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

Not currently recruiting at 209 trial locations

Age: 65+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Methotrexate, others

Disqualifiers: CNS involvement, Active infection, 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

Compensation: Varies

Number of Visits: 6

Duration: 18 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding oral azacitidine, a chemotherapy drug, to the standard treatment R-miniCHOP can more effectively treat diffuse large B-cell lymphoma in patients aged 75 or older. R-miniCHOP combines a monoclonal antibody, which helps the immune system target cancer cells, with several chemotherapy drugs. The trial aims to determine if this new combination can shrink cancer or extend symptom-free time compared to R-miniCHOP alone. Ideal candidates for this trial are those recently diagnosed with diffuse large B-cell lymphoma who have not yet received chemotherapy. As a Phase 2, Phase 3 trial, this study measures the treatment's effectiveness in an initial group and represents the final step before FDA approval, offering patients a chance to contribute to potentially groundbreaking cancer therapy.

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.

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

Research has shown that combining oral azacitidine with the standard R-miniCHOP treatment yields promising results in early studies. This combination has been tested with similar drugs and was generally well-tolerated. Some patients experienced side effects, but these were mostly manageable.

Oral azacitidine is being tested with a lower dose of R-CHOP, known as R-miniCHOP. This regimen includes rituximab, which aids the immune system in attacking cancer cells, along with other chemotherapy drugs. These drugs work together to shrink the cancer or prevent its return.

While previous study results are encouraging, individual experiences can vary. Discuss any treatment safety concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for diffuse large B-cell lymphoma?

Researchers are excited about the combination of oral azacitidine with R-miniCHOP for treating diffuse large B-cell lymphoma (DLBCL) because it introduces a novel approach to the existing treatment landscape. While the standard of care, R-miniCHOP, primarily involves intravenous administration, adding oral azacitidine offers a new mechanism by potentially enhancing the treatment's effectiveness through epigenetic modulation. This could make the cancer cells more susceptible to the chemotherapy drugs used in R-miniCHOP. The oral delivery of azacitidine is also a convenient feature, potentially improving patient adherence compared to purely intravenous regimens.

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

Research shows that adding oral azacitidine to the R-miniCHOP treatment, tested in one arm of this trial, might be more effective for treating diffuse large B-cell lymphoma in older patients. Previous studies combining oral azacitidine with similar treatments have shown promising results, with better response rates compared to standard therapy alone. Oral azacitidine stops cancer cells from growing and spreading. In this trial, participants in one arm will receive oral azacitidine with R-miniCHOP, which may help reduce the cancer or delay the return of symptoms. Early findings suggest that this combination could enhance the effectiveness of the standard treatment. ^{1 6 7 8 9}

Who Is on the Research Team?

Elizabeth A Brem

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Oral Azacitidine
• Prednisone
• Rituximab
• Vincristine Sulfate

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.

How Is the Trial Designed?

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 United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

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

Approved in European Union as Endoxan for:

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

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+

Published Research Related to This Trial

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 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 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 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 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 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 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 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 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]

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 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]

Citations

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Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in ... In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL.

2. ashpublications.org ashpublications.org/blood/article-abstract/139/8/1147/476663

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in ... Martin and colleagues report the results of a phase 1b trial of adding oral azacitidine (CC-486) to R-CHOP. “Priming” with CC-486 is shown ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03450343?cond=Diffuse+Large+B-Cell+Lymphoma&aggFilters=status%3A%2Cphase%3A

Oral Azacitidine Plus Salvage Chemotherapy in Relapsed ... The purpose of this study is to determine the safety and tolerability of adding oral azacitidine to the chemotherapy combination R-ICE.

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34428285/

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in ... In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to ...

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Oral Azacitidine (CC-486) Plus R-CHOP in Patients with ... Previously reported data from the dose escalation phase of this study demonstrated promising response rates in patients with high-risk DLBCL ( ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04799275

NCT04799275 | Testing CC-486 (Oral Azacitidine) Plus the ... This phase II/III trial compares the side effects and activity of oral azacitidine in combination with the standard drug therapy (reduced dose ...

7. ashpublications.org ashpublications.org/blood/article/139/8/1147/476663/Phase-1-study-of-oral-azacitidine-CC-486-plus-R

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in ... Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1879406821002356

A phase II/III randomized study of R-miniCHOP with or ... We present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with ...

9. uchicagomedicine.org uchicagomedicine.org/find-a-clinical-trial/clinical-trial/cirb210713

CLINICAL TRIAL / NCT04799275 This phase II/III trial compares the side effects and activity of oral azacitidine in combination with the standard drug therapy.