Vorinostat + Rituximab + Chemotherapy for Diffuse Large B-Cell Lymphoma

Not currently recruiting at 210 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Valproic acid, Torsades de Pointes risk

Disqualifiers: HIV, Pregnancy, Prior chemotherapy, others

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

Compensation: Varies

Number of Visits: 8

Duration: 24 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a combination of vorinostat (a histone deacetylase inhibitor), rituximab (a monoclonal antibody), and several chemotherapy drugs work together to treat diffuse large B-cell lymphoma, a cancer affecting white blood cells. The main goal is to determine the optimal dose, monitor side effects, and assess the combination's effectiveness in stopping cancer growth. This trial targets individuals recently diagnosed with advanced stages of this lymphoma who have not received prior treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

Do I need to stop taking my current medications for the trial?

The trial requires participants to stop taking any medications that might cause a heart rhythm problem called Torsades de Pointes. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the trial team.

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

Research shows that patients usually tolerate vorinostat well. Studies have found that people taking vorinostat for diffuse large B-cell lymphoma (DLBCL) experienced manageable side effects with different dosing schedules.

Real-world results indicate that rituximab is safe and has improved treatment responses for DLBCL. It is widely used for this condition.

Cyclophosphamide is considered safe and effective, with research highlighting its role in reducing adverse events in DLBCL treatments.

Doxorubicin hydrochloride has been safely used in DLBCL treatments, often as part of combination therapies like the one being tested here.

Vincristine sulfate has been shown to be safe, even with adjusted doses, with studies showing no negative effects on survival outcomes.

Prednisone is generally safe and commonly used in treatment plans for DLBCL, with survival rates supporting its safety.

Overall, the treatments in this trial have good safety records when used alone or together for DLBCL. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for Diffuse Large B-Cell Lymphoma because it introduces Vorinostat, a histone deacetylase inhibitor, which works differently from traditional chemotherapy. While standard treatments typically involve drugs like Rituximab and CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), adding Vorinostat may enhance the effectiveness by altering gene expression and potentially re-sensitizing cancer cells to chemotherapy. This unique mechanism offers a new way to target the cancer cells, and researchers hope it will improve patient outcomes compared to the current standard of care.

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

In this trial, participants will receive a combination of treatments, including vorinostat. Studies have shown that vorinostat stops the growth of cancer cells in diffuse large B-cell lymphoma (DLBCL) by causing cell cycle arrest. Earlier trials demonstrated that vorinostat led to both complete and partial improvements in patients with DLBCL. Participants will also receive rituximab, a monoclonal antibody that blocks cancer cell growth and assists the immune system in attacking cancer cells. Research has shown that combining vorinostat with rituximab and chemotherapy is more effective at killing cancer cells than using these treatments separately. ^{6 7 8 9 10}

Who Is on the Research Team?

Daniel O Persky

Principal Investigator

SWOG Cancer Research Network

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed stage II (bulky), III, or IV diffuse large B-cell lymphoma. Participants must have a certain level of physical fitness (Zubrod performance status 0-2) and adequate organ function as shown by blood tests. They should not be HIV positive, pregnant, or breastfeeding and must agree to use effective contraception. Prior cancer treatments are disallowed except for specific minor cases.

Inclusion Criteria

I have not had chemotherapy, radiation, or antibody therapy for lymphoma.

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

I do not have HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vorinostat orally once daily on days 1-5 or 1-9, rituximab intravenously, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3, and prednisone orally once daily on days 3-7. Treatment repeats every 21 days for 8 courses.

24 weeks

8 cycles, each with multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion every 6 months for 2 years, and then annually for 3 years.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Prednisone
• Rituximab
• Vincristine Sulfate
• Vorinostat

Trial Overview The study is testing the combination of vorinostat with rituximab and chemotherapy drugs like cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone in treating advanced diffuse large B-cell lymphoma. It aims to find the best dose of vorinostat that's effective while monitoring how well this regimen works against cancer cells.

How Is the Trial Designed?

Group I: Treatment (combination chemotherapy) Experimental Treatment 7 Interventions

Patients receive vorinostat PO once daily on days 1-5 or 1-9 (according to dose level), rituximab IV, cyclophosphamide IV over 30-60 minutes, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3. Patients also receive prednisone PO once daily on days 3-7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

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 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]

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard treatment for relapsed diffuse large B-cell lymphoma, but the addition of rituximab has improved outcomes after first-line treatment and relapses.

The CORAL trial found no significant difference in response rates between two salvage regimens (R-ICE and R-DHAP), and identified that factors like early relapse and certain genetic markers significantly affect survival, indicating that over 70% of patients may not benefit from standard salvage therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma? Gisselbrecht, C.[2022]

A phase 3 study involving 407 treatment-naïve patients with diffuse large B-cell lymphoma demonstrated that HLX01, a biosimilar to rituximab, has comparable efficacy to the reference drug, with overall response rates of 94.1% for HLX01 and 92.8% for rituximab, falling within the pre-defined equivalence margin.

The safety profiles of HLX01 and rituximab were similar, with nearly identical rates of treatment-emergent adverse events (99.5% vs. 99.0%) and serious adverse events (34.0% vs. 32.5%), confirming that HLX01 is a safe alternative to rituximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 study of rituximab biosimilar HLX01 in patients with diffuse large B-cell lymphoma. Shi, Y., Song, Y., Qin, Y., et al.[2021]

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 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 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 91 people living with HIV and Burkitt lymphoma, adding rituximab to CODOX-M/IVAC chemotherapy did not increase severe treatment-related toxicities, indicating it is a safe option for this population.

The addition of rituximab significantly improved both overall survival (72% vs. 55%) and progression-free survival (81% vs. 55%) compared to chemotherapy alone, suggesting it enhances treatment efficacy without added risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding rituximab to CODOX-M/IVAC chemotherapy in the treatment of HIV-associated Burkitt lymphoma is safe when used with concurrent combination antiretroviral therapy. Alwan, F., He, A., Montoto, S., et al.[2022]

The R-VNCOP-B regimen, which includes rituximab and several other chemotherapy agents, showed high efficacy and manageable toxicity in treating an elderly patient with high-grade B-cell lymphoma, leading to rapid improvement and long-lasting complete remission.

This case study suggests that R-VNCOP-B could be a promising first-line treatment option for elderly patients with aggressive non-Hodgkin lymphoma, especially those who may not tolerate more intensive regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable response after VNCOP-B and rituximab in an elderly patient with high-grade B-cell lymphoma. Cencini, E., Fabbri, A., Schiattone, L., et al.[2019]

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]

A study involving 86 DLBCL patients identified thirteen specific 5hmC markers in plasma cell-free DNA that are associated with how well patients respond to R-CHOP chemotherapy.

The developed logistic regression model based on these 5hmC modifications showed a prediction performance of 82% sensitivity and 75% specificity, outperforming traditional clinical indicators, suggesting it could be a promising tool for predicting treatment response in a minimally invasive way.

NCBI (Pubmed)

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. Chen, HY., Zhang, WL., Zhang, L., et al.[2021]

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]

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