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

Recruiting at 1 trial location

Overseen by Yazeed Sawalha, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Yazeed Sawalha

Must not be taking: Methotrexate

Disqualifiers: CNS involvement, Cardiovascular conditions, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase Ib trial seeks to find out the best dose and possible side effects and/or benefits of zanubrutinib in combination with the R-PolaCHP in treating patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Zanubrutinib is designed to block a protein called Bruton Tyrosine Kinase in order to stop cancer growth. R-CHOP is the acronym for the combination of five drugs: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. It is the most widely used chemoimmunotherapy regimen for DLBCL and is considered the standard-of-care treatment for patients with DLBCL. Three of the drugs in R-CHOP (cyclophosphamide, doxorubicin and vincristine) are chemotherapy drugs. Rituximab is a type of immunotherapy and prednisone is a type of steroids.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, you may need to discuss your current medications with the trial team to ensure they don't interfere with the study treatment.

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

The addition of rituximab to the R-CHOP regimen has been shown to improve outcomes in patients with diffuse large B-cell lymphoma, and similar regimens like DA-EPOCH-R have demonstrated superior progression-free survival in certain patient groups. ^{1 2 3 4 5}

Is the combination of Zanubrutinib and R-CHOP safe for humans?

The combination of R-CHOP (which includes drugs like cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) has been studied for safety in various forms of lymphoma, and the side effects were generally manageable with no therapy-related deaths reported in some studies. However, specific safety data for Zanubrutinib combined with R-CHOP is not provided in the available research. ^{3 5 6 7 8}

What makes the drug Zanubrutinib + R-CHOP unique for treating diffuse large B-cell lymphoma?

Zanubrutinib + R-CHOP is unique because it combines a new drug, zanubrutinib, with the standard R-CHOP regimen to potentially improve outcomes for patients with a specific type of diffuse large B-cell lymphoma (non-GCB) that involves multiple areas outside the lymph nodes, where traditional R-CHOP alone has shown poor response rates. ^{5 9 10 11 12}

Research Team

Yazeed Sawalha, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

Adults (18+) with newly diagnosed diffuse large B-cell lymphoma can join this trial if they have a performance status of <=2, meaning they're able to carry out daily activities with some effort. They need normal blood counts and organ function, must not be pregnant or breastfeeding, agree to use contraception, and cannot have other serious health issues that could interfere with the study.

Inclusion Criteria

I am 18 years old or older.

My blood, liver, and kidney functions are all within normal ranges.

Ability to understand and sign a written informed consent document and HIPAA consent document

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

Participation in other interventional clinical trials within 21 days of this trial

My cancer has spread to my brain or spinal cord.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive zanubrutinib orally once or twice daily on days 1-21, rituximab intravenously on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone orally on days 1-5. Treatment repeats every 21 days for up to 6 cycles.

18 weeks

6 cycles, each 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 6 months for 2 years.

24 months

Every 6 months

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Doxorubicin Hydrochloride (Anti-tumor antibiotic)
• Prednisone (Corticosteroid)
• Rituximab (Monoclonal Antibodies)
• Vincristine Sulfate (Vinca alkaloids)
• Zanubrutinib (Bruton Tyrosine Kinase Inhibitor)

Trial Overview The trial is testing Zanubrutinib combined with R-CHOP chemotherapy regimen for treating patients with DLBCL. It aims to determine the best dose and assess potential benefits or side effects. R-CHOP includes rituximab (immunotherapy), cyclophosphamide, doxorubicin, vincristine (chemotherapies), and prednisone (steroid).

Participant Groups

Group I: Treatment (zanubrutinib, R-CHOP) Experimental Treatment 6 Interventions

Patients receive zanubrutinib PO on days 1-21, rituximab IV on day 1, cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO QD on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Cyclophosphamide is already approved in Canada, Japan for the following indications:

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Yazeed Sawalha

Lead Sponsor

Trials

3

Recruited

60+

Findings from Research

In a study of 50 patients treated with R-CHOP-14 for aggressive B-cell lymphoma, 82% achieved a complete or improved response, indicating high efficacy of this treatment regimen.

Despite its effectiveness, R-CHOP-14 was associated with significant toxicities, including grade 3-4 neutropenia in 32% of patients and peripheral neuropathy in 45%, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. Aguiar Bujanda, D., Aguiar Morales, J., Bohn Sarmiento, U., et al.[2021]

In a phase III study involving 491 patients with diffuse large B-cell lymphoma, the more intensive treatment regimen DA-EPOCH-R did not show a statistically significant improvement in progression-free survival (PFS) or overall survival (OS) compared to the standard R-CHOP regimen, with 2-year PFS rates of 78.9% for DA-EPOCH-R and 75.5% for R-CHOP.

DA-EPOCH-R was associated with a higher incidence of severe adverse events, including infections and febrile neutropenia, indicating that while it is a more intensive treatment, it does not provide additional survival benefits and carries greater risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. Bartlett, NL., Wilson, WH., Jung, SH., et al.[2021]

In a study of 20 patients with untreated poor prognosis diffuse large B-cell lymphoma (DLBCL), the two-weekly dose-adjusted EPOCH-like chemotherapy (DA-EDOCH14-R) showed a promising three-year progression-free survival (PFS) rate of 95%, compared to 74% in a previous trial with a three-weekly regimen.

