Acalabrutinib + R-CHOP for Diffuse Large B-Cell Lymphoma

(ESCALADE Trial)

Recruiting at 249 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Acerta Pharma BV

Disqualifiers: CNS lymphoma, Cardiovascular disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 6 cycles (21 days per cycle)

611 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if adding acalabrutinib to the standard R-CHOP chemotherapy is more effective for patients aged 75 or younger with untreated non-germinal center diffuse large B-cell lymphoma. Acalabrutinib blocks a protein that helps cancer cells grow, while R-CHOP uses multiple drugs to kill cancer cells.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Acalabrutinib + R-CHOP for Diffuse Large B-Cell Lymphoma?

Research shows that Acalabrutinib, a drug that targets specific proteins in cancer cells, has been effective in other types of blood cancers like chronic lymphocytic leukemia and marginal zone lymphoma. Additionally, R-CHOP, a combination of drugs, is already a standard treatment for Diffuse Large B-Cell Lymphoma, and adding Acalabrutinib may improve its effectiveness. ^{1 2 3 4 5}

What safety data exists for the treatment Acalabrutinib + R-CHOP for Diffuse Large B-Cell Lymphoma?

Doxorubicin, a component of the R-CHOP regimen, is known to potentially cause side effects like myelosuppression (reduced bone marrow activity), cardiotoxicity (heart damage), and alopecia (hair loss). However, studies have shown that doxorubicin can be administered with tolerable and reversible acute side effects and minimal long-term toxicity in certain cancer treatments. ^{6 7 8 9 10}

What makes the drug Acalabrutinib + R-CHOP unique for treating Diffuse Large B-Cell Lymphoma?

The drug Acalabrutinib + R-CHOP is unique because it combines the standard R-CHOP regimen with Acalabrutinib, a second-generation Bruton's tyrosine kinase (Btk) inhibitor, which may offer improved effectiveness and tolerability by specifically targeting dysregulated B-cell receptor signaling, a feature of this lymphoma. ^{5 11 12 13 14}

Eligibility Criteria

This trial is for men and women aged 18-70 with previously untreated non-GCB DLBCL, a type of lymphoma. Participants must have an ECOG performance status ≤2, IPI score of 1 to 5, and Stage II to IV disease. They need adequate organ function and agree to use contraception during the study plus one year after.

Inclusion Criteria

My cancer is classified as Stage II to IV.

My diagnosis of DLBCL is confirmed and samples can be sent for further testing.

I am between 18 and 70 years old.

Exclusion Criteria

I do not have any untreated serious infections.

I have been diagnosed with or currently have PML.

I have not had a stroke or brain bleed in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acalabrutinib or placebo in combination with R-CHOP

6 cycles (21 days per cycle)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Acalabrutinib
• Cyclophosphamide
• Doxorubicin
• Prednisone
• Rituximab
• Vincristine

Trial Overview The trial tests acalabrutinib combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) against a placebo plus R-CHOP in patients under 75 years old. It's randomized and double-blind to compare effectiveness and safety.

Participant Groups

Group I: acalabrutinib + R-CHOP Experimental Treatment 6 Interventions

Acalabrutinib plus Rituximab, Cyclosphosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)

Group II: placebo + R-CHOP Placebo Group 6 Interventions

Placebo plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP)

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?

Acerta Pharma BV

Lead Sponsor

Trials

46

Recruited

5,900+

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

Findings from Research

Acalabrutinib, a Bruton tyrosine kinase inhibitor, showed a 53% overall response rate in patients with relapsed/refractory marginal zone lymphoma, indicating its efficacy in this patient population.

The treatment was generally well tolerated, with a median progression-free survival of 27.4 months and a low incidence of severe adverse events, suggesting improved safety compared to other treatments like ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. Strati, P., Coleman, M., Champion, R., et al.[2022]

In a study of 56 adults with newly diagnosed diffuse large B-cell lymphomas (DLBCL), replacing vindesine with vincristine in the modified R-ACVBP protocol resulted in an 80% complete response rate and an 87% overall survival rate after 2 years.

