Immunotherapy + Chemotherapy for High-Risk Neuroblastoma

Not currently recruiting at 10 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants

Disqualifiers: Bone marrow failure, Pregnancy, 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: 3

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining immunotherapy and chemotherapy can improve treatment for people with high-risk neuroblastoma, a type of cancer. The study examines the effectiveness of combining dinutuximab, which helps the immune system fight cancer, and sargramostim, which boosts white blood cells, with chemotherapy. Participants may include those diagnosed with high-risk neuroblastoma, particularly if they have tumor cell features like MYCN amplification (a specific genetic change) or have experienced certain disease progressions. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients on immunosuppressive medications. It's best to discuss your specific medications with the trial team.

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

Research has shown that dinutuximab, a type of targeted therapy, is generally well-tolerated in treating high-risk neuroblastoma. It attaches to specific proteins on cancer cells, potentially stopping the cancer from growing. Some studies have found it effective, though side effects like pain and allergic reactions can occur; these are often manageable.

Carboplatin, a chemotherapy drug used in similar situations, has been associated with severe blood-related side effects in only 20% of patients. Cisplatin, another chemotherapy drug used for various cancers, including neuroblastoma, has a known safety profile with manageable side effects.

Cyclophosphamide is part of the treatment plan and has shown effectiveness when combined with other drugs like topotecan. Doxorubicin, another chemotherapy drug in the treatment mix, is commonly used and has a known safety record, though it can sometimes cause heart issues.

Etoposide is included in this treatment and, while it has reported side effects, it is generally used safely in cancer treatments. Melphalan, when combined with a stem cell transplant, has been reported as safe and tolerable in children. Lastly, topotecan, used in chemotherapy, is well-tolerated and works well when paired with cyclophosphamide.

Overall, this combination of treatments has a well-established safety profile, although side effects can occur. The current trial aims to better understand these effects and improve outcomes for patients with high-risk neuroblastoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for high-risk neuroblastoma, which typically involve chemotherapy alone, this new approach combines immunotherapy with chemotherapy. Specifically, the treatment includes dinutuximab, an antibody that targets neuroblastoma cells, potentially boosting the body's immune response against the cancer. Researchers are excited because this combination might enhance the effectiveness of chemotherapy, potentially leading to better outcomes for patients. This dual approach aims to provide a more powerful attack on cancer cells, offering hope for improved survival rates in a condition that is notoriously difficult to treat.

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

This trial will evaluate the combination of dinutuximab with chemotherapy for patients with high-risk neuroblastoma. Research has shown that combining dinutuximab with chemotherapy can improve outcomes. Specifically, studies indicate that 57% of patients treated with dinutuximab remain free of cancer events after five years, compared to 46% of those who do not receive it. Additionally, dinutuximab reduces the overall death rate. Chemotherapy drugs like carboplatin, cisplatin, and cyclophosphamide, included in this trial, have proven to increase survival rates and improve treatment response. Sargramostim, a drug that boosts white blood cells, is also part of this trial to enhance the effectiveness of dinutuximab. Together, these treatments aim to increase survival chances and slow cancer growth. ^{1 4 5 6 7}

Who Is on the Research Team?

Sara M Federico

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

This trial is for children and young adults with high-risk neuroblastoma or ganglioneuroblastoma, confirmed by pathology analysis or bone marrow clumps with elevated urinary catecholamines. Participants must have certain heart function levels, adequate liver function, and kidney clearance rates. They should not have had extensive prior treatments except under specific circumstances and must be able to undergo stem cell collection. Pregnant females, patients over 18 months with non-amplified MYCN regardless of other features, those on immunosuppressants (except for allergies/adrenal therapy), breastfeeding females, and sexually active individuals not using contraception are excluded.

Inclusion Criteria

Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. The following disease groups are eligible:

Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features: MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features; OR Age > 547 days regardless of biologic features;

Creatinine clearance (CrCl) or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows: Age 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL); Age 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL); Age 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL); Age 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL); Age 6 to < 10 years (male 1 mg/dL, female 1 mg/dL); Age 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL); Age 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL); Age >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to enrollment).

