Acalabrutinib + Venetoclax + Durvalumab for Richter Syndrome

Recruiting at 2 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Proton pump inhibitors

Disqualifiers: Cardiovascular disease, Uncontrolled infection, Autoimmune disorders, 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: 106

Duration: 12 months

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of three treatments—acalabrutinib, venetoclax, and durvalumab—to determine their effectiveness in treating Richter transformation, a rare and aggressive lymphoma that develops from chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Acalabrutinib and venetoclax block proteins essential for cancer cell survival, while durvalumab aids the immune system in attacking the cancer. The trial seeks participants diagnosed with Richter transformation from CLL or SLL who have noticeable symptoms visible in scans. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking a strong CYP3A inhibitor or inducer, or a proton pump inhibitor, you may need to switch to an alternative medication before starting the trial.

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

Research has shown that acalabrutinib, venetoclax, and durvalumab are generally safe. Acalabrutinib is usually well-tolerated, with manageable side effects like headaches and diarrhea. Venetoclax, already FDA-approved for other uses, is known to be safe, especially when the dose is increased slowly to prevent tumor lysis syndrome, a serious condition that occurs when cancer cells break down too quickly. Studies have reported that gradually increasing the daily dose of venetoclax has been safe, with no cases of tumor lysis syndrome. Durvalumab, an immunotherapy drug, is also considered safe, though it may cause immune-related side effects, such as tiredness or skin rash.

These findings suggest that using these treatments together might also be safe for most people. However, since they are combined in this trial, monitoring for any new or unexpected side effects is important. Participants should discuss potential risks with their healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of acalabrutinib, venetoclax, and durvalumab for treating Richter Syndrome because it targets the disease in a novel way. Unlike traditional chemotherapy, which broadly attacks fast-growing cells, acalabrutinib is a BTK inhibitor that specifically disrupts cancer cell signaling, potentially reducing side effects. Venetoclax works by inducing cancer cell death by blocking a protein called BCL-2, which helps cancer cells survive. Durvalumab is an immunotherapy that boosts the body's immune response against cancer cells. This multi-pronged approach offers a promising new strategy that could improve outcomes for patients with Richter Syndrome.

What evidence suggests that acalabrutinib, venetoclax, and durvalumab could be effective for Richter transformation?

In this trial, participants will receive a combination of acalabrutinib, venetoclax, and durvalumab to treat Richter transformation, a serious type of lymphoma. Research has shown that these drugs might work well together. Specifically, studies found that venetoclax-based treatments led to higher complete remission rates, ranging from 25% to 38%. Acalabrutinib blocks certain enzymes that help cancer cells grow, while venetoclax targets a protein called Bcl-2, which cancer cells need to survive. Durvalumab enhances the immune system's ability to attack cancer cells. Together, these treatments may improve survival for patients with this rare and fast-growing lymphoma. ^{1 4 5 6 7}

Who Is on the Research Team?

Paul J. Hampel, M.D.

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

Adults diagnosed with Richter transformation from chronic lymphocytic leukemia or small lymphocytic lymphoma can join this trial. They must have a certain level of physical fitness, no pregnancy, and agree to use effective contraception. People who've had recent heart issues, uncontrolled infections, autoimmune diseases without remission for 3 years (except stable hypothyroidism), active pneumonitis, CNS involvement by cancer requiring therapy, or those on strong CYP3A inhibitors/inducers are excluded.

Inclusion Criteria

Negative pregnancy test for women of childbearing potential

Provide informed written consent

Use of highly effective contraception methods for sexually active patients

Exclusion Criteria

Life expectancy < 12 weeks

I recently had a stem cell transplant or have chronic GVHD.

I do not have uncontrolled heart problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib, venetoclax, and durvalumab. Treatment repeats every 28 days for 12 cycles.

12 months

Monthly visits for 12 cycles

Maintenance

Participants receive acalabrutinib and venetoclax. Treatment repeats every 90 days for 4 cycles.

12 months

Quarterly visits for 4 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 5 years

Every 90 days until 5 years from study enrollment

What Are the Treatments Tested in This Trial?

