DFMO Maintenance Therapy for Neuroblastoma

(NMTT Trial)

Recruiting at 54 trial locations

Overseen By BCC Enroll

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Giselle Sholler

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 104 weeks

441 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called DFMO (Difluoromethylornithine) to determine if it can prevent neuroblastoma, a type of cancer, from returning in patients currently in remission. The trial focuses on individuals who were once high-risk and have completed standard cancer treatments. Ideal candidates have no current signs of neuroblastoma, have finished their initial treatments, and seek to prevent recurrence. Participants will take DFMO orally for 730 days. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires that participants stop taking other anticancer agents before joining. The protocol does not specify about other medications, so it's best to discuss your current medications with the study team.

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

Research has shown that difluoromethylornithine (DFMO) is generally well-tolerated. In one study, 96% of patients using DFMO were alive after four years, compared to 84% of those not using it. This suggests DFMO might be a safe option for individuals with high-risk neuroblastoma. Another study found that 84% of those taking DFMO did not experience a return of cancer during the study period.

While these studies focus on DFMO's effectiveness, they also indicate that side effects are manageable, as patients continued treatment for years. However, since this trial is in phase 2, researchers are still closely studying its safety. Safety concerns are taken seriously, and any severe side effects would have been identified before reaching this phase. ^{1 2 3 4 5}

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

Difluoromethylornithine (DFMO) is unique because it targets the polyamine synthesis pathway, which is crucial for cancer cell growth. Unlike standard treatments for neuroblastoma, such as chemotherapy and immunotherapy, DFMO operates by inhibiting the enzyme ornithine decarboxylase, potentially reducing tumor growth and recurrence. Researchers are excited about DFMO because it offers a novel approach that could provide a long-term maintenance therapy option with fewer side effects, improving the quality of life for patients with neuroblastoma.

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

Research has shown that Difluoromethylornithine (DFMO) can reduce the chance of cancer recurrence in children with high-risk neuroblastoma. Studies have found that using DFMO after immunotherapy can improve long-term survival. Typically, the five-year survival rate for these patients is about 50%, but DFMO has been shown to lower the risk of cancer returning. The FDA approved DFMO for this purpose, highlighting its effectiveness. This approval is based on evidence showing better outcomes for patients who used DFMO after their initial treatments. Participants in this trial will receive DFMO as maintenance therapy to further evaluate its effectiveness in preventing cancer recurrence. ^{1 2 6 7 8}

Who Is on the Research Team?

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer at Atrium Health

Are You a Good Fit for This Trial?

This trial is for high-risk neuroblastoma patients under 30.99 years old in remission after intensive treatment, including chemotherapy, surgery, stem cell transplant, radiotherapy, immunotherapy with dinutuximab and retinoic acid. They must have no residual disease or bone marrow involvement over 10%, be within a specific time frame post-treatment, agree to birth control if applicable, and not be on other investigational drugs.

Inclusion Criteria

My scans show no signs of cancer, and my bone marrow is clear.

I can do most activities and am expected to live for at least 2 more months.

I am under 31 and have high-risk neuroblastoma, or it became high-risk after diagnosis.

Exclusion Criteria

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.

My infections are under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 730 days of oral difluoromethylornithine (DFMO) to prevent recurrence of neuroblastoma

104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Difluoromethylornithine (DFMO)

Trial Overview The trial tests DFMO as an oral maintenance therapy for preventing neuroblastoma recurrence. Participants will take DFMO daily for two years at doses adjusted by body surface area. The study includes multiple patient groups based on their previous response to standard therapies.

How Is the Trial Designed?

Group I: Difluoromethylornithine (DFMO) Experimental Treatment 1 Intervention

Subjects will receive 730 Days of oral difluoromethylornithine (DFMO) at a dose of 750 mg/m2 ± 250 mg/m2 BID (strata 1, 2, 3, and 4) OR 2500 mg/m2 BID (stratum 1B) on each day of study.

Who Is Running the Clinical Trial?

Giselle Sholler

Lead Sponsor

Trials

23

Recruited

2,500+

Giselle SaulnierSholler

Lead Sponsor

Trials

22

Recruited

2,400+

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Beat NB Cancer Foundation

Collaborator

Trials

6

Recruited

1,300+

Team Parker for Life

Collaborator

Trials

3

Recruited

1,100+

Published Research Related to This Trial

In a study involving 32 colon cancer patients, administration of Modufolin® resulted in significantly higher levels of the active folate metabolite, methyleneTHF, in both tumor and mucosal tissues compared to Isovorin® (levo-leucovorin).

The increased concentrations of methyleneTHF after Modufolin® administration suggest it may enhance the efficacy of 5-fluorouracil-based chemotherapy, warranting further clinical evaluation as a potential alternative to Isovorin®.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study. Wettergren, Y., Taflin, H., Odin, E., et al.[2021]

In a study of 1,739 colorectal cancer patients, specific genetic variations in folate-mediated one-carbon metabolism (FOCM) genes were linked to overall survival, suggesting that these genes may influence patient outcomes after treatment with 5-fluorouracil (5-FU).

One particular polymorphism in the paraoxonase 1 (PON1) gene was significantly associated with worse overall survival, indicating that genetic factors can modify the effectiveness of 5-FU-based chemotherapy and highlighting the importance of personalized medicine in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients. Ose, J., Botma, A., Balavarca, Y., et al.[2023]

Combination therapy of 5-fluorouracil (5-FU) with leucovorin (LV) shows improved response rates in colorectal cancer patients compared to single-agent 5-FU (25% vs 14%), but it does not significantly extend median survival (12.2 months vs 11.4 months).

