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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two medications, venetoclax and acalabrutinib, to evaluate their combined effectiveness in treating mantle cell lymphoma—a type of cancer that hasn't responded to past treatments or has returned. Venetoclax kills cancer cells by blocking their survival mechanisms, while acalabrutinib (also known as Calquence) inhibits their growth by interfering with necessary enzymes. The trial seeks participants previously treated for mantle cell lymphoma who need further treatment because their disease has returned or didn’t respond before. As a Phase 2 trial, this 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 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.

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

Research shows that patients generally tolerate the combination of venetoclax and acalabrutinib well. In a study with a similar treatment, most patients managed without serious side effects. The most common issues were mild, such as fatigue or slight digestive problems, while serious side effects were rare.

Acalabrutinib is already approved for treating other blood cancers, confirming its safety. Venetoclax has also been used safely for other conditions. Another study demonstrated promising results with manageable side effects when using acalabrutinib and venetoclax together. This suggests that patients with mantle cell lymphoma might experience similar safety outcomes. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for mantle cell lymphoma?

Researchers are excited about the combination of acalabrutinib and venetoclax for treating Mantle Cell Lymphoma because it offers a novel approach compared to standard chemotherapy and immunotherapy options. Acalabrutinib is a targeted therapy that inhibits Bruton's tyrosine kinase, which plays a crucial role in the growth of cancer cells. Venetoclax works by targeting and blocking the BCL-2 protein, which helps cancer cells survive. This combination aims to more effectively kill cancer cells by attacking them through two different pathways, potentially leading to better outcomes with fewer side effects than traditional treatments.

What evidence suggests that venetoclax and acalabrutinib might be effective for mantle cell lymphoma?

Research has shown that using venetoclax and acalabrutinib together may effectively treat mantle cell lymphoma. In this trial, participants will receive a combination of these two drugs. Venetoclax blocks a process that cancer cells use to survive, causing them to die. Acalabrutinib stops cancer cells from growing by blocking certain necessary enzymes. Studies have found that this combination can kill more cancer cells in patients with mantle cell lymphoma. Additionally, this approach has demonstrated the ability to shrink or eliminate tumors while keeping side effects manageable. ^{2 6 7 8 9}

Who Is on the Research Team?

Luhua (Michael) Wang

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38781315/

Acalabrutinib plus venetoclax and rituximab in treatment- ... This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL).

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03946878

NCT03946878 | Venetoclax and Acalabrutinib in Treating ... Giving venetoclax and acalabrutinib together may kill more cancer cells in patients with mantle cell lymphoma. Detailed Description. PRIMARY OBJECTIVES: I ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6355471/

Efficacy of venetoclax monotherapy in patients with relapsed ... Although ibrutinib monotherapy provides significant efficacy [overall response rate (ORR), 68%; complete response rate, 21%; partial response rate, 47%] and is ...

4. ashpublications.org ashpublications.org/bloodadvances/article/8/17/4539/516190/Acalabrutinib-plus-venetoclax-and-rituximab-in

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL).

5. onclive.com onclive.com/view/acalabrutinib-plus-venetoclax-obinutuzumab-demonstrates-efficacy-safety-in-mantle-cell-lymphoma

Acalabrutinib Plus Venetoclax/Obinutuzumab ... - OncLive Acalabrutinib plus venetoclax and obinutuzumab demonstrated antitumor activity with a manageable safety profile in mantle cell lymphoma.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11399641/

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL).

7. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-acalabrutinib-plus-venetoclax-with-or-without-obinutuzumab-significantly-improved-progression-free-survival-in-first-line-chronic-lymphocytic-leukemia-in-amplify-phase-iii-trial.html

Fixed-duration CALQUENCE® (acalabrutinib) plus ... Favorable trend in overall survival was also observed. Positive high-level results from an interim analysis of the AMPLIFY Phase III trial ...

8. 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

9. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124011121

Seven-year outcomes of venetoclax-ibrutinib therapy in ... In relapsed MCL, venetoclax-ibrutinib achieves 7-year PFS of 30%, TTF of 39%, OS of 43%, and durable remissions in 10 of 17 responders.