Immunotherapy for Neuroblastoma

Recruiting at 11 trial locations

Overseen By Araz Marachelian, MD, MS

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: Thalidomide

Disqualifiers: Pregnancy, Breastfeeding, CNS metastasis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of dinutuximab and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with dinutuximab, for treatment of children with refractory or recurrent neuroblastoma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot receive other anti-cancer agents or radiotherapy while participating in the trial.

What data supports the effectiveness of the treatment for neuroblastoma?

Research shows that the treatment using the anti-GD2 antibody dinutuximab, often combined with other agents like interleukin-2 and natural killer cells, improves survival rates in children with high-risk neuroblastoma. This combination therapy has been approved by the FDA for its effectiveness in increasing event-free and overall survival in these patients. ^{1 2 3 4 5}

Is the immunotherapy treatment for neuroblastoma, including dinutuximab and NK cells, generally safe for humans?

Dinutuximab, used in combination with other treatments, has been approved for high-risk neuroblastoma in children and has been studied for safety and tolerability. While it improves survival, some patients may experience side effects, and safety evaluations have been conducted to ensure its use in pediatric patients. ^{1 2 3 4 6}

How is the treatment with Ch14.18, Dinutuximab, and NK Cells different from other treatments for neuroblastoma?

This treatment is unique because it combines the anti-GD2 antibody dinutuximab with natural killer (NK) cells to target neuroblastoma cells, enhancing the immune system's ability to attack the cancer. Dinutuximab binds to GD2, a molecule found on neuroblastoma cells, and works with NK cells to improve survival rates in high-risk patients. ^{1 2 3 4 5}

Research Team

Araz Marachelian, MD, MS

Principal Investigator

Children's Hospital Los Angeles

Eligibility Criteria

This trial is for children with neuroblastoma that hasn't responded to initial treatments or has come back. They must have a certain type of tumor activity visible on specific scans, be under 30 years old, and have an expected lifespan of at least 12 weeks. Their heart, kidney, liver, and blood functions need to meet set levels. Pregnant or breastfeeding individuals can't join.

Inclusion Criteria

My disease is either coming back, not responding, or has never fully gone away.

My neuroblastoma is classified as high-risk according to COG.

I am expected to live at least 12 weeks and can do some daily activities on my own.

Exclusion Criteria

I do not have any ongoing or uncontrolled infections.

I have chosen not to participate in the NANT 2004-05 study.

My cancer has spread to my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NK cells on Day 5 and dinutuximab on Days 1-4, with lenalidomide added for Dose Level 4 from Day -6 through 14

3 weeks

Multiple visits for administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of toxicities and response

4 weeks

Regular follow-up visits

Extension

Optional continuation of treatment to further assess long-term effects and safety

Long-term

Treatment Details

Interventions

• Ch14.18
• Dinutuximab
• Lenalidomide
• NK Cells

Trial Overview The study tests the highest dose kids can handle of NK cells (a type of immune cell) combined with dinutuximab (an antibody therapy). It also looks at adding lenalidomide (a cancer drug) to this mix for those who've had no luck with standard treatments for their aggressive neuroblastoma.

Participant Groups

Group I: NK cells with Dinutuximab & Lenalidomide Experimental Treatment 3 Interventions

Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of dinutuximab on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment.

Who Is Running the Clinical Trial?

New Approaches to Neuroblastoma Therapy Consortium

Lead Sponsor

Trials

19

Recruited

1,700+

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

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Findings from Research

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]

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]

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. 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]

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

Dinutuximab: first global approval. [2019]

4. 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]

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

Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032. [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]