Acalabrutinib + Venetoclax + Rituximab for Mantle Cell Lymphoma

(TrAVeRse Trial)

Not currently recruiting at 43 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AstraZeneca

Must not be taking: CYP3A4 inhibitors, Warfarin, Immunosuppressants

Disqualifiers: CNS involvement, Cardiovascular disease, 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: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—acalabrutinib, venetoclax, and rituximab—to evaluate their effectiveness for people with mantle cell lymphoma, a type of blood cancer. Researchers aim to determine if this treatment can achieve a deep remission, where no cancer cells are detectable, after 13 cycles of therapy. If successful, participants may either continue with acalabrutinib or be monitored without treatment, with the option to restart if the cancer returns. Individuals diagnosed with mantle cell lymphoma who require systemic treatment might be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong CYP3A4 inhibitors/inducers and warfarin, before starting the study. However, some medications like certain anticoagulants and low-dose corticosteroids may be allowed. It's best to discuss your specific medications with the study team.

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

Research shows that the combination of acalabrutinib, venetoclax, and rituximab (AVR) has been tested for safety in people with mantle cell lymphoma. In earlier studies, most patients tolerated this combination well, experiencing mostly mild or moderate side effects.

Common side effects included tiredness, diarrhea, and nausea. These effects are typical with many cancer treatments and were not severe for most people. Serious side effects were less common but did occur in some cases.

Overall, safety information from past studies suggests that while there are some risks, the treatment is manageable for many people. It's always important to discuss possible side effects with a doctor and decide if joining a trial is right for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Acalabrutinib, Venetoclax, and Rituximab for treating Mantle Cell Lymphoma because it targets cancer cells in a novel way compared to standard treatments like chemotherapy and R-CHOP. Acalabrutinib is a next-generation inhibitor of Bruton's tyrosine kinase (BTK), which plays a crucial role in the growth of lymphoma cells. Venetoclax works by blocking the BCL-2 protein, which helps cancer cells survive, leading them to self-destruct. Together with Rituximab, which marks cancer cells for destruction by the immune system, this combination offers a multi-pronged attack, potentially improving effectiveness and reducing the chance of resistance compared to traditional therapies.

What evidence suggests that this trial's treatments could be effective for Mantle Cell Lymphoma?

Research has shown that a combination of the drugs acalabrutinib, venetoclax, and rituximab, which participants in this trial will receive, holds promise for treating mantle cell lymphoma (MCL) without traditional chemotherapy. This combination has achieved high success rates in patients who have not previously received treatment for MCL. One study found that using acalabrutinib and venetoclax together reduced the risk of disease progression or death by 35%. This combination aims to more effectively target cancer cells, making it a strong option for treating MCL. ^{2 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed Mantle Cell Lymphoma (MCL) who need treatment and have not received any prior therapies for MCL. They should be in clinical Stage II, III, or IV, able to consent, and have at least one measurable site of disease. Participants must agree to use effective contraception and cannot join if they are pregnant or breastfeeding, have severe illnesses that could affect the study's safety or outcomes, active infections like HIV/Hepatitis B/C, other active cancers (with some exceptions), significant heart issues, or known allergies to the drugs being tested.

Inclusion Criteria

My condition is at a moderate to advanced stage and needs treatment.

My tumor samples are available for detailed genetic testing.

My cancer is confirmed as mantle cell lymphoma with specific genetic features.

Exclusion Criteria

I do not have uncontrolled autoimmune blood disorders.

Participants with a known hypersensitivity to acalabrutinib, venetoclax, or rituximab or any of the excipients of the product

Currently pregnant or breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive a combination of acalabrutinib, venetoclax, and rituximab for 13 cycles

13 cycles (each cycle is 4 weeks)

Monthly visits for drug administration and monitoring

MRD Assessment and Randomization

Participants are assessed for MRD-negative CR and randomized to continued acalabrutinib or observation

1 cycle (4 weeks)

1 visit for MRD assessment and randomization

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 67 months

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Rituximab
• Venetoclax

Trial Overview The TrAVeRse study tests a combination of Acalabrutinib plus Venetoclax and Rituximab (AVR) in treatment-naïve MCL patients. It aims to see how many achieve MRD-negative complete remission after 13 cycles of AVR. Those who do will either continue with Acalabrutinib or enter observation. If participants progress during observation, they may receive Acalabrutinib again.

