Dinutuximab + Chemotherapy for High-Risk Neuroblastoma

Recruiting at 141 trial locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Bone marrow failure, Primary immunodeficiency, Pregnancy, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic immunosuppressive medications for reasons other than certain treatments, you may not be eligible to participate.

What data supports the effectiveness of the drug dinutuximab combined with chemotherapy for high-risk neuroblastoma?

Research shows that combining dinutuximab with chemotherapy improves survival rates in children with high-risk neuroblastoma. In one study, 64% of patients responded to the treatment, with 32% achieving complete remission, indicating that this combination can be effective in treating this aggressive cancer. ^{1 2 3 4 5}

Is the combination of Dinutuximab and chemotherapy safe for treating high-risk neuroblastoma?

Dinutuximab combined with chemotherapy has been shown to have an acceptable safety profile in treating high-risk neuroblastoma, with common side effects including pain, allergic reactions, fever, and capillary leak syndrome. No unexpected severe toxicities were reported, and the treatment did not cause major delays in therapy. ^{1 2 3 4 6}

How is the drug dinutuximab combined with chemotherapy unique for treating high-risk neuroblastoma?

Dinutuximab is unique because it is a monoclonal antibody that targets GD2, a molecule found on neuroblastoma cells, and works by helping the immune system attack these cancer cells. When combined with chemotherapy, it has shown to improve survival rates in patients with high-risk neuroblastoma, offering a promising option for those who have not responded well to other treatments. ^{1 2 3 4 5}

Research Team

Sara M Federico

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children with high-risk neuroblastoma, a type of cancer. It's open to those under 30 at diagnosis and includes various stages of the disease if certain conditions are met, like specific genetic features or prior limited treatment. Participants need a minimum body surface area and must consent to molecular testing.

Inclusion Criteria

I was diagnosed with a high-risk disease before turning 31.

I haven't had cancer treatment except as allowed in the criteria.

Patients must be enrolled on APEC14B1 and have consented to testing through the Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131

Exclusion Criteria

I am on long-term immunosuppressive medication for a condition not specified.

All patients and/or their parents or legal guardians must sign a written informed consent

My age, cancer stage, and genetic test results do not match certain criteria.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive chemotherapy and are randomized to receive either standard treatment or chemoimmunotherapy with dinutuximab. This phase includes multiple cycles of chemotherapy and surgery.

5 cycles (approximately 15 weeks)

Multiple visits for chemotherapy administration and surgery

Extended Induction

For patients with poor tumor response, additional cycles of chemoimmunotherapy with dinutuximab, temozolomide, and irinotecan are administered.

Up to 6 cycles (approximately 18 weeks)

Consolidation

Patients undergo two autologous hematopoietic stem cell transplantations and receive high-dose chemotherapy.

Approximately 10-14 weeks

Post-Consolidation

Participants receive dinutuximab and isotretinoin to maintain the response achieved with previous therapy.

5 cycles (approximately 20 weeks)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 10 years

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

Treatment Details

Interventions

• Chemotherapy (Chemotherapy)
• Dinutuximab (Monoclonal Antibodies)
• Stem Cell Transplantation (Stem Cell Transplantation)
• Surgery (Surgery)

Trial Overview The study tests dinutuximab added to induction chemotherapy, followed by surgery, radiation therapy, stem cell transplantation, and more chemo. Dinutuximab targets cancer cells for immune destruction; other drugs aim to stop cancer growth or spread.

Participant Groups

Group I: Arm B (Dinutuximab in induction) Experimental Treatment 27 Interventions

See detailed description

Group II: Arm A (SOC treatment) Active Control 27 Interventions

See detailed description

Chemotherapy is already approved in Canada, Japan, China, Switzerland for the following indications:

Approved in Canada as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Japan as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in China as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Switzerland as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 3 trial involving 406 children and young people with high-risk neuroblastoma, the addition of subcutaneous IL-2 to dinutuximab beta did not improve event-free survival rates compared to dinutuximab beta alone, with 3-year event-free survival rates of 60% and 56% respectively.

The combination treatment with subcutaneous IL-2 resulted in significantly higher toxicity, leading to a lower treatment completion rate (62% vs. 87% for dinutuximab beta alone), indicating that dinutuximab beta with isotretinoin should remain the standard care for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Ladenstein, R., Pötschger, U., Valteau-Couanet, D., et al.[2022]

Dinutuximab is a monoclonal antibody that targets GD2, a glycolipid overexpressed in neuroblastoma, and has been approved by the US FDA for treating high-risk neuroblastoma in children when used in combination with other therapies.

The drug works by inducing immune responses that kill cancer cells, and its development has progressed through multiple phases, with ongoing regulatory reviews in the EU and other countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. Dhillon, S.[2019]

In a study of 25 patients with relapsed/refractory neuroblastoma, the combination of dinutuximab beta with chemotherapy regimens N5 and N6 showed an acceptable safety profile, with no unexpected severe toxicities reported.

The treatment resulted in a 48% objective response rate and a 1-year overall survival rate of 44%, indicating promising efficacy in heavily pretreated patients, suggesting the need for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. Lode, HN., Ladenstein, R., Troschke-Meurer, S., et al.[2023]

In a study involving seven patients with high-risk neuroblastoma, dinutuximab treatment led to complete remission in two patients and partial response in three, highlighting its potential effectiveness in eradicating minimal residual disease.

While dinutuximab shows promise as a first-line treatment for high-risk neuroblastoma, it carries a significant risk of severe adverse reactions, necessitating administration by experienced pediatric oncology centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects. Achbergerová, M., Hederová, S., Mikesková, M., et al.[2021]

In a study of 25 children with relapsed or refractory high-risk neuroblastoma, combining irinotecan/temozolomide chemotherapy with the anti-GD2 antibody dinutuximab beta resulted in a 64% objective response rate, with 32% achieving complete remission.

The treatment was well tolerated, even in patients who had previously received dinutuximab beta, and no patients discontinued due to toxicities, suggesting it is a promising option for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma. Wieczorek, A., Zaniewska-Tekieli, A., Ehlert, K., et al.[2023]

Dinutuximab beta (Qarziba®) has been integrated into the standard treatment for high-risk neuroblastoma in Europe, showing positive clinical responses in both first-line and relapsed cases, which has improved patient outcomes.

While effective, dinutuximab beta can cause significant adverse effects such as pain, allergic reactions, and capillary leak syndrome, highlighting the need for optimized management strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma. Balaguer, J., García Hidalgo, L., Hladun, R., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. [2019]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. [2023]

4. Czech Republic pubmed.ncbi.nlm.nih.gov

Implementation of immunotherapy into the treatment of neuroblastoma - single center experience with the administration of dinutuximab and management of its adverse effects. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Dinutuximab beta combined with chemotherapy in patients with relapsed or refractory neuroblastoma. [2023]

6. France pubmed.ncbi.nlm.nih.gov

Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma. [2023]