The treatment was well-tolerated with manageable toxicity and no therapy-related deaths, highlighting its safety, especially for patients with a high-risk prognosis (age-adjusted International Prognostic Index of 3), where PFS reached 100% compared to just 30% in the previous trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. García-Suárez, J., Flores, E., Callejas, M., et al.[2015]

In a study of 435 patients with diffuse large B-cell lymphoma (DLBCL), the addition of rituximab to CHOP chemotherapy (R-CHOP) was associated with a reduced risk of central nervous system (CNS) relapse, showing a trend of 6.4% risk in R-CHOP patients compared to 9.7% in those treated with CHOP.

Rituximab significantly lowered the risk of CNS relapse (hazard ratio 0.45) and this benefit was even greater for patients who achieved a complete response (hazard ratio 0.18), indicating that R-CHOP is particularly effective in preventing CNS involvement in DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Villa, D., Connors, JM., Shenkier, TN., et al.[2022]

In a study of 13 elderly patients (median age 79) with diffuse large B cell lymphoma, the combination of rituximab with CHOP or THP-COP resulted in a 54% complete response rate and a 62% two-year survival rate, indicating its efficacy in this age group.

The treatment was generally safe, although 69% of patients experienced bone marrow suppression, and infusion reactions occurred in 30.7%, which were manageable by adjusting the rituximab dosage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy and adverse effects of rituximab with CHOP or THP-COP in old-old and extremely old patients with diffuse large B cell lymphoma]. Kikukawa, M., Miyazaki, K., Kiuchi, A., et al.[2019]

In a study of 115 patients with Waldeyer's ring diffuse large B-cell lymphoma, those treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) showed significantly better progression-free survival (PFS) and overall survival (OS) compared to those receiving standard R-CHOP treatment, with 2-year PFS rates of 90.1% versus 80.5%.

The DA-EPOCH-R treatment was associated with fewer deaths (2 out of 42 patients) compared to R-CHOP (9 out of 42 patients) during a median follow-up of 45 months, while both treatments had similar clinical responses and treatment-related toxicities, indicating that DA-EPOCH-R is a safer and more effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution. Liang, Y., Liu, X., Yang, J., et al.[2023]

In a study of 40 patients with low-grade or follicular B-cell non-Hodgkin's lymphoma, the combination of Rituxan (Rituximab) and CHOP chemotherapy resulted in a high overall response rate of 95%, with 55% achieving complete remission.

The combination therapy showed promising safety, with common side effects being manageable, and it also indicated potential for clearing minimal residual disease, as evidenced by the conversion of the bcl-2 translocation from positive to negative in several patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. Czuczman, MS., Grillo-López, AJ., White, CA., et al.[2022]

In a study of 397 newly diagnosed diffuse large B-cell lymphoma patients treated with R-CHOP, non-neutropenic fever (NNF) occurred in 9.8% of patients, primarily after the third cycle, with interstitial pneumonitis being the most common cause.

NNF was associated with a higher mortality rate of 10.3% compared to febrile neutropenia (FN), which had a mortality rate of only 1.3%, highlighting the need for careful monitoring and management of febrile complications during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Significance of Non-neutropenic Fever in the Management of Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP: Comparison with Febrile Neutropenia and Risk Factor Analysis. Park, S., Kang, CI., Chung, DR., et al.[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 26 patients with newly diagnosed non-GCB diffuse large B-cell lymphoma (DLBCL) and extranodal involvement, the combination of zanubrutinib with R-CHOP (ZR-CHOP) demonstrated a high overall response rate of 91.3%, with a complete response rate of 82.6%.

The treatment showed promising safety and efficacy, with a 1-year progression-free survival (PFS) of 80.8% and overall survival (OS) of 88.5%, indicating that ZR-CHOP could be a viable option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of zanubrutinib plus R-CHOP in treatment of non-GCB DLBCL with extranodal involvement. Geng, H., Jia, S., Zhang, Y., et al.[2023]

In a retrospective study of 11 elderly patients (median age 83) with diffuse large B-cell lymphoma (DLBCL) who were not suitable for standard R-CHOP treatment, 45% achieved a complete response and 27% a partial response to rituximab combined with low-dose trofosfamide.

The treatment showed promising safety with a 1-year overall survival rate of 54.5% and manageable toxicity, primarily leukopenia, suggesting that this combination could be a viable alternative for elderly patients with DLBCL who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose trofosfamide plus rituximab is an effective and safe treatment for diffuse large B-cell lymphoma of the elderly: a single center experience. Schelker, RC., Herr, W., Reichle, A., et al.[2019]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. [2021]

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

Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. [2021]

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

Two-weekly dose-adjusted (DA)-EPOCH-like chemotherapy with high-dose dexamethasone plus rituximab (DA-EDOCH14-R) in poor-prognostic untreated diffuse large B-cell lymphoma. [2015]

4. Germany pubmed.ncbi.nlm.nih.gov

5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients. [2021]

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

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

[The efficacy and adverse effects of rituximab with CHOP or THP-COP in old-old and extremely old patients with diffuse large B cell lymphoma]. [2019]

7. China pubmed.ncbi.nlm.nih.gov

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution. [2023]

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

Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. [2022]

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

Clinical Significance of Non-neutropenic Fever in the Management of Diffuse Large B-Cell Lymphoma Patients Treated with Rituximab-CHOP: Comparison with Febrile Neutropenia and Risk Factor Analysis. [2018]

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

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

11. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and safety of zanubrutinib plus R-CHOP in treatment of non-GCB DLBCL with extranodal involvement. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Low-dose trofosfamide plus rituximab is an effective and safe treatment for diffuse large B-cell lymphoma of the elderly: a single center experience. [2019]