Advanced Therapy for Neuroblastoma

(PEDS-PLAN Trial)

Recruiting at 26 trial locations

Overseen By Michael Isakoff, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Giselle Sholler

Must not be taking: Investigational drugs

Disqualifiers: Lactating, Malabsorption, Mental illness, 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

Compensation: Varies

Number of Visits: Unknown

500 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot be on any investigational drugs at the same time as this trial.

What data supports the effectiveness of the drug Ceritinib, Danyelza, naxitamab-gqgk, humanized 3F8, hu3F8, Dasatinib, Sprycel, DFMO, Eflornithine, DL-alpha-difluoromethylornithine, Iwilfin, 2-(difluoromethyl)ornithine, alpha-difluoromethylornithine, Sorafenib, Nexavar, Vorinostat, Zolinza, Suberoylanilide hydroxamic acid, SAHA, MK-0683, MK0683, N-hydroxy-N'-phenyloctanediamide, N1-hydroxy-N8-phenyloctanediamide, Suberanilohydroxamic acid for neuroblastoma?

The research does not provide direct evidence for the effectiveness of the specific drugs listed in the treatment for neuroblastoma. However, it mentions the potential of other drugs like ponatinib and axitinib, which are multiple tyrosine kinase inhibitors, showing promise in inhibiting neuroblastoma cell growth and tumor invasion in preclinical studies. ^{1 2 3 4 5}

Is naxitamab safe for treating neuroblastoma?

Naxitamab, when used in combination with other drugs for high-risk neuroblastoma, has shown some side effects like myelosuppression (reduced bone marrow activity) and diarrhea, as well as pain and high blood pressure. Severe side effects occurred in 85% of patients, but these were expected and managed during outpatient treatment. ^{2 5 6 7 8}

What makes the drug combination of Ceritinib, Dasatinib, DFMO, Sorafenib, and Vorinostat unique for treating neuroblastoma?

This drug combination is unique because it includes multiple targeted therapies that work together to attack neuroblastoma cells through different mechanisms, potentially increasing effectiveness. These drugs are known for their roles in inhibiting specific pathways that cancer cells use to grow and survive, offering a novel approach compared to traditional chemotherapy. ^{1 2 4 7 8}

What is the purpose of this trial?

A prospective open label, multicenter study to evaluate the feasibility and acute toxicity of using molecularly guided therapy in combination with standard therapy followed by a Randomized Controlled Trial of standard immunotherapy with or without DFMO followed by DFMO maintenance for Subjects with Newly Diagnosed High-Risk Neuroblastoma.

Research Team

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer

Eligibility Criteria

This trial is for children and young adults up to 21 years old with high-risk neuroblastoma. Participants must have proper heart, liver, and kidney function, not have had more than one cycle of certain chemotherapies, and be able to undergo stem cell collection. Pregnant or breastfeeding individuals can't join; neither can those with conditions that might affect the study's results.

Inclusion Criteria

I have been diagnosed with neuroblastoma or ganglioneuroblastoma.

I was 21 years old or younger when first diagnosed.

All subjects and/or legal guardians must sign informed written consent

Exclusion Criteria

Subjects with any other medical condition deemed by the Investigator to interfere with the interpretation of the results or the subject's ability to cooperate and participate in the study

Lactating females are not eligible unless they have agreed not to breastfeed their infants

Subjects receiving any investigational drug concurrently

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive molecularly guided therapy in combination with standard chemotherapy

Cycles 3-6 (approximately 6 months)

Randomized Controlled Trial

Participants receive standard immunotherapy with or without DFMO

2 years

DFMO Maintenance

Participants receive DFMO BID for 730 days

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Ceritinib
• Dasatinib
• DFMO
• Sorafenib
• Vorinostat

Trial Overview The study tests molecularly guided therapy combined with standard treatments for neuroblastoma. It includes a randomized trial comparing standard immunotherapy alone versus with DFMO (an investigational drug), followed by maintenance therapy using DFMO.

Participant Groups

Group I: Standard Immunotherapy without DFMO Active Control 4 Interventions

One of the following drugs will be chosen for each subject based on molecular guided results: ceritinib, dasatinib, sorafenib or vorinostat. This will be followed standard immunotherapy with Dinutuximab/GM-CSF/IL-2 and isotretinoin. At the end of immunotherapy, DFMO will be given to all subjects BID for 730 days.

Group II: Standard Immunotherapy with DFMO Active Control 5 Interventions

One of the following drugs will be chosen for each subject based on molecular guided results: ceritinib, dasatinib, sorafenib or vorinostat. This will be followed standard immunotherapy with Dinutuximab/GM-CSF/IL-2 and isotretinoin PLUS 1000mg/m2 BID of DFMO. At the end of immunotherapy, all subjects will go on to receive DFMO BID for 730 days.

Ceritinib is already approved in United States for the following indications:

Approved in United States as Danyelza for:

• High-risk neuroblastoma in the bone or bone marrow

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+

K C Pharmaceuticals Inc.

