Chemotherapy + Stem Cell Rescue for Neuroblastoma

Overseen By Lisa Burke

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Uncontrolled infection, Inadequate organ function, 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

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests an advanced treatment for individuals with high-risk neuroblastoma, a cancer affecting nerve tissues. It combines powerful chemotherapy drugs with stem cell rescue, where healthy stem cells rebuild the immune system after treatment. Participants will undergo two rounds of chemotherapy followed by stem cell rescue to determine if this approach improves outcomes. Ideal candidates have recently completed initial chemotherapy and shown some response. Eligible participants must have already collected a specific number of their own stem cells for the trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, contributing to significant advancements in cancer care.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of drugs used in this treatment has some safety evidence from previous studies. Thiotepa and melphalan, when used together, demonstrated a 100% survival rate at day 100 after a stem cell transplant, indicating their safety in this context. However, they can be harmful, so this is important to consider.

Cyclophosphamide has been well-tolerated in other treatments, with patients responding well and experiencing manageable side effects. Etoposide also has promising safety data. Studies have reported better survival rates and fewer relapses, suggesting it is generally safe.

Carboplatin has been linked to some side effects, mainly affecting blood cells, but severe reactions are rare. One study reported that only 20% of patients experienced higher levels of blood-related side effects, with no fatal outcomes.

Overall, these drugs have been used safely in similar treatments. Evidence for their safety varies, but they are generally considered tolerable when managed carefully. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the chemotherapy and stem cell rescue treatment for neuroblastoma because it combines potent chemotherapy drugs with an innovative stem cell rescue approach. Unlike standard treatments that rely solely on chemotherapy, this approach uses drugs like thiotepa, cyclophosphamide, melphalan, etoposide, and carboplatin in high doses to aggressively target cancer cells. The unique aspect is the Peripheral Blood Stem Cell (PBSC) rescue, which helps regenerate healthy blood cells after high-dose chemotherapy, potentially reducing side effects and enhancing recovery. This combination could offer improved outcomes and quicker recovery compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for high-risk neuroblastoma?

Research has shown that using thiotepa and cyclophosphamide together, followed by a stem cell rescue, can extend the lives of patients with high-risk neuroblastoma. One study found a 73.7% chance of remaining disease-free for three years with this method, which is encouraging. In this trial, participants will receive this combination as part of their treatment. Additionally, participants will receive another combination of drugs—melphalan, etoposide, and carboplatin—followed by a second stem cell rescue. Studies indicate that this combination can effectively support patients after initial chemotherapy. Both treatments are being studied in this trial for their potential to improve outcomes in neuroblastoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Ashish Gupta, MD, PhD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

This trial is for patients under 30 years old with high-risk neuroblastoma who've finished induction chemotherapy. They should show some response to treatment, have no uncontrolled infections, and enough harvested stem cells for transplants. Participants need good liver, heart, lung, and kidney function and must provide consent.

Inclusion Criteria

I was diagnosed with neuroblastoma before turning 30.

Hematopoietic Recovery from last induction course of chemotherapy

My cancer responded to initial treatment or remained stable.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Consolidation Course #1

Participants receive thiotepa and cyclophosphamide followed by a PBSC rescue

4-6 weeks

In-patient stay for chemotherapy and PBSC rescue

Consolidation Course #2

Participants receive melphalan, etoposide, and carboplatin followed by a second PBSC rescue

4-6 weeks

In-patient stay for chemotherapy and PBSC rescue

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Autologous Stem Cell Infusion
• Carboplatin
• Cyclophosphamide
• Etoposide
• Granulocyte colony stimulating factor
• Melphalan
• Thiotepa

Trial Overview The study tests a two-course myeloablative consolidation therapy followed by autologous stem cell rescue in high-risk neuroblastoma patients post-induction chemotherapy. Drugs used include Carboplatin, Thiotepa, Cyclophosphamide, Melphalan, Etoposide along with stem cell infusion and growth factor support.

How Is the Trial Designed?

