Combination Chemotherapy for Diffuse Large B-Cell Lymphoma

Recruiting at 18 trial locations

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiretrovirals

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Opportunistic infections, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 9

Duration: 18 weeks

46 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase I trial studies the side effect and best dose of ibrutinib in combination with rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride in treating patients with human immunodeficiency virus (HIV)-positive stage II-IV diffuse large B-cell lymphomas. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, 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. Giving ibrutinib and etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride may work better in treating patients with HIV-positive diffuse large B-cell lymphomas.

Will I have to stop taking my current medications?

The trial requires that participants not be on certain medications, including some antiretroviral drugs like cobicistat, indinavir, or ritonavir, or any drugs that strongly inhibit CYP3A4. If you are on these medications, you must switch to a different regimen at least one week before starting the trial.

Is the combination chemotherapy for diffuse large B-cell lymphoma safe for humans?

The combination chemotherapy, including drugs like rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, has been studied for safety in humans. In trials, toxicity was manageable, and there were no therapy-related deaths, although adding ibrutinib increased toxicity, including a higher chance of nerve damage (peripheral neuropathy). ^{1 2 3 4 5}

How is the combination chemotherapy for diffuse large B-cell lymphoma unique?

This treatment combines ibrutinib, a novel oral drug that targets specific cancer cell pathways, with a standard chemotherapy regimen (R-CHOP), potentially enhancing effectiveness for patients with diffuse large B-cell lymphoma. ^{1 6 7 8 9}

What data supports the effectiveness of the drug combination used in the clinical trial for Diffuse Large B-Cell Lymphoma?

Research shows that combining VP-16-213 (etoposide) with doxorubicin resulted in higher complete remission rates compared to using VP-16-213 alone or with cyclophosphamide. Additionally, the R-CEOP regimen, which substitutes etoposide for doxorubicin in R-CHOP, has shown curative potential in patients with DLBCL who cannot use anthracyclines, suggesting the effectiveness of these components in similar treatments. ^{7 10 11 12 13}

Who Is on the Research Team?

Ida C Wong-Sefidan

Principal Investigator

AIDS Malignancy Consortium

Are You a Good Fit for This Trial?

This trial is for HIV-positive adults with stage II-IV diffuse large B-cell lymphomas who haven't had prior chemotherapy or radiotherapy for this condition. They must have a certain level of physical fitness, adequate organ function, and agree to use contraception. Those with severe illnesses, recent major surgery, other active cancers, or known brain metastases are excluded.

Inclusion Criteria

HIV positive with documentation of HIV-1 infection

Absolute neutrophil count: >= 1,000/mm^3

Total bilirubin: =< 1.5 institutional upper limit of normal

Exclusion Criteria

I haven't had chemotherapy (except R-EPOCH or R-CHOP) or radiotherapy in the last 4 weeks.

Receiving any other investigational agents

My heart condition fits the trial's specific timeframes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive rituximab, etoposide, doxorubicin hydrochloride, vincristine sulfate, prednisone, cyclophosphamide, and ibrutinib. Treatment repeats every 21 days for up to 6 courses.

18 weeks

6 cycles, each with multiple visits for IV administration

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

2 years

Every 3 months for 2 years, then every 6 months up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Etoposide
• Ibrutinib
• Laboratory Biomarker Analysis
• Pharmacological Study
• Rituximab
• Vincristine Sulfate

Trial Overview The trial tests the best dose and side effects of combining ibrutinib with rituximab and standard chemotherapy drugs (etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride) in treating patients. It aims to find out if this combination is more effective for those with HIV-associated lymphoma.

How Is the Trial Designed?

Group I: Treatment (R-da-EPOCH) Experimental Treatment 11 Interventions

Patients receive rituximab IV on day 1 (for CD20 positive patients only), etoposide IV over 96 hours on days 1-4, doxorubicin hydrochloride IV over 96 hours on days 1-4, vincristine sulfate IV over 96 hours on days 1-4, prednisone PO daily on days 1-5, cyclophosphamide IV over 1 hour on day 5, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive pegfilgrastim SC from 1 calendar day up to 48 hours or filgrastim SC beginning on day 6 for up to 10 days until ANC is satisfactory.

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 randomized trial of 118 patients with advanced diffuse lymphocytic lymphoma, the combination of the drug VP-16-213 with doxorubicin resulted in a higher complete remission rate of 54%, compared to 39% with VP-16-213 alone and 26% with VP-16-213 combined with cyclophosphamide.

The study found that combining VP-16-213 with cyclophosphamide led to significantly lower remission rates, suggesting that doxorubicin is a more effective partner for VP-16-213 in treating this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VP-16-213 in the treatment of stage III and IV diffuse lymphocytic lymphoma of the large cell (histiocytic) variety: an interim report. Jacobs, P., King, HS., Cassidy, F., et al.[2013]

In a study of 81 patients with advanced diffuse large cell lymphoma, the epipodophyllotoxin VP-16-213 alone achieved a complete remission rate of 55%, while its combination with doxorubicin also showed a high remission rate of 62%, indicating that VP-16-213 is an effective treatment option.