The treatment was associated with manageable side effects, including anemia and febrile neutropenia, suggesting that mR-ACVBP is a feasible alternative to the original protocol, but further validation in larger trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas. El Sayed, R., El Darsa, H., Kort, J., et al.[2022]

In a pivotal phase 3 study with 310 patients, acalabrutinib significantly improved progression-free survival (PFS) compared to standard treatments (Idelalisib plus rituximab or bendamustine plus rituximab), with a median PFS not reached for acalabrutinib versus 16.8 months for IdR/BR.

After approximately 4 years of follow-up, acalabrutinib demonstrated a favorable safety profile, with lower rates of treatment discontinuation due to adverse events compared to IdR/BR, while maintaining similar rates of serious infections and other significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Ghia, P., Pluta, A., Wach, M., et al.[2022]

The ACCEPT trial is investigating the safety and efficacy of adding acalabrutinib, a second-generation Btk inhibitor, to the standard R-CHOP regimen in patients with untreated Diffuse Large B-cell Lymphoma (DLBCL), with a focus on establishing the recommended dose and assessing overall response rates.

This open-label trial includes up to 39 participants and aims to provide preliminary evidence on the combination's effectiveness and safety, potentially paving the way for larger Phase II/III trials in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial. Davies, A., Barrans, S., Burton, C., et al.[2021]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

Doxorubicin, an anthracycline, has been shown to be effective in adjuvant therapy for metastatic breast cancer, with clinical evidence supporting its safety and efficacy over follow-up periods of up to 19 years.

Trials at the University of Texas M.D. Anderson Cancer Center indicate that doxorubicin can be administered with manageable acute side effects and minimal long-term toxicity, leading to improved disease-free and overall survival rates compared to regimens without doxorubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present status of anthracyclines in the adjuvant treatment of breast cancer. Hortobágyi, GN., Buzdar, AU.[2018]

The R-CHOP regimen, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, is a standard first-line treatment for diffuse large B-cell lymphoma, highlighting its importance in oncology.

Nursing implications of administering R-CHOP are significant, as the combination of these drugs requires careful monitoring for side effects and patient management during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nursing Alchemy: Transforming R-CHOP Information Into Essentials. Sakowski, AK., Patel, PR.[2023]

In a study of 582 patients with diffuse large B-cell lymphoma (DLBCL) treated in Germany, both R-CHOP-14 and R-CHOP-21 regimens showed similar overall survival rates at 3 years, with 84% for R-CHOP-14 and 84% for R-CHOP-21.

The findings confirm previous randomized clinical trials that indicated no superiority of the dose-dense R-CHOP-14 over the standard R-CHOP-21, supporting the use of either regimen in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Similar effectiveness of R-CHOP-14 and -21 in diffuse large B-cell lymphoma-data from the prospective German Tumour Registry Lymphatic Neoplasms. Knauf, W., Abenhardt, W., Mohm, J., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). [2020]

2. England pubmed.ncbi.nlm.nih.gov

A phase 2, multicentre, open-label trial (ACE-LY-003) of acalabrutinib in patients with relapsed or refractory marginal zone lymphoma. [2022]

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

Safety and Efficacy of Replacing Vindesine with Vincristine in R-ACVBP Regimen for the Treatment of Large B Cell Lymphomas. [2022]

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

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. [2022]

5. England pubmed.ncbi.nlm.nih.gov

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Euterpe oleracea Mart. (Açai) Supplementation Attenuates Acute Doxorubicin-Induced Cardiotoxicity in Rats. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Barleria prionitis L. extracts ameliorate doxorubicin-induced acute kidney injury via modulation of oxidative stress, inflammation, and apoptosis. [2023]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Present status of anthracyclines in the adjuvant treatment of breast cancer. [2018]

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

Evaluation of potential interaction between vinorelbine and clarithromycin. [2018]

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

Nursing Alchemy: Transforming R-CHOP Information Into Essentials. [2023]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. [2020]

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

A Fondazione Italiana Linfomi cohort study of R-COMP vs R-CHOP in older patients with diffuse large B-cell lymphoma. [2023]

14. England pubmed.ncbi.nlm.nih.gov

Similar effectiveness of R-CHOP-14 and -21 in diffuse large B-cell lymphoma-data from the prospective German Tumour Registry Lymphatic Neoplasms. [2020]