Patients receive acalabrutinib PO BID on days 1-28. Starting cycle 2 day 1, patients also receive venetoclax PO daily. Cycles repeat every 28 days in the absence of disease progression or 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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

The combination of venetoclax (VEN) and ibrutinib (IBR) showed a high overall response rate of 93.8% at the optimal dosing of VEN 200 mg and IBR 420 mg in treating relapsed mantle cell lymphoma (MCL) among 35 participants.

The study found that higher doses of VEN and IBR did not improve efficacy and were associated with increased toxicity, highlighting the importance of dose optimization in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. Portell, CA., Wages, NA., Kahl, BS., et al.[2022]

In a study of 24 patients with relapsed mantle cell lymphoma (MCL) who had undergone multiple prior therapies, venetoclax treatment resulted in a 50% overall response rate and a 21% complete response rate, with a median follow-up of 17 months.

Genomic analysis revealed that resistance to venetoclax is linked to mutations in non-BCL2 genes, with specific alterations like SMARCA4 and KMT2C/D emerging after treatment progression, indicating a need for further research into combination therapies and the mechanisms of resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. Zhao, S., Kanagal-Shamanna, R., Navsaria, L., et al.[2020]

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 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 a phase I trial involving 106 patients with various subtypes of non-Hodgkin lymphoma, venetoclax, a BCL-2 inhibitor, was found to be generally well tolerated, with a 44% overall response rate across different lymphoma types.

The study identified 1,200 mg as the recommended dose for future studies in follicular lymphoma and diffuse large B-cell lymphoma, while 800 mg was effective for mantle cell lymphoma, indicating varying efficacy based on lymphoma subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. Davids, MS., Roberts, AW., Seymour, JF., et al.[2018]

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, a BCL2-targeting drug, shows promising anticancer activity in mantle cell lymphoma (MCL), but resistance mechanisms involving proapoptotic proteins BIM and NOXA complicate its effectiveness.

Combining venetoclax with the MCL1 inhibitor S63845 resulted in synthetic lethality in patient-derived xenografts of relapsed MCL, suggesting this combination could be a novel treatment strategy for patients with chemoresistant MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. Prukova, D., Andera, L., Nahacka, Z., et al.[2020]

References

1. France pubmed.ncbi.nlm.nih.gov

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

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

Dose-finding study of ibrutinib and venetoclax in relapsed or refractory mantle cell lymphoma. [2022]

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

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients. [2020]

4. 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]

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

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

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

Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma. [2018]

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

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

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

Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma. [2020]