The combination of VP-16-213 with cyclophosphamide was found to be inferior, with a complete remission rate of only 29%, suggesting that this combination may not be beneficial for patients with this type of lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VP-16-213 in the treatment of stage III and IV diffuse large cell lymphoma. Jacobs, P., King, HS., Dent, DM., 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 70 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with R-CEOP (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone), the treatment showed comparable outcomes in terms of time to progression and disease-specific survival when matched against a control group of 140 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Although R-CEOP demonstrated similar progression-free and disease-specific survival rates, it was associated with a lower overall survival rate (30% vs 49% for R-CHOP), likely due to the higher comorbidities and frailty in the R-CEOP group, indicating that while R-CEOP is a viable alternative for patients who cannot tolerate anthracyclines, it may not be as effective overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. Moccia, AA., Schaff, K., Freeman, C., et al.[2021]

The combination treatment of epratuzumab and rituximab with standard CHOP chemotherapy (ER-CHOP) was feasible for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), with a high overall response rate of 87% and a complete response rate of 67% among 15 patients.

Despite a high incidence of grade 3 or 4 neutropenia (93% of patients), there were no severe infusion-related toxicities, and the treatment showed promising survival rates with 1-year progression-free survival (PFS) at 93% and overall survival (OS) at 100% at a median follow-up of 30 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. Micallef, IN., Kahl, BS., Maurer, MJ., et al.[2017]

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 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 pooled analysis of 150 patients with HIV-associated aggressive B-cell non-Hodgkin lymphoma, those treated with R-EPOCH showed significantly better event-free survival (EFS) and overall survival (OS) compared to those receiving R-CHOP, particularly in patients with a CD4 count ≥100/μL.

Patients with CD4 counts <50/μL experienced a much higher rate of treatment-related deaths (37% vs 6%), indicating that lower immune function increases the risk of lethal toxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Barta, SK., Lee, JY., Kaplan, LD., et al.[2022]

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]

The study indicates that adding acalabrutinib to R-CHOP therapy poses a low risk of drug-drug interactions (DDIs) with vincristine, suggesting it may not significantly increase the risk of peripheral neuropathy associated with vincristine treatment.

In contrast, the BTK inhibitor ibrutinib was found to increase vincristine exposure in muscle tissue, indicating a higher potential for toxicity when used with vincristine compared to acalabrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors. Pilla Reddy, V., Fretland, AJ., Zhou, D., et al.[2022]

Rituximab combined with CHOP chemotherapy is the most effective first-line treatment for diffuse large B-cell lymphoma (DLBCL), significantly improving long-term survival rates for patients.

Chronic pain in areas like the back and pelvis should be thoroughly investigated with imaging techniques like CT scans and MRIs, as they can indicate serious conditions like DLBCL, which was diagnosed in a 25-year-old female patient after such evaluations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

25 Years Old Women With Inflammatory Low Back Pain. Soltani, Z., Davatchi, F.[2023]

In a study of 1,807 patients with diffuse large B-cell lymphoma (DLBCL) treated in Chile, the addition of rituximab to the standard CHOP regimen significantly improved overall survival rates, with 5-year survival at 66% for R-CHOP compared to 48% for CHOP alone.

The long-term benefits of R-CHOP were evident, with a 10-year survival rate of 53% versus 35% for CHOP, demonstrating that rituximab not only enhances treatment efficacy but also justifies its cost in national health protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diffuse Large B-Cell Lymphoma in Chile: The Impact of Combined CHOP Plus Rituximab in the Public Health System. Cabrera, ME., Peña, C., Leon, P., et al.[2023]

In a phase 1b study involving 33 patients with untreated CD20-positive B-cell non-Hodgkin lymphoma, the combination of ibrutinib and R-CHOP was found to be well tolerated, with a recommended dose of 560 mg per day for ibrutinib, and a high overall response rate of 94% among those treated.

The study indicated that ibrutinib did not interfere with the pharmacokinetics of R-CHOP components, suggesting a safe combination therapy that could enhance treatment responses, particularly in patients with different subtypes of diffuse large B-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Younes, A., Thieblemont, C., Morschhauser, F., et al.[2021]

Citations

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

VP-16-213 in the treatment of stage III and IV diffuse lymphocytic lymphoma of the large cell (histiocytic) variety: an interim report. [2013]

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

VP-16-213 in the treatment of stage III and IV diffuse large cell lymphoma. [2019]

3. 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]

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

Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines. [2021]

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

A pilot study of epratuzumab and rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. [2017]

6. 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]

7. 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]

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

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. [2022]

9. 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]

10. Germany pubmed.ncbi.nlm.nih.gov

Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors. [2022]

11. Bosnia and Herzegovina pubmed.ncbi.nlm.nih.gov

25 Years Old Women With Inflammatory Low Back Pain. [2023]

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

Diffuse Large B-Cell Lymphoma in Chile: The Impact of Combined CHOP Plus Rituximab in the Public Health System. [2023]

13. England pubmed.ncbi.nlm.nih.gov

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. [2021]