Acalabrutinib + Lenalidomide + Rituximab for Mantle Cell Lymphoma

Overseen By Rita Vaccaro, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Must be taking: Aspirin, Antivirals

Must not be taking: CYP3A4 inhibitors, Warfarin

Disqualifiers: Blastoid histology, CNS involvement, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment options for people with mantle cell lymphoma, a type of blood cancer. Researchers are testing two drug combinations: one includes acalabrutinib (a type of targeted therapy), lenalidomide, and rituximab, while the other uses acalabrutinib, lenalidomide, and obinutuzumab. The goal is to assess the effectiveness and safety of these combinations in treating the condition. Individuals who have never received systemic therapy for mantle cell lymphoma and have a measurable tumor might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 proton pump inhibitors, before starting the study drugs. If you are on moderate CYP3A inhibitors, you may need a 7-day washout period (time without taking these medications) before joining the trial.

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

Research has shown that the combination of acalabrutinib, lenalidomide, and rituximab (ALR) is generally well-tolerated by patients with certain types of lymphoma. In earlier studies, patients experienced manageable side effects, allowing most to continue treatment. Common side effects included tiredness, low blood cell counts, and mild infections, while serious side effects were less common.

For the combination of acalabrutinib, lenalidomide, and obinutuzumab (ALO), similar safety results have been observed. Patients also experienced manageable side effects, such as low blood cell counts and mild infections.

Both combinations are currently in a phase 2 study, indicating they have shown some safety in earlier research. This phase aims to further assess their effectiveness and safety in a larger group of people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for mantle cell lymphoma because they offer a novel approach by combining acalabrutinib, lenalidomide, and rituximab (or obinutuzumab). Unlike traditional chemotherapy-based treatments, this combination targets specific pathways in cancer cells. Acalabrutinib is a Bruton's tyrosine kinase (BTK) inhibitor, which interferes with cancer cell growth and survival. Lenalidomide modulates the immune system to attack cancer cells, while rituximab and obinutuzumab are monoclonal antibodies that specifically target and destroy lymphoma cells. This multi-faceted strategy could potentially enhance treatment effectiveness and offer new hope for patients with this challenging type of lymphoma.

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

Research has shown that the combination of acalabrutinib, lenalidomide, and rituximab (ALR), which participants in this trial may receive, yields promising results for treating mantle cell lymphoma. Previous studies have found that this combination can provide long-lasting benefits for patients with this type of cancer. One study found that this treatment, even without traditional chemotherapy, is very effective. Additionally, the pair of lenalidomide and rituximab, part of the ALR combination, has succeeded as an initial treatment for this condition. Overall, these findings suggest that ALR could be a strong option for treating mantle cell lymphoma.

In another part of this trial, the combination of acalabrutinib, lenalidomide, and obinutuzumab (ALO) is being tested. While less data exists on this exact combination, acalabrutinib and lenalidomide have been effective in similar situations. Obinutuzumab, like rituximab, is an antibody used in cancer treatments and has proven effective in other types of lymphomas. This suggests that ALO may also be a promising treatment for mantle cell lymphoma, though more research is needed. ^{1 2 4 6 7}

Who Is on the Research Team?

Jia Ruan, M.D., Ph.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

This trial is for adults with untreated mantle cell lymphoma who need treatment, have good liver and kidney function, can follow the study schedule, and agree to use birth control. People with certain heart conditions, active infections like HIV or hepatitis B/C, recent major surgery, other cancers within 5 years (except some skin or localized cancers), or those on specific medications are excluded.

Inclusion Criteria

Understand and voluntarily sign an ICF prior to any study related assessments and procedures are conducted

I am registered and can follow the Revlimid REMS program.

I can take care of myself and do some daily activities.

Exclusion Criteria

I have a condition that affects how my body absorbs food.

I am at high risk for blood clots and refuse to take preventive medication.

I do not have a bleeding disorder like hemophilia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive 12 cycles of acalabrutinib, lenalidomide, and rituximab (ALR) treatment

12 months

Monthly visits for each cycle

Maintenance

Responding subjects continue maintenance ALR until disease progression, unacceptable toxicity, or withdrawal

Until disease progression or withdrawal

Follow-up

Participants are monitored every 6 months for alternate anti-cancer therapy and survival

4 years

Biannual visits

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Lenalidomide
• Rituximab

Trial Overview The trial tests a combination of acalabrutinib, lenalidomide and rituximab (ALR) in patients with untreated mantle cell lymphoma over an induction phase of 12 cycles followed by maintenance therapy until disease progression or unacceptable side effects occur. The effectiveness and safety of this regimen will be monitored throughout the study.

