DFMO + Etoposide for Neuroblastoma

Recruiting at 30 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

Trial Summary

What is the purpose of this trial?

This trial uses two drugs, DFMO and etoposide, to treat children whose neuroblastoma has come back or didn't respond to initial treatments. DFMO stops cancer cells from growing, and etoposide helps kill them. The study includes patients who are recovering after additional therapy, those who have had the disease return but are currently without symptoms, and those with active disease. DFMO has been evaluated as a follow-up treatment for severe neuroblastoma in previous studies.

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.

What data supports the effectiveness of the drug DFMO + Etoposide for treating neuroblastoma?

Research shows that DFMO (Eflornithine) as a maintenance therapy for high-risk neuroblastoma can improve survival rates, with a two-year event-free survival of 84% and overall survival of 97% in patients who completed standard therapy. Additionally, etoposide has shown effectiveness in treating neuroblastoma, with some patients experiencing significant tumor reduction. ^{1 2 3 4 5}

Is DFMO safe for use in humans?

DFMO (also known as Eflornithine) has been used in clinical trials for neuroblastoma and is generally well tolerated, with studies indicating it is safe for maintenance therapy in children with high-risk neuroblastoma. It has also been FDA-approved for other conditions, suggesting a recognized safety profile. ^{1 2 6 7 8}

What makes the drug DFMO + Etoposide unique for treating neuroblastoma?

The drug DFMO (Eflornithine) is unique for treating neuroblastoma because it targets ornithine decarboxylase (ODC), an enzyme linked to poor prognosis, and is used as a maintenance therapy to prevent relapse after standard treatment, showing improved survival rates. It is administered orally and has been shown to be well tolerated, offering a novel approach compared to traditional therapies. ^{1 2 5 9 10}

Research Team

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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 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]

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]

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]

References

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

Eflornithine as Postimmunotherapy Maintenance in High-Risk Neuroblastoma: Externally Controlled, Propensity Score-Matched Survival Outcome Comparisons. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Maintenance DFMO Increases Survival in High Risk Neuroblastoma. [2019]

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

Epipodophyllotoxin VM-26 in the treatment of childhood neuroblastoma. [2013]

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

Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. [2013]

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

Oral etoposide for refractory and relapsed neuroblastoma. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Pilot study of high-dose vincristine, etoposide, carboplatin and melphalan with autologous bone marrow rescue in advanced neuroblastoma. [2019]

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

Cytotoxic activity of difluoromethylornithine compared with fenretinide in neuroblastoma cell lines. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Probenecid increases renal retention and antitumor activity of DFMO in neuroblastoma. [2021]

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

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma. [2022]

10. United States 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. [2013]