DFMO + Etoposide for Neuroblastoma

Recruiting at 35 trial locations

Overseen By BCC Enroll

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Giselle SaulnierSholler

Must not be taking: Investigational drugs, Anticancer agents

Disqualifiers: Uncontrolled infection, BSA <0.25 m2, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: approximately 2 years

131 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for neuroblastoma, a cancer that often affects young children. Researchers are examining the effectiveness of the drugs DFMO (Eflornithine) and etoposide in patients whose cancer has returned or did not respond to previous treatments. Those who have undergone aggressive chemotherapy for neuroblastoma and show no active disease based on specific scans might be suitable candidates. Participants will receive the treatment over several months to determine if it can prevent the cancer from returning. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking other anticancer agents before participating. You must also have recovered from the effects of previous chemotherapy. The protocol does not specify about other types of medications, so it's best to discuss with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that eflornithine (DFMO) is generally safe for patients with high-risk neuroblastoma, a type of cancer. Studies have found that DFMO maintenance therapy is well-tolerated, meaning most people can take it without serious problems. It is linked to good survival rates when used during remission, which is when the cancer is not active. In one study, 84% of patients taking DFMO lived for four years without the cancer returning. Another study found that using DFMO after immunotherapy improved survival chances.

Overall, DFMO appears safe, with studies not reporting major side effects. This suggests DFMO is fairly safe for neuroblastoma patients. Prospective trial participants should discuss any concerns with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for neuroblastoma?

Researchers are excited about Eflornithine (DFMO) for neuroblastoma because it offers a unique approach compared to standard treatments like chemotherapy and radiation. Unlike these treatments, which target rapidly dividing cells in a more general way, Eflornithine works by specifically inhibiting an enzyme called ornithine decarboxylase, which is crucial for cancer cell growth. This targeted mechanism could potentially lead to fewer side effects and better outcomes. Additionally, the treatment involves an extended course of Eflornithine alone, which might provide long-term suppression of the cancer.

What evidence suggests that this treatment might be an effective treatment for neuroblastoma?

Research has shown that eflornithine (DFMO) can benefit children with high-risk neuroblastoma, a serious cancer type. Studies have found that DFMO can extend the time patients live without cancer recurrence, sometimes improving survival by 10%-12% over several years. This trial will evaluate DFMO combined with etoposide, another cancer drug, to assess its effectiveness in controlling neuroblastoma. These findings suggest DFMO is a promising treatment option for children whose neuroblastoma has returned or is difficult to treat. ^{1 2 3 5 6}

Who Is on the Research Team?

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer

Are You a Good Fit for This Trial?

This trial is for individuals under 31 years old with neuroblastoma that has come back or didn't respond to treatment. They must have completed at least 4 cycles of intense chemotherapy, have good organ function, and a performance score of 60% or higher. Women who can have children need a negative pregnancy test and agree to use birth control.

Inclusion Criteria

My scans show no remaining cancer.

I will start the trial within 60 days of my last cancer treatment.

I have recovered from previous cancer treatments without lingering side effects.

Exclusion Criteria

I have never taken DFMO at a dose higher than 1000mg/m2 twice a day before this study.

My body surface area is less than 0.25 square meters.

I am not currently on any cancer treatments and have recovered from previous ones.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone

approximately 2 years

Regular visits as per cycle schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Open-label extension

Participants may continue to receive DFMO long-term

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Eflornithine

Trial Overview

The study tests Eflornithine (DFMO) in combination with etoposide on patients with relapsed/refractory neuroblastoma. It's an open-label, multicenter trial meaning all participants know what treatment they're getting and it involves multiple locations.

How Is the Trial Designed?

Group I: Eflornithine (DFMO) Experimental Treatment 1 Intervention

In this study subjects will receive six 21-day cycles of Etoposide and DFMO followed by an additional 630 days of DFMO alone. Etoposide will be given at 50 mg/m2/dose PO daily for the first 14 days of each 21 days until 6 cycles of etoposide are completed. DFMO (difluoromethylornithine) will be given at a dose of 1000 mg/m2 BID on each day of study.

Eflornithine is already approved in European Union, United States for the following indications:

Approved in European Union as Vaniqa for:

• Hirsutism
• African trypanosomiasis

Approved in United States as Vaniqa for:

• Hirsutism

Approved in United States as Iwilfin for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Giselle SaulnierSholler

Lead Sponsor

Trials

22

Recruited

2,400+

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Giselle Sholler

Lead Sponsor

Trials

23

Recruited

2,500+

Beat NB Cancer Foundation

Collaborator

Trials

6

Recruited

1,300+

Team Parker for Life

Collaborator

Trials

3

Recruited

1,100+

K C Pharmaceuticals Inc.

Industry Sponsor

Trials

5

Recruited

790+

USWM, LLC

Collaborator

Trials

1

Published Research Related to This Trial

In a study of 20 patients with poor-prognosis neuroblastoma treated with the high-dose multiagent regimen OMEC, 20% experienced treatment-related deaths due to severe gastrointestinal toxicity, highlighting significant safety concerns.

Only 1 out of 5 patients achieved complete remission, and 65% relapsed within a median of 10 months, indicating that OMEC was not more effective than high-dose melphalan alone, suggesting that such multiagent regimens may not be advisable due to their high toxicity and limited efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot study of high-dose vincristine, etoposide, carboplatin and melphalan with autologous bone marrow rescue in advanced neuroblastoma. Corbett, R., Pinkerton, R., Pritchard, J., et al.[2019]

In a study of 11 patients with olfactory neuroblastoma, neoadjuvant chemotherapy using the VIP regimen (etoposide, ifosfamide, and cisplatin) resulted in an 82% objective response rate, with 2 complete responses and 7 partial responses.

