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

Trial Summary

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.

What data supports the effectiveness of the treatment for neuroblastoma?

Research shows that high-dose chemotherapy with stem cell rescue, including drugs like carboplatin, etoposide, and melphalan, improves event-free survival in patients with high-risk neuroblastoma. Additionally, a regimen including topotecan, thiotepa, and carboplatin has shown favorable results for disease control in neuroblastoma, although it may not prevent relapse in the central nervous system. ^{1 2 3 4 5}

Is the combination of chemotherapy and stem cell rescue generally safe for treating neuroblastoma?

The combination of chemotherapy drugs like thiotepa, carboplatin, etoposide, and melphalan with stem cell rescue has been studied for neuroblastoma, showing manageable toxicity but with some severe side effects like mucositis (painful inflammation and ulceration of the mucous membranes lining the digestive tract) and gastrointestinal issues. Some studies reported treatment-related deaths and severe toxicities, indicating that while the regimen can be effective, it also carries significant risks. ^{1 2 6 7 8}

How does the chemotherapy and stem cell rescue treatment for neuroblastoma differ from other treatments?

This treatment combines high-dose chemotherapy drugs like carboplatin, cyclophosphamide, etoposide, melphalan, and thiotepa with stem cell rescue to help patients recover from the intense treatment. It is unique because it uses a combination of drugs that have different toxicity profiles and aims to improve survival in high-risk neuroblastoma patients, although the best regimen is still being studied. ^{1 3 9 10 11}

What is the purpose of this trial?

This is a phase II single center study to administer two courses of myeloablative consolidation chemotherapy each followed by an autologous peripheral blood stem cell (PBSC) rescue in patients with high-risk neuroblastoma who have completed induction chemotherapy (independent of this study). Ideally, patients should begin consolidation chemotherapy no later than 8 weeks after the start of Induction Cycle #5; however it is strongly recommended to begin consolidation within 4-6 weeks after the start of Induction Cycle #5.

Research Team

Ashish Gupta, MD, PhD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Eligibility Criteria

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.

My cancer responded to initial treatment or remained stable.

Hematopoietic Recovery from last induction course of chemotherapy

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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 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]

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]

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]

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 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 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]

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]

References

1. England 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. [2022]

2. England 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. [2013]

3. United States 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. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system. [2013]

5. Japan pubmed.ncbi.nlm.nih.gov

[Clinical evaluation of A 1 protocol in advanced neuroblastoma]. [2015]

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

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. [2020]

8. Greece pubmed.ncbi.nlm.nih.gov

Effect of amifostine on neuroblastoma during high dose chemotherapy: in vivo and in vitro investigations. [2013]

9. United States 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. [2019]

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

Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. [2017]

11. England 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. [2019]