DFMO Maintenance Therapy for Neuroblastoma

(NMTT Trial)

Recruiting at49 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Giselle Sholler

Must not be taking: Investigational drugs, Anticancer agents

Disqualifiers: Uncontrolled infection, BSA <0.25 m2, others

No Placebo Group

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a medication called DFMO in patients with high-risk neuroblastoma who are in remission. The goal is to prevent the cancer from returning by stopping an enzyme that cancer cells need to grow. DFMO was initially developed as a cancer therapeutic agent but gained renewed interest as a preventive agent after showing effectiveness in inhibiting cancer development in rodent models.

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.

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

Research shows that DFMO can reduce tumor growth by depleting polyamines, which are compounds that help cancer cells grow. This effect was observed in studies on head and neck cancers and feline oral cancers, suggesting potential benefits for other cancers like neuroblastoma. ^{1 2 3 4 5}

Is DFMO safe for use in humans?

DFMO (also known as Eflornithine) has been used safely in clinical trials for neuroblastoma, showing it is well tolerated in children. It is also FDA-approved for treating other conditions like African sleeping sickness, indicating its general safety in humans. ^{6 7 8 9 10}

How does DFMO maintenance therapy for neuroblastoma differ from other treatments?

DFMO (2-difluoromethylornithine) is unique because it targets polyamine levels, which are compounds involved in cell growth, and has shown effectiveness in reducing tumor polyamine levels without severe toxicities. This approach is different from traditional chemotherapy, which often targets DNA synthesis or cell division directly. ^{1 4 11 12 13}

Research Team

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer at Atrium Health

Eligibility Criteria

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

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.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• Difluoromethylornithine (DFMO) (Polyamine Synthesis Inhibitor)

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.

Participant Groups

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+

Dr. L. Ebony Boulware

Wake Forest University Health Sciences

Chief Medical Officer since 2022

MD from Duke University School of Medicine, MPH from Johns Hopkins Bloomberg School of Public Health

Dr. Julie Ann Freischlag

Wake Forest University Health Sciences

Chief Executive Officer since 2020

BS from University of Illinois, MD from Rush University

Beat NB Cancer Foundation

Collaborator

Trials

6

Recruited

1,300+

Team Parker for Life

Collaborator

Trials

3

Recruited

1,100+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

References

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

Polyamine inhibitors for treatment of feline oral squamous cell carcinoma: a proof-of-concept study. [2017]

2. Japan pubmed.ncbi.nlm.nih.gov

[Chemotherapy]. [2018]

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

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

4. Germany 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. [2019]

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

Modulation of tumor cell proliferation and apoptosis by polyamine depletion in cells of head and neck squamous cell carcinomas. [2013]

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

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

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

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

8. China pubmed.ncbi.nlm.nih.gov

Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

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

10. United States 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. [2021]

11. Germany 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. [2021]

12. Germany pubmed.ncbi.nlm.nih.gov

Hyperammonemia-induced impaired consciousness following mFOLFOX6 therapy in a patient with recurrent rectal cancer. [2021]

13. United States 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. [2023]