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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial tests whether acalabrutinib, venetoclax, and durvalumab work in treating patients with Richter transformation from chronic lymphocytic leukemia or small lymphocytic lymphoma. Richter transformation is a rare condition in which chronic lymphocytic leukemia or small lymphocytic lymphoma changes into a fast-growing type of lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving acalabrutinib, venetoclax, and durvalumab may help improve survival in patients with Richter transformation.

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.

What data supports the effectiveness of the drug Durvalumab?

Durvalumab has shown effectiveness in combination with other treatments for various cancers, such as small-cell lung cancer, where it improved survival outcomes. It has also demonstrated antitumor activity when used with other drugs, suggesting potential benefits in cancer treatment. ^{1 2 3 4 5}

What safety information is available for Durvalumab in humans?

Durvalumab, used in cancer treatments, has been associated with some serious side effects like myocarditis (inflammation of the heart muscle) and heart block, although these are rare. Other side effects include hypertension (high blood pressure), diarrhea, and fatigue, but it generally has a more favorable side effect profile compared to traditional chemotherapy. ^{1 4 6 7 8}

What makes the drug combination of Acalabrutinib, Venetoclax, and Durvalumab unique for treating Richter Syndrome?

This drug combination is unique because it combines Acalabrutinib, which targets specific proteins in cancer cells, Venetoclax, which helps kill cancer cells by affecting their survival mechanisms, and Durvalumab, an immunotherapy that helps the immune system attack cancer cells. This multi-faceted approach is novel for treating Richter Syndrome, a condition with limited standard treatment options. ^{9 10 11 12 13}

Research Team

Paul J. Hampel, M.D.

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2022]

2. United States 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitor-related acral vasculitis. [2019]

4. Canada pubmed.ncbi.nlm.nih.gov

Durvalumab for Extensive-Stage of Small-Cell Lung Cancer With Lambert-Eaton Myasthenic Syndrome. [2023]

5. England 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. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Acute Myocarditis Due to PD-L1 Inhibitor Durvalumab Monotherapy in a Patient With Lung Squamous Cell Carcinoma. [2022]

7. Switzerland 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. [2023]

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

Durvalumab-Associated Myocarditis Initially Presenting With Sinus Bradycardia Progressing Into Complete Heart Block. [2023]

9. United States 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. [2013]

10. United States 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). [2021]

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

Vaccination of metastatic renal cancer patients with MVA-5T4: a randomized, double-blind, placebo-controlled phase III study. [2022]

12. Germany 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. [2020]

13. United States 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. [2021]