Interventions

• Acalabrutinib
• Durvalumab
• Venetoclax

Trial Overview The trial is testing the combination of acalabrutinib (blocks enzymes for cell growth), venetoclax (BCL-2 inhibitor stopping cancer cell survival), and durvalumab (monoclonal antibody boosting immune attack on cancer). It aims to see if this combo improves survival in patients with fast-growing types of lymphoma developed from other blood cancers.

How Is the Trial Designed?

Group I: Treatment (acalabrutinib, durvalumab, venetoclax) Experimental Treatment 8 Interventions

Patients receive acalabrutinib PO BID on days 1-28, durvalumab IV over 1 hour on day 1, and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive acalabrutinib PO BID and venetoclax PO QD on days 1-90 of each cycle. Cycles repeat every 90 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy, and PET/CT or CT throughout the study.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) was found to be safe for patients with castration-resistant prostate cancer (CRPC), with no serious treatment-related adverse events reported and only mild skin reactions observed.

The treatment successfully boosted immune responses in a significant portion of patients, with 67% showing enhanced cytotoxic T lymphocyte responses, and a median survival time of 23.8 months, suggesting promising antitumor activity that warrants further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer. Noguchi, M., Uemura, H., Naito, S., et al.[2013]

The TroVax Renal Immunotherapy Survival Trial, involving 733 patients with metastatic renal cell cancer, found that the MVA-5T4 vaccine combined with standard-of-care treatments did not significantly improve overall survival compared to placebo (20.1 months vs. 19.2 months).

Despite no overall survival benefit, the study indicated that a stronger antibody response to the 5T4 antigen from the vaccine was linked to better survival, suggesting that certain patient subgroups may benefit more from this treatment, warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. Amato, RJ., Hawkins, RE., Kaufman, HL., et al.[2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

Durvalumab, an immune checkpoint inhibitor used for treating advanced cancers, can cause rare but serious side effects like myocarditis and complete heart block, as seen in a case involving a 71-year-old male patient.

Corticosteroid treatment, specifically methylprednisolone, showed some effectiveness in reducing troponin levels associated with myocarditis, but the patient ultimately required a permanent pacemaker due to persistent heart conduction issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab-Associated Myocarditis Initially Presenting With Sinus Bradycardia Progressing Into Complete Heart Block. Bae, S., Vaysblat, M., Ng, J., et al.[2023]

Re-treatment with radium-223 in patients with castration-resistant prostate cancer and bone metastases was well tolerated, with no new safety concerns or serious drug-related adverse events reported during a 2-year follow-up of 44 patients.

The treatment provided continued disease control, with a median radiographic progression-free survival of 9.9 months and a median overall survival of 24.4 months, indicating its efficacy in managing disease progression in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Re-treatment with radium-223: 2-year follow-up from an international, open-label, phase 1/2 study in patients with castration-resistant prostate cancer and bone metastases. Sartor, O., Heinrich, D., Mariados, N., et al.[2021]

In a study of 57 patients with castration-resistant prostate cancer, personalized peptide vaccination (PPV) combined with low-dose estramustine phosphate (EMP) significantly improved progression-free survival (PFS) compared to standard-dose EMP, with a median PFS of 8.5 months versus 2.8 months.

The combination of PPV and low-dose EMP was well tolerated, showing no major adverse effects and enhancing immune responses, indicating it could be a safer and more effective treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer. Noguchi, M., Kakuma, T., Uemura, H., et al.[2020]

RNA sequencing of circulating tumor cells (CTCs) from patients treated with abiraterone or enzalutamide revealed mutations in the androgen receptor and identified the TGFβ and cyclin D1 signaling pathways as key players in resistance to these therapies.

Targeting the downstream effects of SMAD3 and CCND1 may offer new treatment strategies for patients with metastatic castration-resistant prostate cancer who develop resistance to current androgen receptor-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of mechanisms of resistance to treatment with abiraterone acetate or enzalutamide in patients with castration-resistant prostate cancer (CRPC). Pal, SK., Patel, J., He, M., et al.[2021]

A 67-year-old male with lung squamous cell carcinoma developed myocarditis after receiving durvalumab, a PD-L1 inhibitor, highlighting the potential for serious cardiac side effects from this treatment.

