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

(ESCALADE Trial)

Not currently recruiting at 310 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)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat diffuse large B-cell lymphoma, a type of blood cancer. Researchers compare the effects of adding acalabrutinib, a cancer treatment, to a standard treatment called R-CHOP, which includes several cancer-fighting drugs, against using R-CHOP with a placebo. The goal is to determine if the new combination is more effective and safe for patients. The trial seeks participants diagnosed with diffuse large B-cell lymphoma who have not yet received treatment. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

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.

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

Research shows that acalabrutinib is generally well-tolerated when combined with R-CHOP, a common chemotherapy treatment. Studies have found that patients taking acalabrutinib with R-CHOP did not experience unexpected side effects beyond those typically associated with standard chemotherapy.

Earlier research identified the most common side effects as mild, such as headaches and tiredness, similar to those experienced with other treatments for diffuse large B-cell lymphoma. Serious side effects did not occur significantly more often than with R-CHOP alone.

Overall, evidence suggests that adding acalabrutinib to R-CHOP does not significantly increase the risk of serious side effects. This information provides a clearer understanding of the safety of this treatment option. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lymphoma?

Unlike the standard treatment for diffuse large B-cell lymphoma, which typically involves R-CHOP, the investigational treatment adds acalabrutinib to the mix. Acalabrutinib is unique because it targets a specific enzyme called Bruton's tyrosine kinase (BTK), which plays a crucial role in the growth and survival of cancer cells. Researchers are excited because this targeted approach might enhance the effectiveness of the existing regimen, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for diffuse large B-cell lymphoma?

This trial will compare the effectiveness of adding acalabrutinib to the usual R-CHOP treatment versus a placebo with R-CHOP for diffuse large B-cell lymphoma. Studies have shown that adding acalabrutinib to R-CHOP might improve outcomes. Research indicates that acalabrutinib targets certain proteins in cancer cells, making them easier to destroy. Early findings suggest that this combination is not only safe but also might be more effective than R-CHOP alone. Patients treated with both have demonstrated promising results, indicating a better chance of controlling the disease. While more information is needed, the early signs are encouraging for those considering this treatment option. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

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.

My organs and bone marrow are working well.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS7572

ESCALADE: A phase 3 study of acalabrutinib in ... A phase 3, randomized, global, double-blind study of A vs placebo in combination with R-CHOP for treatment of newly diagnosed non-GCB DLBCL.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7551525/

ACCEPT - combining acalabrutinib with rituximab ... : Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J ...

3. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D8227C00001

A Combination of Acalabrutinib with R-CHOP in Subjects ... Phase 3 randomized, double-blind, placebo-controlled, study to evaluate the efficacy and safety of acalabrutinib plus rituximab,cyclophosphamide, doxorubicin, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04546620

NCT04546620 | Acalabrutinib in Combination With R- ... This study evaluates the addition of Acalabrutinib to current standard therapy of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118704126

Acalabrutinib in Combination with Rituximab, ... Conclusions: Acalabrutinib is well tolerated when given in combination with R-CHOP chemotherapy and may be associated with improved efficacy ...