How Is the Trial Designed?

Group I: Acalabrutinib + Venetoclax + Rituximab Experimental Treatment 3 Interventions

Acalabrutinib + Venetoclax + Rituximab (AVR)

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

Published Research Related to This Trial

In a multicenter study of 28 patients with untreated mantle cell lymphoma (MCL), the combination of lenalidomide, rituximab, and venetoclax demonstrated a high overall response rate of 96% and a complete response rate of 86%, indicating strong efficacy for this treatment regimen.

The treatment was found to be safe, with no dose-limiting toxicities reported, although common side effects included neutropenia and thrombocytopenia, suggesting that this combination could be a promising option for patients who are ineligible for transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma. Phillips, TJ., Bond, D., Takiar, R., et al.[2023]

In a study of 20 patients with mantle cell lymphoma (MCL), the combination of rituximab and chlorambucil (R-Chl) achieved a high overall response rate of 95%, with 90% of patients reaching complete remission (CR).

The treatment resulted in a 3-year progression-free survival rate of 89% and was well-tolerated, with no serious side effects reported, making it a promising first-line option for patients with indolent disease features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Sachanas, S., Pangalis, GA., Vassilakopoulos, TP., et al.[2019]

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]

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 involving 10 patients with relapsed/refractory chronic lymphocytic leukemia (CLL), the addition of rituximab to venetoclax therapy resulted in a 50% response rate, with three patients achieving complete responses and two achieving partial responses.

The combination treatment was well tolerated, suggesting that adding rituximab after progression on venetoclax may provide a beneficial option for some patients with R/R CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of rituximab in relapsed/refractory chronic lymphocytic leukemia after progression on venetoclax monotherapy. Handunnetti, S., Anderson, MA., Roberts, AW., et al.[2022]

Acalabrutinib, a selective BTK inhibitor, is effective for treating mantle cell lymphoma (MCL) in patients who have already undergone at least one therapy, with serious side effects being rare.

While common side effects like headaches are generally mild and resolve quickly, patients should be cautious about drug interactions and consult their physician before taking additional medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of acalabrutinib in patients with mantle cell lymphoma. Awan, FT., Jurczak, W.[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 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]

In a phase 1/2 study involving 12 Japanese patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), venetoclax demonstrated a 100% objective response rate (ORR) in patients receiving monotherapy, with a complete remission (CR) rate of 17%.

When combined with rituximab, venetoclax achieved a 67% ORR and a 50% CR rate, indicating that both treatment strategies are effective and well-tolerated, with a safety profile consistent with previous studies in Western populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 study of venetoclax, a BCL-2 inhibitor, in Japanese patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Izutsu, K., Yamamoto, K., Kato, K., et al.[2021]

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]

Citations

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

Acalabrutinib plus venetoclax and rituximab in treatment-naive ... Acalabrutinib plus venetoclax and rituximab resulted in high clinical and molecular response rates in patients with TN MCL. This chemotherapy-free, targeted ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05951959

NCT05951959 | A Study of Acalabrutinib Plus Venetoclax ... This study aims to evaluate the efficacy of a chemotherapy-free triplet combination regimen of a Bruton's Tyrosine Kinase-inhibitor (acalabrutinib), a BCL2 ...

3. astrazeneca.com astrazeneca.com/content/astraz/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 ... At a median follow up of 41 months, results showed Calquence plus venetoclax reduced the risk of disease progression or death by 35% compared to ...

4. mdpi.com mdpi.com/2072-6694/17/11/1889

A Triple Oral Combination of Bendamustine, Acalabrutinib ... More recently, a study demonstrated that the incorporation of ACAL with Bendamustine and rituximab significantly improved PFS in transplant-ineligible patients ...

5. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(22)00237-3/fulltext

Treatment Landscape of Relapsed/Refractory Mantle Cell ... The incidence of clinical TLS was 3.7%. These data indicate that venetoclax has poor outcomes in late disease stages and its role may be better ...

6. 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).

7. 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).

8. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2025/fixed-duration-calquence-approved-in-eu-for-1l-cll.html

Fixed-duration Calquence-based regimens approved in ... Calquence plus venetoclax with obinutuzumab demonstrated a 58% reduction in the risk of disease progression or death compared to ...