How Is the Trial Designed?

Group I: ALR in Combination Experimental Treatment 3 Interventions

Acalabrutinib, lenalidomide, and rituximab in combination

Group II: ALO in Combination Experimental Treatment 3 Interventions

Acalabrutinib, lenalidomide and obinutuzumab in combination

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?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Celgene Corporation

Industry Sponsor

Trials

446

Recruited

58,500+

Mark Alles

Celgene Corporation

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Sol J. Barer

Celgene Corporation

Chief Medical Officer since 2006

PhD in Organic and Physical Chemistry from Rutgers University

AstraZeneca

Industry 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 phase 2 trial involving 124 patients with relapsed or refractory mantle cell lymphoma, acalabrutinib was associated with common treatment-related adverse events (AEs) like headache and diarrhea, but these did not lead to any treatment discontinuations.

Effective management strategies, including patient education and the use of over-the-counter medications for mild AEs, helped maintain treatment adherence and allowed for better tracking and management of nonadherence issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. Badillo, M., Nava, D., Rosa, M., et al.[2022]

Bruton's tyrosine kinase inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are effective and well-tolerated treatment options for patients with mantle cell lymphoma who have already undergone one line of therapy.

These inhibitors offer a promising alternative for patients who experience relapse or drug resistance after initial chemo-immunotherapy, highlighting the need for novel treatment strategies in this aggressive lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma. Hanna, KS., Campbell, M., Husak, A., et al.[2021]

In a phase 2 trial involving 50 patients with relapsed or refractory mantle cell lymphoma, the combination of ibrutinib, lenalidomide, and rituximab resulted in a high overall response rate of 76%, with 56% achieving a complete response, suggesting this triplet therapy is effective.

While the treatment showed promising efficacy, it was associated with significant adverse events, including neutropenia in 38% of patients and three treatment-related deaths, highlighting the need for careful monitoring and further evaluation in randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. Jerkeman, M., Eskelund, CW., Hutchings, M., et al.[2022]

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]

The maximum tolerated dose (MTD) of lenalidomide when combined with rituximab for treating relapsed or refractory mantle-cell lymphoma (MCL) was determined to be 20 mg, with the combination showing a manageable safety profile despite some grade 3-4 hematological toxicities.

In a phase 2 trial involving 44 patients, the combination therapy resulted in a 57% overall response rate, with 36% achieving a complete response and a median overall survival of 24.3 months, indicating its efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Wang, M., Fayad, L., Wagner-Bartak, N., et al.[2023]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10981676/

Combination of acalabrutinib with lenalidomide and rituximab ... Another clinical trial on R2A for mantle cell lymphoma reported hematologic toxicity in up to 38% of patients. Notably, in our study, the ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/746/530366/MRD-Driven-Time-Limited-Therapy-of-Acalabrutinib

MRD-Driven Time-Limited Therapy of Acalabrutinib and ... We previously reported durable efficacy of the lenalidomide and rituximab (LR) regimen as frontline MCL therapy (NEJM 2015:373:1835; Blood 2018: ...

3. clinicaltrials.gov clinicaltrials.gov/show/NCT03863184

Acalabrutinib-Lenalidomide-Rituximab in Patients With ... This is a multi-arm phase 2 study to evaluate the preliminary evidence of efficacy and safety of the combination of acalabrutinib, lenalidomide and rituximab ( ...

4. nature.com nature.com/articles/s41467-025-62509-z

Frontline acalabrutinib, lenalidomide and rituximab for ... This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with ...

5. youtube.com youtube.com/watch?v=G5pzbyg97Cs

A trial of acalabrutinib, lenalidomide, and rituximab or ... There's more and more evidence suggesting that novel agents combination without chemotherapy has been very effective.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05214183

NCT05214183 | Acalabrutinib and Rituximab in Elderly ... This is a phase II trial, with the aim of developing a chemotherapy-free regimen for untreated patients with mantle cell lymphoma (MCL).

7. 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 ...