Exclusion Criteria

Lactating females who plan to breastfeed their infants.

Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.

Patients >18 months of age with INRG stage L2, MYCN non-amplified, regardless of additional biologic features.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive multi-agent chemotherapy and immunotherapy with dinutuximab and sargramostim during cycles 3-5

15 weeks

Multiple visits for chemotherapy administration

Consolidation

Patients undergo autologous stem cell transplant following high-dose chemotherapy

2-3 weeks

Radiation Therapy

Patients receive external beam radiation therapy daily for up to 20 days

3-4 weeks

Post-Consolidation

Patients receive sargramostim, dinutuximab, and isotretinoin in cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up visits at months 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60

What Are the Treatments Tested in This Trial?

Interventions

• Autologous Hematopoietic Stem Cell Transplantation
• Carboplatin
• Cisplatin
• Cyclophosphamide
• Dinutuximab
• Doxorubicin
• Etoposide
• External Beam Radiation Therapy
• Melphalan
• Sargramostim
• Topotecan

Trial Overview The study tests the effectiveness of dinutuximab combined with sargramostim alongside a chemotherapy regimen before a stem cell transplant in treating high-risk neuroblastoma. The chemotherapy includes cisplatin, etoposide, vincristine, doxorubicin among others. This approach aims to improve immune response against cancer cells while making space in the bone marrow for new blood-forming cells.

How Is the Trial Designed?

Group I: Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT) Experimental Treatment 15 Interventions

See Detailed Description

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a Phase II trial involving 25 children with advanced neuroblastoma, the combination of topotecan, vincristine, and doxorubicin showed a promising overall response rate of 64%, with 4 complete responses and 12 partial responses.

The treatment was generally well tolerated, with limited toxicity primarily affecting the hematopoietic system, and only one patient experiencing dose-limiting Grade 4 liver toxicity, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Garaventa, A., Luksch, R., Biasotti, S., et al.[2020]

In a study of 42 children with newly diagnosed stage III or IV neuroblastoma, the OPEC chemotherapy regimen resulted in a good partial response in 74% of patients, with an even higher response rate of 78% among those who strictly followed the treatment protocol.

The OPEC regimen was found to be at least as effective as the more toxic OPEC-D regimen, with significantly lower treatment-related complications, suggesting it could be a safer alternative for treating advanced neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. Shafford, EA., Rogers, DW., Pritchard, J.[2017]

Citations

1. 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 ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.01066

Improving Outcomes in Children With High-Risk ... Outcomes for children with newly diagnosed high-risk neuroblastoma have improved significantly over the past 20 years, but despite intensive ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S235246422500241X

Late effects after high-risk neuroblastoma (LEAHRN): a ... 18, 19 Several randomised clinical trials in high-risk neuroblastoma show improved survival with tandem SCT (versus single),6 carboplatin ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8299367/

Efficacy of Carboplatin and Isotretinoin in Children With High ... The addition of carboplatin during radiotherapy improved survival from 54% to 73% only for children with high-risk group 3 medulloblastoma.

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

escp-high-risk-neuroblastoma-standard-clinical-practice- ... The initial results reported by MSKCC (overall CR/VGPR of 83%) have not been replicated by 2 randomized studies conducted by the French (SFOP) and Austrian ...

6. ascopubs.org ascopubs.org/doi/10.1200/EDBK_349783

High-Risk and Relapsed Neuroblastoma: Toward More ... Patients treated during this trial had a 97% end-induction response rate and a 73.7% 3-year EFS rate, both of which compare favorably to ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10453838/

Treatment of High-Risk Neuroblastoma - PMC - PubMed Central While children with low-risk and intermediate-risk neuroblastoma have excellent outcomes with 5-year overall survival over 95%, while 5-year ...