Combination Therapy for Neuroblastoma

Recruiting at 13 trial locations

Overseen By Araz Marachelian, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Pregnancy, Organ transplant, HIV, 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: 6 cycles of 21-28 days each

62 Participants Needed

Trial Summary

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 have received certain treatments like myelosuppressive chemotherapy, monoclonal antibodies, or strong inducers or inhibitors of CYP3A4 within specific time frames before joining the study. It's best to discuss your current medications with the study team.

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

Research shows that the combination of dinutuximab with other drugs like temozolomide and irinotecan, along with GM-CSF, has been effective in treating relapsed or refractory neuroblastoma, improving survival rates in patients. Additionally, dinutuximab has been approved by the FDA for use in high-risk neuroblastoma, indicating its effectiveness when used with other supportive treatments. ^{1 2 3 4 5}

What safety data exists for the combination therapy involving Dinutuximab and other agents in treating neuroblastoma?

Dinutuximab, when used in combination with other agents like granulocyte-macrophage colony-stimulating factor and interleukin-2, has been studied for safety and tolerability in treating high-risk neuroblastoma in children. These studies have shown that the combination therapy is generally safe, although it is important to monitor for potential side effects. ^{1 2 3 5 6}

What makes the combination therapy for neuroblastoma unique?

This treatment is unique because it combines several components, including dinutuximab, which targets GD2 on tumor cells, and Universal Donor TGFβi NK Cells, which are specially modified immune cells. This combination aims to enhance the immune system's ability to attack neuroblastoma cells, potentially improving outcomes for patients with high-risk or relapsed neuroblastoma. ^{1 2 4 5 7}

What is the purpose of this trial?

This is a phase II study looking at patient response to treatment with the combination dinutuximab, temozolomide, irinotecan, and GM-CSF.

Research Team

Keri Streby, MD

Principal Investigator

Nationwide Children's Hospital

Mark Ranalli, MD

Principal Investigator

Nationwide Children's Hospital

Eligibility Criteria

This trial is for patients with neuroblastoma, a type of cancer that usually affects children. Specific eligibility criteria are not provided, but typically participants would need to meet certain health standards and have no conflicting conditions.

Inclusion Criteria

I am between 1 and 31 years old.

My blood, kidney, liver, heart, lung, reproductive system, and brain functions meet the required health standards.

I have been diagnosed with neuroblastoma confirmed by tests.

Exclusion Criteria

Patients who are pregnant, breast feeding, or unwilling to use effective contraception during the study

Patients who may not be able to comply with the safety monitoring requirements of the study

I have severe diarrhea.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive chemoimmunotherapy with temozolomide, irinotecan, GM-CSF, and dinutuximab for 5 consecutive days, followed by TGF-beta NK cells on day 8. Treatment can continue for up to 6 cycles.

6 cycles of 21-28 days each

Daily visits during treatment days, additional visits for NK cell infusion

Follow-up

Participants are monitored for safety and effectiveness after treatment, including toxicity assessments and response evaluations.

6 months

Regular visits for monitoring and assessments

Treatment Details

Interventions

• Dinutuximab
• GM-CSF
• Irinotecan
• Temozolomide
• Universal Donor (UD) TGFβi NK Cells

Trial Overview The study tests how well patients respond to a combination treatment including dinutuximab (an antibody), temozolomide and irinotecan (chemotherapy drugs), and GM-CSF (a substance that stimulates white blood cell growth).

Participant Groups

Group I: Treatment Experimental Treatment 5 Interventions

Patients will be treated with chemoimmunotherapy (temozolomide, irinotecan, GM-CSF, and dinutuximab) plus UD TGFβi NK cells.

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?

New Approaches to Neuroblastoma Therapy Consortium

Lead Sponsor

Trials

19

Recruited

1,700+

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

United Therapeutics

Industry Sponsor

Trials

112

Recruited

14,500+

Dr. Martine Rothblatt

United Therapeutics

Chief Executive Officer since 1996

PhD in Medical Ethics from the Royal London College of Medicine and Dentistry, JD and MBA from UCLA

Dr. Michael Benkowitz

United Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Children's Neuroblastoma Cancer Fund

Collaborator

Trials

1

Recruited

60+

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]

The combination of γδ T cells with the anti-GD2 antibody dinutuximab significantly enhances tumor cell lysis in neuroblastoma, showing a 30% increase in effectiveness compared to γδ T cells alone.

In preclinical models, the treatment regimen of dinutuximab, temozolomide, and expanded γδ T cells effectively reduced tumor burden and improved survival in mice with neuroblastoma, supporting further testing of this chemo-immunotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model. Zoine, JT., Knight, KA., Fleischer, LC., et al.[2021]

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]

Galunisertib enhances the effectiveness of the anti-GD2 antibody dinutuximab by suppressing SMAD2 activation in neuroblastoma cells and restoring the cytotoxic functions of activated natural killer (aNK) cells, which are crucial for targeting neuroblastoma tumors.

In preclinical models, combining galunisertib with aNK cells and dinutuximab significantly reduced tumor growth and improved survival rates in mice, indicating a promising strategy for improving immunotherapy outcomes in high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. Tran, HC., Wan, Z., Sheard, MA., et al.[2022]

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]

Combining the anti-GD2 antibody dinutuximab with ex vivo-activated human natural killer (aNK) cells after surgical removal of neuroblastoma tumors significantly improved survival rates in a mouse model, indicating a promising approach for treating residual disease.

In vitro studies showed that this combination not only increased cytotoxicity against neuroblastoma cells but also reduced their invasiveness, suggesting a dual mechanism of action that could enhance the effectiveness of immunotherapy in high-risk neuroblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma. Barry, WE., Jackson, JR., Asuelime, GE., et al.[2020]

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

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model. [2021]

4. 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]

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

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. [2022]

6. 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]

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

Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma. [2020]