Industry Sponsor

Trials

5

Recruited

790+

Team Parker for Life

Collaborator

Trials

3

Recruited

1,100+

Dell, Inc.

Industry Sponsor

Trials

3

Recruited

740+

Findings from Research

FTY720 shows potent anti-cancer activity against neuroblastoma (NB) in preclinical models, effectively inducing cell death and inhibiting tumor growth, especially when combined with the chemotherapy drug topotecan.

The mechanism of action for FTY720 involves the inhibition of sphingosine kinase 2 and the alteration of sphingolipid levels, leading to a unique, caspase-independent cell death pathway that may enhance treatment strategies for advanced NB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. Li, MH., Hla, T., Ferrer, F.[2021]

A high-content screening of 349 FDA-approved anticancer drugs identified ponatinib and axitinib as promising candidates for repurposing to treat high-risk neuroblastoma, showing effectiveness in inhibiting cell viability and inducing apoptosis in both 2D and 3D models.

Ponatinib demonstrated superior effects by consistently blocking cell migration and invasion, and it effectively inhibited tumor growth in mice with neuroblastoma, supporting its potential as a new treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy. Sidarovich, V., De Mariano, M., Aveic, S., et al.[2020]

Neuroblastoma, the most common childhood cancer, has a poor prognosis with a 5-year event-free survival rate of only 40% for high-risk patients, despite advancements in chemotherapy and maintenance therapies.

Novel targeted therapies, such as ALK inhibitors (like crizotinib and TAE684) and aurora kinase A inhibitors (like MLN8237), show promise in treating neuroblastoma by specifically targeting genetic mutations and may lead to more personalized treatment plans based on individual tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of treatment strategies for advanced neuroblastoma. Hara, J.[2021]

The combination treatment of irinotecan, temozolomide, dintuximab, and GM-CSF (I/T/DIN/GM-CSF) showed significant antitumor activity in patients with relapsed or refractory neuroblastoma, with an overall objective response rate of 41.5% across 53 patients.

The treatment was associated with a one-year progression-free survival rate of 67.9% and an overall survival rate of 84.9%, although it also resulted in notable grade ≥ 3 toxicities, including fever/infection and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. Mody, R., Yu, AL., Naranjo, A., et al.[2021]

A phase 1 study demonstrated that lorlatinib is both safe and effective for children with treatment-refractory or relapsed ALK-driven neuroblastoma, highlighting its potential as a new treatment option.

These preliminary findings suggest that lorlatinib could provide hope for young patients who have not responded to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. Suk, Y., Singh, SK.[2023]

The FDA has approved dinutuximab, marking a significant advancement in the treatment of high-risk neuroblastoma, as it is the first major new therapy for this condition in over ten years.

Dinutuximab is used in combination with three other agents, enhancing its efficacy in treating this aggressive form of cancer in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab approved for high-risk neuroblastoma. [2020]

In a study of 34 patients with high-risk neuroblastoma who did not respond completely to initial therapy, the combination of naxitamab, irinotecan, temozolomide, and GM-CSF showed a complete response rate of 29% and a significant improvement in overall survival (OS) and event-free survival (EFS) when treatment was started early.

Patients receiving early treatment (cohort 1) had a 3-year OS of 84.8% and EFS of 54.4%, which were significantly better than those in the late treatment group (cohort 2), highlighting the importance of timing in administering this chemo-immunotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes. Muñoz, JP., Larrosa, C., Chamorro, S., et al.[2023]

Activating mutations in the ALK gene are common in neuroblastoma, making it a key target for new treatments, as preclinical studies show that ALK inhibitors can effectively combat tumor growth.

The first approved ALK inhibitor, Crizotinib, has shown promising results in pediatric phase I trials for neuroblastoma, and a new international phase I study for the second-generation ALK inhibitor, LDK-378, is set to begin, expanding treatment options for young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapy for Neuroblastoma: ALK Inhibitors. Schulte, JH., Schulte, S., Heukamp, LC., et al.[2022]

References

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

FTY720 inhibits tumor growth and enhances the tumor-suppressive effect of topotecan in neuroblastoma by interfering with the sphingolipid signaling pathway. [2021]

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

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy. [2020]

3. Japan pubmed.ncbi.nlm.nih.gov

Development of treatment strategies for advanced neuroblastoma. [2021]

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

Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children's Oncology Group. [2021]

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

Safety and efficacy of lorlatinib against ALK-driven refractory or relapsed neuroblastoma. [2023]

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

Dinutuximab approved for high-risk neuroblastoma. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Early Salvage Chemo-Immunotherapy with Irinotecan, Temozolomide and Naxitamab Plus GM-CSF (HITS) for Patients with Primary Refractory High-Risk Neuroblastoma Provide the Best Chance for Long-Term Outcomes. [2023]

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

Targeted Therapy for Neuroblastoma: ALK Inhibitors. [2022]