Group I: Patients Treated for Neuroblastoma Experimental Treatment 7 Interventions

Consolidation course #1 consists of thiotepa and cyclophosphamide followed by a PBSC rescue. Consolidation course #2 consists of melphalan, etoposide and carboplatin followed by a second PBSC rescue. Post infusion, patients will receive Granulocyte-Colony Stimulating Factor beginning on Day 0 of each consolidation course.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Published Research Related to This Trial

In a study of 16 patients with advanced neuroblastoma receiving high-dose chemotherapy followed by autologous bone marrow rescue, 10 patients remained alive and disease-free after a median of 12.5 months, indicating potential efficacy of the treatment despite significant risks.

The treatment caused severe side effects, including high rates of bone marrow toxicity, mucositis, and unexpected severe renal failure, leading to three treatment-related deaths, highlighting the need for caution in using such aggressive regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of single-day high-dose vincristine, melphalan, etoposide and carboplatin consolidation with autologous bone marrow rescue in advanced neuroblastoma. Gordon, SJ., Pearson, AD., Reid, MM., et al.[2019]

In a study involving 8 pediatric patients with advanced neuroblastoma, the A 1 chemotherapy protocol was found to be effective for round cell type neuroblastoma but ineffective for composite type ganglioneuroblastoma.

The results suggest that more than 3 courses of the A 1 protocol are needed to achieve a significant therapeutic effect, although the chemotherapy's effectiveness did not correlate with patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical evaluation of A 1 protocol in advanced neuroblastoma]. Iwafuchi, M., Ohsawa, Y., Hirota, M., et al.[2015]

The TMT (treosulfan, melphalan, and thiotepa) regimen was well tolerated in 17 children with recurrent or refractory neuroblastoma, showing manageable toxicity and no severe neurologic, cardiac, or dermatologic side effects.

Patients with primary resistance had a significantly better overall survival rate (100%) compared to those with relapsed disease (22.6%), and post-transplant dinutuximab beta immunotherapy greatly improved 5-year overall survival (66.7% vs. 11.4%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma. Wawrzyniak-Dzierżek, E., Gajek, K., Rybka, B., et al.[2020]

Topotecan, used in a myeloablative regimen with thiotepa and carboplatin, showed promising efficacy in treating poor-prognosis tumors, particularly in neuroblastoma and brain tumors, with a follow-up of up to 32 months revealing significant event-free survival rates.

The treatment was associated with manageable toxicities, although severe mucositis and other complications were noted, indicating that while the regimen is effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors, and other poor-risk solid tumors in children and young adults. Kushner, BH., Cheung, NK., Kramer, K., et al.[2013]

In a phase II study involving 47 children with metastatic neuroblastoma, the combination of etoposide and carboplatin showed a 43% response rate, including 4 complete remissions and 13 partial remissions, indicating potential efficacy as an alternative treatment.

The treatment was associated with significant hematologic toxicity, leading to a median delay of 39 days between courses, and some patients experienced notable kidney and hearing side effects, suggesting the need for careful monitoring and further evaluation in newly diagnosed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. Frappaz, D., Michon, J., Hartmann, O., et al.[2017]

The three-drug myeloablative regimen for high-risk neuroblastoma, involving topotecan, thiotepa, and carboplatin, showed manageable toxicity but failed to prevent central nervous system (CNS) relapses, with significant non-hematologic side effects including mucositis and skin issues.

Among 46 patients who underwent stem cell transplantation in first complete or very good partial remission, the event-free survival rate was 54% at 36 months, highlighting the need for improved strategies to prevent CNS relapses, as several patients experienced brain relapses despite treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system. Kushner, BH., Kramer, K., Modak, S., et al.[2013]

In a study involving 14 patients with stage 4 neuroblastoma, amifostine did not show significant benefits in terms of hematological recovery or renal toxicity compared to a historical control group of 24 patients.

However, amifostine was associated with a notable reduction in severe mucositis, as none of the patients in the amifostine group required artificial ventilation, suggesting it may offer protective benefits in conventional neuroblastoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of amifostine on neuroblastoma during high dose chemotherapy: in vivo and in vitro investigations. Renner, S., Krümpelmann, S., Bruchelt, G., et al.[2013]

In a study involving 1347 patients with high-risk neuroblastoma, the high-dose chemotherapy regimen of busulfan and melphalan resulted in a significantly better 3-year event-free survival rate of 50% compared to 38% for the carboplatin, etoposide, and melphalan regimen.

