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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of medications and immune cells to evaluate their effectiveness against neuroblastoma, a cancer affecting nerve tissues. The treatments include chemotherapy drugs, such as Dinutuximab (a chimeric anti-GD2 monoclonal antibody), and specialized immune cells designed to target the cancer. It is open to patients with high-risk neuroblastoma that has not responded well to previous treatments or has recurred. This trial may suit those with persistent or recurring symptoms despite multiple therapy rounds. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from innovative therapies.

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.

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

Research has shown that combining dinutuximab, GM-CSF, irinotecan, and temozolomide is generally safe. The FDA has approved dinutuximab for treating high-risk neuroblastoma in children, indicating its safety for them. Studies have found that GM-CSF, when used with dinutuximab, is safe and enhances the body's ability to fight cancer.

Irinotecan often causes diarrhea later in treatment for many patients, but some studies suggest it is less toxic for certain groups. Temozolomide is usually well-tolerated, though it can lead to low platelet counts, affecting blood health.

Early research on universal donor TGFβi NK cells (a type of immune cell) suggests they are safe and work well with other cancer treatments. Overall, while some side effects are possible, the treatments in this trial have been studied for their safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment options for neuroblastoma, which typically include chemotherapy and immunotherapy drugs like temozolomide, irinotecan, GM-CSF, and dinutuximab, this new combination therapy introduces Universal Donor TGFβi NK cells. These NK cells are a type of immune cell engineered to enhance the body's ability to fight cancer more effectively. Researchers are excited because these cells can potentially boost the immune response against neuroblastoma, offering a new mechanism of action that could be more effective than existing therapies. Additionally, the use of these engineered NK cells may lead to better outcomes with fewer side effects compared to traditional treatments.

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

This trial will evaluate a combination therapy for neuroblastoma, where participants will receive chemoimmunotherapy consisting of temozolomide, irinotecan, GM-CSF, and dinutuximab, plus Universal Donor TGFβi NK cells. Studies have shown that dinutuximab, which targets specific markers on neuroblastoma cells, significantly improves survival rates for patients with high-risk neuroblastoma. Research indicates that using GM-CSF with anti-GD2 antibodies like dinutuximab boosts the immune system's ability to fight cancer. Irinotecan has effectively shrunk neuroblastoma tumors, even at lower doses. Temozolomide, while less effective on its own, is used in combination with other treatments to potentially improve results. Universal Donor TGFβi NK cells, which strengthen the body's natural killer cells to attack cancer, show promise when used with these treatments. Together, these treatments form a potentially powerful combination therapy for neuroblastoma. ^{5 6 7 8 9}

Who Is on the Research Team?

Keri Streby, MD

Principal Investigator

Nationwide Children's Hospital

Mark Ranalli, MD

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 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]

Citations

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Dinutuximab Beta for the Treatment of High-Risk Neuroblastoma This retrospective study demonstrates that dinutuximab beta is an effective and safe treatment for high-risk neuroblastoma, achieving a 54.1% ...

2. unituxin.com unituxin.com/hcp/about-unituxin/clinical-trial-data/

Efficacy and Clinical Trial Data 5-year EFS was 57±4.7% for patients randomized to the Unituxin group (n=114) vs 46±5.1% for those randomized to the RA-only group (n=112; P=0.042).4. 5-year EFS ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10729685/

Safety and efficacy of dinutuximab in the treatment of ... Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e22000

Efficacy and safety of dinutuximab in the management ... Conclusions: Our findings suggest that dinutuximab is linked to a significant reduction in overall mortality and a noteworthy improvement in the ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1072751519309305

Treatment-Resistant Neuroblastoma Populations after Anti ... Conclusions. NB cells treated with combination aNK-dinutuximab therapy exhibit a transient decrease in GD2 expression without changes in NK ligands and immune ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26917818/

Dinutuximab: An Anti-GD2 Monoclonal Antibody for High- ... Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/125516Orig1s000PharmR.pdf

125516Orig1s000 - accessdata.fda.gov Dinutuximab is a chimeric mouse/human IgG1 monoclonal antibody produced in the SP2/0 cell line that binds to the GD2 disialonganglioside. GD2 is ...

8. unituxin.com unituxin.com/hcp/

Healthcare Professionals Home FDA approved. The first antibody therapy FDA-approved for children with high-risk neuroblastoma.2,5. 200+ children's hospitals.

9. aetna.com aetna.com/cpb/medical/data/800_899/0895.html

Dinutuximab (Unituxin) - Medical Clinical Policy Bulletins The authors concluded that dinutuximab is the 1st anti-GD2 monoclonal antibody (MAb) approved in combination with GM-CSF, IL-2, and RA for maintenance treatment ...