Oral Azacitidine + R-miniCHOP for Diffuse Large B-Cell Lymphoma

Recruiting at 202 trial locations

Age: 65+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Waitlist Available

Sponsor: National Cancer Institute (NCI)

Must not be taking: Methotrexate, others

Disqualifiers: CNS involvement, Active infection, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the side effects and activity of oral azacitidine in combination with the standard drug therapy (reduced dose rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone \[R-miniCHOP\]) versus R-miniCHOP alone in treating patients 75 years or older with newly diagnosed diffuse large B cell lymphoma. R-miniCHOP includes a monoclonal antibody (a type of protein), called rituximab, which attaches to the lymphoma cells and may help the immune system kill these cells. R-miniCHOP also includes prednisone which is an anti-inflammatory medication and a combination of 3 chemotherapy drugs, cyclophosphamide, doxorubicin, and vincristine. These 3 chemotherapy drugs, as well as oral azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Combining oral azacitidine with R-miniCHOP may shrink the cancer or extend the time without disease symptoms coming back or extend patient's survival when compared to R-miniCHOP alone.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it mentions that participants must not currently be receiving any other investigational agents and should not have received certain chemotherapy drugs for the newly diagnosed condition. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Oral Azacitidine + R-miniCHOP for Diffuse Large B-Cell Lymphoma?

The addition of rituximab to CHOP chemotherapy has been shown to improve outcomes in patients with diffuse large B-cell lymphoma, and similar combinations like DA-EPOCH-R have shown improved progression-free survival in high-risk patients. These findings suggest that combining rituximab with other chemotherapy regimens can be effective for this condition. ^{1 2 3 4 5}

Is the combination of oral azacitidine and R-miniCHOP safe for treating diffuse large B-cell lymphoma?

The safety of treatments similar to R-miniCHOP, which includes drugs like cyclophosphamide, vincristine, prednisone, and rituximab, has been studied in various forms. These treatments are generally considered manageable in terms of side effects, although they can increase the risk of certain conditions like fractures, especially in older patients. ^{1 2 3 6 7}

What makes the drug Oral Azacitidine + R-miniCHOP unique for treating diffuse large B-cell lymphoma?

This treatment is unique because it combines oral azacitidine, a drug that affects DNA methylation (a process that can influence how genes are turned on or off), with a modified version of the standard R-CHOP regimen, potentially addressing resistance issues in diffuse large B-cell lymphoma. ^{1 8 9 10 11}

Research Team

Elizabeth A Brem

Principal Investigator

SWOG Cancer Research Network

Eligibility Criteria

This trial is for people aged 75 or older with newly diagnosed diffuse large B cell lymphoma. They must have certain types of this cancer, adequate organ function, and no history of specific treatments for DLBCL. HIV-positive patients can join if their viral load is undetectable, but those with CNS involvement or certain gastrointestinal issues cannot participate.

Inclusion Criteria

My lymphoma is advanced (Grade IIIB) or high-grade with specific genetic changes.

You need to be tested for chronic hepatitis B virus within 28 days before joining the study.

I can take care of myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

Participants must not currently be receiving any other investigational agents

I do not have any uncontrolled illnesses besides my cancer.

You have not had allergic reactions to certain medications.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CC-486 and R-miniCHOP or R-miniCHOP alone for up to 6 cycles

18 weeks

6 cycles, each 21 days apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Oral Azacitidine (Anti-metabolites)
• Prednisone (Corticosteroid)
• Rituximab (Monoclonal Antibodies)
• Vincristine Sulfate (Vinca alkaloids)

Trial Overview The study compares oral azacitidine plus R-miniCHOP (a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) against R-miniCHOP alone to see which is better at shrinking the cancer or extending symptom-free survival in elderly patients.

Participant Groups

Group I: Arm I (oral azacitidine, R-miniCHOP) Experimental Treatment 8 Interventions

Patients receive CC-486 PO for 7 days prior to cycle 1. Patients then receive CC-486 PO on days 8-21. Treatment repeats every 21 days for cycles 1-5 in the absence of disease progression or unacceptable toxicity. Patients also receive rituximab IV (or SC for cycles 2-6), cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for cycles 1-6 (6 cycles total) in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study.

Group II: Arm II (R-miniCHOP) Active Control 7 Interventions

Patients receive rituximab IV (or SC for cycles 2-6), cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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 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 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 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]

In a study of 80 patients with high-risk diffuse large B cell lymphoma (DLBCL), the DA.R-EPOCH treatment showed comparable progression-free and overall survival rates to the standard R-CHOP treatment, indicating similar efficacy.

However, DA.R-EPOCH was associated with significantly higher treatment costs, averaging around USD 106,940 compared to USD 58,509 for R-CHOP, highlighting a trade-off between cost and treatment choice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Analysis of R-CHOP Versus Dose-Adjusted R-EPOCH in Treatment of Diffuse Large B-Cell Lymphoma with High-Risk Features. Dholaria, B., Vanegas, YAM., Diehl, N., et al.[2021]

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 729 patients aged 70 and older with diffuse large B-cell lymphoma treated with R-CHOP, the cumulative fracture incidence was found to be 11.4% within 18 months, indicating a significant risk of fractures in this population.

Factors such as a history of osteoporosis, DLBCL bone involvement, and the use of prephase steroids were identified as independent risk factors for fractures, highlighting the need for careful monitoring of bone health in older patients undergoing R-CHOP treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma. Booth, S., Plaschkes, H., Kirkwood, AA., et al.[2021]

In a phase 1 study involving patients with untreated intermediate- to high-risk diffuse large B-cell lymphoma (DLBCL), the combination of oral azacitidine (CC-486) with R-CHOP chemotherapy showed a high overall response rate of 94.9%, with 88.1% of patients achieving complete responses.

The treatment was generally safe, with the maximum tolerated dose established at 300 mg, although some patients experienced significant hematologic toxicities like neutropenia. The study suggests that using CC-486 as an epigenetic primer before R-CHOP can be a promising strategy for improving outcomes in DLBCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL. Martin, P., Bartlett, NL., Chavez, JC., et al.[2022]

In a phase II study involving 14 elderly patients (median age 85) with aggressive B-cell lymphomas, the combination of rituximab and bendamustine resulted in a 54% complete response rate and a median overall survival of 7.7 months.

The treatment showed low toxicity, with major side effects like neutropenia occurring in only 17% of patients, suggesting that this regimen could be a safer alternative for elderly patients who are not candidates for the more aggressive R-CHOP therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. Weidmann, E., Neumann, A., Fauth, F., et al.[2020]

In a study of 576 patients with diffuse large B-cell lymphoma (DLBCL), omitting or reducing vincristine in the R-CHOP regimen was associated with a significant decrease in overall survival (OS), particularly when the relative dose intensity was less than 25%.

Patients who had vincristine omitted or reduced showed a 4-year OS of only 53%, compared to 82% for those who received the full dose, highlighting the importance of vincristine for maintaining treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Omission/Reduction of Vincristine From R-CHOP in Treatment of DLBCL. Marshall, S., Nishimura, N., Inoue, N., et al.[2022]

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]

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. 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]

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. 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]

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

Cost Analysis of R-CHOP Versus Dose-Adjusted R-EPOCH in Treatment of Diffuse Large B-Cell Lymphoma with High-Risk Features. [2021]

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

Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma. [2021]

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

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. [2020]

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

Impact of Omission/Reduction of Vincristine From R-CHOP in Treatment of DLBCL. [2022]

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

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