Combination Chemotherapy for Neuroblastoma

Recruiting at 153 trial locations

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Oncology Group

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Pregnancy, Myelodysplastic syndrome, 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

Duration: 18-24 weeks

94 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well irinotecan hydrochloride, temozolomide, and dinutuximab work with or without eflornithine in treating patients with neuroblastoma that has come back (relapsed) or that isn't responding to treatment (refractory). Drugs used in chemotherapy, such as irinotecan hydrochloride and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as dinutuximab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Eflornithine blocks the production of chemicals called polyamines that are important in the growth of cancer cells. Giving eflornithine with irinotecan hydrochloride, temozolomide, and dinutuximab, may work better in treating patients with relapsed or refractory neuroblastoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are on certain medications like systemic steroids, immunosuppressive drugs, or specific anticonvulsants. It's best to discuss your current medications with the trial team to see if they are allowed.

What data supports the effectiveness of the drug combination chemotherapy for neuroblastoma?

Research shows that combining chemotherapy with the drug dinutuximab beta can improve response and survival rates in children with relapsed or refractory high-risk neuroblastoma. In one study, 64% of patients responded to the treatment, with 32% achieving complete remission, indicating that this combination is a promising option for these patients. ^{1 2 3 4 5}

Is the combination chemotherapy for neuroblastoma safe for humans?

The combination of chemotherapy with dinutuximab beta has been well tolerated in patients with relapsed or refractory high-risk neuroblastoma, even in those who were heavily pre-treated. Toxicities were similar to those reported for the individual therapies, and no treatment discontinuations due to toxicities occurred. ^{1 2 3 4 5}

How is the combination chemotherapy with dinutuximab, irinotecan, and temozolomide unique for treating neuroblastoma?

This treatment is unique because it combines dinutuximab, a monoclonal antibody that targets GD2 on tumor cells, with chemotherapy drugs irinotecan and temozolomide, which have shown increased response and survival rates in patients with relapsed or refractory high-risk neuroblastoma. The combination has been well tolerated and offers a promising option for patients who have not responded to other treatments. ^{1 2 5 6 7}

Research Team

Margaret E Macy

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients with high-risk neuroblastoma that's either come back or isn't responding to treatment. They should have measurable tumor growth, more than 5% bone marrow disease involvement, and a performance status of ECOG 0-2. Patients must not have received certain prior treatments like long-acting myeloid growth factors within specific time frames and must meet various health criteria including adequate organ function.

Inclusion Criteria

Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT eligible for this study

My cancer is confirmed as neuroblastoma or ganglioneuroblastoma with high urinary catecholamines.

I took DFMO without my cancer getting worse during or within 3 months after treatment.

Exclusion Criteria

You cannot take medication orally or have difficulty absorbing medication from your digestive system.

I have a serious health issue not related to my cancer that could affect the study treatment.

I am not taking any immunosuppressive medications like cyclosporine or tacrolimus.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive chemotherapy and immunotherapy with or without eflornithine in cycles

18-24 weeks

Multiple visits per cycle, including in-person and possible virtual follow-ups

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic visits

Treatment Details

Interventions

• Dinutuximab
• Eflornithine Hydrochloride
• Irinotecan Hydrochloride
• Temozolomide

Trial Overview The trial tests if combining chemotherapy drugs irinotecan hydrochloride and temozolomide with the immunotherapy drug dinutuximab improves when adding eflornithine in patients with relapsed or refractory neuroblastoma. It aims to see whether this combination can better stop cancer cells from growing by killing them, stopping their division, or preventing their spread.

Participant Groups

Group I: Regimen B (eflornithine, chemotherapy, dinutuximab) Experimental Treatment 5 Interventions

Patients receive eflornithine PO, via NG, or G tube on days -6 to 7 and days 15-21 of cycle 1 and days 1-7 and 15-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment duration is 28 days for cycle 1 and then every 21 days in subsequent cycles for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Regimen A (chemotherapy, dinutuximab, sargramostim) Active Control 4 Interventions

Patients receive temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12 of a 21-day cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Unituxin for:

• Neuroblastoma

Approved in European Union as Dinutuximab for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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]

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]

In a study involving 35 children with relapsed or refractory neuroblastoma, the combination of irinotecan, temozolomide, and dinutuximab showed significant anti-tumor activity, with 53% of patients achieving an objective response, including complete responses.

In contrast, the combination of irinotecan, temozolomide, and temsirolimus had a much lower response rate, with only 6% of patients showing a partial response, indicating that the dinutuximab combination is more promising for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Mody, R., Naranjo, A., Van Ryn, C., 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 28 children with high-risk neuroblastoma, the monoclonal antibody dinutuximab produced by United Therapeutics (UTC) showed pharmacokinetic comparability to the National Cancer Institute's (NCI) version, indicating similar drug exposure levels.

Both UTC and NCI products had comparable safety profiles and adverse events, suggesting that UTC's dinutuximab can be used interchangeably with NCI's version without compromising efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy. Marachelian, A., Desai, A., Balis, F., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

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

2. 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]

3. 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]

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

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. [2022]

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

Dinutuximab: first global approval. [2019]

6. 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]

7. Germany pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy. [2019]