Different dosing schedules of 5-FU/LV are therapeutically equivalent, with higher doses of LV on a weekly schedule leading to slightly better efficacy but increased toxicity, such as severe diarrhea (26% vs 14%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic treatment options in advanced colorectal cancer: perspectives on combination 5-fluorouracil plus leucovorin. Grem, JL.[2013]

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]

In a phase II trial involving 81 children with high-risk neuroblastoma (HRNB), maintenance therapy with DFMO after standard treatment significantly improved event-free survival (EFS) and overall survival (OS) compared to a historical control group of 76 patients, with 2-year EFS rates of 86.4% versus 78.3%.

The 5-year OS for patients receiving DFMO was 95.1%, compared to 81.6% in the historical cohort, indicating that DFMO may play a crucial role in preventing relapse in HRNB and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma. Lewis, EC., Kraveka, JM., Ferguson, W., et al.[2021]

The combination of 5-fluorouracil (5-FU) and leucovorin (FL) has improved response rates for colorectal cancer treatment to about 20-30%, with a median survival time of 10 to 12 months.

The FOLFOX 4 regimen, which combines the de Gramont method of 5-FU and leucovorin with oxaliplatin, has shown improved median survival times over a year and is now considered the standard treatment for advanced colorectal cancer due to its effectiveness and manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy]. Aiba, K.[2018]

A 64-year-old man with rectal cancer developed hyperammonemia and impaired consciousness after receiving the mFOLFOX6 chemotherapy regimen, highlighting a rare but serious adverse effect of this treatment.

The patient's symptoms improved rapidly with rehydration and branched-chain amino acid (BCAA) supplementation, suggesting that hyperammonemia should be monitored and managed in patients undergoing FOLFOX therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer. Kurokawa, T., Kanemoto, Y., Azuma, Y., et al.[2021]

In a study involving 77 patients with advanced solid tumors, the folate antagonist DDMP was administered before a single injection of folinic acid (CF), showing therapeutic activity against certain tumors only at lower CF doses (9 and 15 mg/m2).

Higher doses of CF did not lead to increased therapeutic effects and were associated with a lack of hematologic toxicity, indicating that increasing CF doses may not provide additional benefits in this treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II clinical trial of DDMP (2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine) and folinic acid (CF) in solid tumors. de Jager, R., Brugarolas, A., Hansen, M.[2019]

In a study involving 14 client-owned cats with oral squamous cell carcinoma (SCC), the polyamine inhibitor DFMO effectively reduced total polyamine levels in tumor tissue and normal mucosa, indicating its potential as a treatment option.

While DFMO treatment led to some side effects, such as ototoxicity in some cats and mild thrombocytopenia, it did not cause life-threatening toxicities, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study. Lewis, JR., O'Brien, TG., Skorupski, KA., et al.[2017]

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 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]

DFMO (difluoromethylornithine) is being repurposed as a potential treatment for high-risk neuroblastoma, targeting the MYC oncogene and inhibiting polyamine synthesis, which is crucial for tumor growth.

Pre-clinical studies show that DFMO can effectively block tumor initiation and exhibit anti-tumor activity in established neuroblastoma, leading to its testing in clinical trials for children, with varying dosages and combinations with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Bassiri, H., Benavides, A., Haber, M., et al.[2020]

Alpha-difluoromethylornithine (DFMO) effectively inhibits the proliferation of squamous cell carcinoma (SCC) cells without causing cytotoxicity, as it significantly depletes polyamine levels while maintaining cell viability.

DFMO treatment enhances apoptosis in SCC cells when combined with staurosporine, suggesting that manipulating polyamine levels could be a potential strategy to improve therapeutic outcomes in head and neck cancer, especially in conjunction with radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of tumor cell proliferation and apoptosis by polyamine depletion in cells of head and neck squamous cell carcinomas. Bock, JM., Pickart, MA., Pink, JJ., et al.[2013]

Citations

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

Eflornithine as Postimmunotherapy Maintenance in High-Risk ... Long-term survival in high-risk neuroblastoma (HRNB) is approximately 50%, with mortality primarily driven by relapse. Eflornithine (DFMO) ...

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. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37883734/

Externally Controlled, Propensity Score-Matched Survival ... The externally controlled analyses presented show a relapse risk reduction in patients with HRNB treated with postimmunotherapy DFMO.

4. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-eflornithine-adult-and-pediatric-patients-high-risk-neuroblastoma

FDA approves eflornithine for high-risk neuroblastoma The Food and Drug Administration approved eflornithine (IWILFIN, USWM, LLC) to reduce the risk of relapse in adult and pediatric patients with high-risk ...

5. hcp.iwilfin.com hcp.iwilfin.com/clinical-data

Clinical Data The efficacy of IWILFIN is based on an externally controlled trial comparison of outcomes between Study 3b and Study ANBL0032.

6. fda.gov fda.gov/media/172661/download

eflornithine (dfmo) tablets to reduce the risk of ... Survival Outcomes for Study 3b DFMO vs ... enrollment on Study 3b, and/or for their prognostic significance in neuroblastoma outcomes.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01586260

Study Details | NCT01586260 | Preventative Trial of ... The purpose of this research study is to evaluate a new investigational drug to prevent reoccurrence of neuroblastoma that is in remission.

8. 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 ... According to the analysis3, Four-year Event Free Survival from the end of immunotherapy was 84% in the DFMO group versus 72% in the non-DFMO ...