The busulfan and melphalan treatment also led to fewer severe adverse events, with only 4% of patients experiencing life-threatening toxicities, compared to 10% in the carboplatin, etoposide, and melphalan group, suggesting it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Ladenstein, R., Pötschger, U., Pearson, ADJ., et al.[2022]

In a study of high-risk neuroblastoma patients undergoing autologous stem cell rescue, those treated with the carboplatin/etoposide/melphalan (CEM) regimen required longer use of antibiotics, antihypertensives, and analgesics compared to those treated with busulfan/melphalan (BuMel).

Patients receiving BuMel had a longer median hospitalization duration and a higher incidence of mechanical ventilation and sinusoidal obstruction syndrome (SOS), indicating that while CEM may require more supportive care resources, BuMel may lead to more severe complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resource Utilization and Toxicities After Carboplatin/Etoposide/Melphalan and Busulfan/Melphalan for Autologous Stem Cell Rescue in High-Risk Neuroblastoma Using a National Administrative Database. Desai, AV., Seif, AE., Li, Y., et al.[2018]

In a study comparing high-dose chemotherapy regimens for high-risk neuroblastoma in Egypt and the United States, patients in Egypt experienced delayed engraftment and higher rates of severe complications, particularly sinusoidal obstruction syndrome, linked to pre-existing hepatitis infections.

Despite these challenges, the study concluded that autologous stem-cell transplantation is feasible in resource-limited settings, highlighting the need for careful management of patient comorbidities and treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources. Elzembely, MM., Park, JR., Riad, KF., et al.[2019]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29674658/

High-dose Carboplatin/Etoposide/Melphalan increases risk ... We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7765864/

Melphalan, Etoposide, and Carboplatin Megatherapy with ... The aim of our retrospective study was to analyze the outcome of 18 children with GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy and ...

3. ahdbonline.com ahdbonline.com/issues/2011/august-2011-vol-4-no-4-special-issue/article-788

New Standard of Care for Childhood Neuroblastoma The 3-year overall survival was 60% with busulfan-melphalan versus 48% with CEM without immunotherapy. The busulfan-melphalan group had a lower relapse rate and ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/095980499290509Z

Pilot study of high-dose vincristine, etoposide, carboplatin ... High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. 2005 ...

5. ascopubs.org ascopubs.org/doi/pdf/10.1200/JCO.1992.10.10.1592

Etoposide and carboplatin in neuroblastoma In these heavily pretreated patients,. 16% had a more than 50% decrease in creatinine clear- ance and a 22% World Health Organization (WHO) grade. 2 ototoxicity ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/8040674/

Phase II investigational window using carboplatin, iproplatin ... Results: After phase II therapy, only 20% of patients experienced grade 3/4 hematopoietic toxicity. No toxic deaths occurred. Objective response rates (partial ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2468124525000348

Clinical profile and outcome of children with Neuroblastoma This study describes the clinical and epidemiological profile and outcome of neuroblastoma from a large public hospital in Northern India.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7586261/

The Inhibitory Effect of Carboplatin Injection on Human ... The results in all these aspects showed that carboplatin injection had a significant inhibitory effect on neuroblastoma SK-N-SH. Literature review found that ...

9. siope.eu siope.eu/media/documents/escp-high-risk-neuroblastoma-standard-clinical-practice-recommendations.pdf

escp-high-risk-neuroblastoma-standard-clinical-practice- ... Prognosis of patients with high-risk neuroblastoma (HR-NBL) remains poor despite multimodal treatment including induction chemotherapy, local treatment (surgery ...

10. ascopubs.org ascopubs.org/doi/10.1200/EDBK_349783

High-Risk and Relapsed Neuroblastoma: Toward More ... With this treatment paradigm, 5-year event-free survival (EFS) was 51% in a recent analysis of patients with HRNB from the Children's Oncology ...