The patient's myocarditis led to a significant decrease in heart function but improved rapidly with glucocorticoid therapy, suggesting that timely intervention can effectively manage this rare but severe adverse event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma. Zhou, B., Li, M., Chen, T., et al.[2022]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

The ADRIATIC study is a phase III clinical trial investigating the efficacy of durvalumab, with or without tremelimumab, as a consolidation therapy for patients with limited-stage small-cell lung cancer (LS-SCLC) who have not progressed after standard chemotherapy and radiotherapy, involving around 600 participants.

The primary goals of the study are to assess progression-free survival and overall survival, aiming to improve outcomes for LS-SCLC patients, who currently face high rates of relapse after standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Rationale for a Phase III, Randomized, Placebo-controlled Trial of Durvalumab With or Without Tremelimumab After Concurrent Chemoradiotherapy for Patients With Limited-stage Small-cell Lung Cancer: The ADRIATIC Study. Senan, S., Okamoto, I., Lee, GW., et al.[2021]

A case of acral vasculitis was reported following treatment with a combination of anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) in a patient with metastatic urothelial bladder cancer, highlighting a potential side effect of these immunotherapies.

Unlike previous reports, this case showed significant improvement with the use of oral corticosteroids, suggesting a possible effective treatment strategy for managing vasculitis induced by these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitor-related acral vasculitis. Comont, T., Sibaud, V., Mourey, L., et al.[2019]

Durvalumab, an immune checkpoint inhibitor, combined with chemotherapy, was effective in treating a 62-year-old female patient with extensive-stage small-cell lung cancer (ES-SCLC) and preexisting Lambert-Eaton myasthenic syndrome (LEMS), achieving nearly complete response without worsening her LEMS symptoms.

The treatment led to a significant decrease in the titer of anti-P/Q-type voltage-gated calcium channel antibodies, suggesting that ICI therapy may not only be safe but could also improve symptoms of preexisting paraneoplastic syndromes like LEMS in patients with ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome. Machiyama, H., Minami, S.[2023]

The combination of the FRα vaccine TPIV200 and the PD-L1 inhibitor durvalumab was well tolerated in 27 patients with advanced platinum-resistant ovarian cancer, showing a low grade 3 toxicity rate of 18.5%.

While the overall response rate was low (3.7% partial response and 33.3% stable disease), the median overall survival was notably long at 21 months, suggesting potential benefits from this immunotherapy approach in a heavily pretreated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial. Zamarin, D., Walderich, S., Holland, A., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05388006

Study Details | NCT05388006 | Acalabrutinib, Venetoclax ... Giving acalabrutinib, venetoclax, and durvalumab may help improve survival in patients with Richter transformation. Detailed Description. PRIMARY OBJECTIVE: I.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11127193/

A multicenter study of venetoclax-based treatment for ... In this retrospective study, venetoclax-based combination regimens led to higher complete remission rates (25%-38%) than historical studies.

3. ckb-core.genomenon.com ckb-core.genomenon.com/therapy/show/13570

Therapy Detail - CKB CORE - Genomenon Calquence (acalabrutinib) selectively inhibits BTK, resulting in decreased B-cell receptor signaling, and potentially leading to decreased tumor cell ...

4. mayo.edu mayo.edu/research/clinical-trials/diseases-conditions/chronic-lymphocytic-

Chronic Lymphocytic Clinical Trials The purpose of this study is to determine if the drug combination of acalabrutinib, durvalumab, and venetoclax will work to treat Richter's transformation, and ...

5. withpower.com withpower.com/trial/phase-2-leukemia-lymphocytic-chronic-b-cell-4-2022-28249

Acalabrutinib + Venetoclax + Durvalumab for Richter Syndrome Durvalumab has shown effectiveness in combination with other treatments for various cancers, such as small-cell lung cancer, where it improved survival outcomes ...

6. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/acalabrutinib?pn=1

Clinical Trials Using Acalabrutinib - NCI NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying acalabrutinib.

7. ashpublications.org ashpublications.org/hematology/article/2023/1/427/506445/Richter-transformation-is-there-light-at-the-end

Richter transformation—is there light at the end of this tunnel? Daily venetoclax ramp-up was safe with no tumor lysis syndrome events reported. The encouraging deep and durable responses have led to an ...