The treatment was associated with manageable side effects, primarily hematologic toxicity, but all adverse events were reversible, and there were no chemotherapy-related deaths, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Kim, DW., Jo, YH., Kim, JH., et al.[2013]

The ODC inhibitor difluoromethylornithine (DFMO) is safe and well tolerated in children with relapsed neuroblastoma, with no dose-limiting toxicities observed at doses between 500-1500 mg/m2.

Patients with the minor T allele at rs2302616 of the ODC gene showed better responses to DFMO therapy, indicating that genetic factors may influence treatment efficacy and suggesting a potential for personalized therapy based on genetic profiling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. Saulnier Sholler, GL., Gerner, EW., Bergendahl, G., et al.[2022]

alpha-Difluoromethylornithine (DFMO) effectively inhibits the growth of Burkitt's lymphoma cells, showing significant reductions in cell proliferation and colony formation at concentrations of 50 micrograms/ml or higher.

When combined with doxorubicin or cisplatin, DFMO enhances the effectiveness of these chemotherapy agents, demonstrating synergistic effects that could improve treatment outcomes for lymphoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of alpha-difluoromethylornithine alone and in combination with doxorubicin hydrochloride, cis-diamminedichloroplatinum (II), and vinblastine sulfate on the growth of P3J cells in vitro. Allen, ED., Natale, RB.[2013]

In a study involving 13 children with refractory neuroblastoma, the treatment with the epipodophyllotoxin VM-26 resulted in partial responses in 3 patients, indicating its potential efficacy in reducing tumor size and tumor cell presence in bone marrow.

The treatment was associated with minimal acute nonhematologic toxicity, although hematologic toxicity was difficult to assess due to pre-existing bone marrow involvement from the tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epipodophyllotoxin VM-26 in the treatment of childhood neuroblastoma. Rivera, G., Green, A., Hayes, A., et al.[2013]

In a Phase II study involving 101 children with high-risk neuroblastoma (HRNB), maintenance therapy with the drug difluoromethylornithine (DFMO) showed a high two-year event-free survival (EFS) rate of 84% and overall survival (OS) rate of 97% after standard therapy.

For patients who had relapsed or refractory disease, DFMO also demonstrated efficacy with a two-year EFS of 54% and OS of 84%, indicating that DFMO is a well-tolerated treatment option that may help prevent relapse in HRNB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance DFMO Increases Survival in High Risk Neuroblastoma. Sholler, GLS., Ferguson, W., Bergendahl, G., et al.[2019]

Fenretinide demonstrated significant cytotoxic activity against neuroblastoma cell lines, achieving over 1 log cell kill at clinically relevant concentrations, while DFMO showed minimal cytotoxicity.

DFMO did not significantly increase apoptosis in neuroblastoma cells, whereas fenretinide induced a much higher level of apoptosis, suggesting that fenretinide may be a more effective option for maintenance therapy in neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines. Makena, MR., Cho, HE., Nguyen, TH., et al.[2022]

The combination of the ODC inhibitor DFMO with the renal clearance inhibitor probenecid significantly enhances the antitumor activity of DFMO in neuroblastoma patient-derived xenografts, suggesting a promising strategy to improve treatment efficacy.

DFMO/probenecid treatment leads to decreased levels of polyamines and MYCN protein, as well as dephosphorylation of retinoblastoma protein, indicating that this combination may induce cell cycle arrest in neuroblastoma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma. Schultz, CR., Swanson, MA., Dowling, TC., et al.[2021]

Oral etoposide was effective in treating resistant stage 4 neuroblastoma in 9 out of 9 children with either refractory disease or asymptomatic relapses, showing significant improvement in disease markers without major organ toxicity or severe side effects.

The treatment demonstrated minimal myelosuppression and no need for transfusions, suggesting that low-dose oral etoposide could be a safe option for consolidative therapy in pediatric patients with minimal residual disease after intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral etoposide for refractory and relapsed neuroblastoma. Kushner, BH., Kramer, K., Cheung, NK.[2017]

In a study involving 141 high-risk neuroblastoma patients treated with eflornithine (DFMO) after immunotherapy, DFMO significantly improved event-free survival (EFS) and overall survival (OS) compared to historical controls, with hazard ratios of 0.50 and 0.38, respectively.

The findings were supported by a median follow-up of 6.1 years for DFMO-treated patients and robust statistical analyses, indicating that DFMO may effectively reduce relapse risk in high-risk neuroblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons. Oesterheld, J., Ferguson, W., Kraveka, JM., et al.[2023]

Citations

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10730038/

Eflornithine as Postimmunotherapy Maintenance in High-Risk ...

The magnitude of the effect size, with HRs consistently around 0.5 and a 4-year EFS point estimate improvement of 10%-12%, aligns with ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.10060

Survival outcomes in patients with high-risk neuroblastoma ...

Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality.

3.

fda.gov

fda.gov/media/172726/download

Eflornithine (DFMO) for patients with high-risk ...

conclude that DFMO improves event-free survival in patients with high-risk neuroblastoma?

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10190116/

Difluoromethylornithine (DFMO) and Neuroblastoma

DFMO represents a promising therapeutic option for high-risk neuroblastoma, a deadly childhood cancer that currently lacks effective treatments.

5.

cclg.org.uk

cclg.org.uk/sites/default/files/2025-03/cclg-dfmo-statement-for-patients-and-families-8-10-24.pdf

Eflornithine (DFMO) in the treatment of high-risk ...

Eflornithine (Difluoromethylornithine or DFMO) is an oral drug, which has been investigated for its effects in neuroblastoma.

6.

nature.com

nature.com/articles/s41598-018-32659-w

Maintenance DFMO Increases Survival in High Risk ...

DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic ...