Combination Therapy for Neuroblastoma

Recruiting in Palo Alto (17 mi)

+13 other locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: Pregnancy, Organ transplant, HIV, others

No Placebo Group

Prior Safety Data

Trial Summary

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.

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}

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.

Trial 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 (Monoclonal Antibodies)
• GM-CSF (Other)
• Irinotecan (Chemotherapy)
• Temozolomide (Chemotherapy)
• Universal Donor (UD) TGFβi NK Cells (Other)

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Cincinnati Children's Hospital Medical Center Cincinnati, OH

Children's Hospital of Philadelphia Philadelphia, PA

Children's Hospital Colorado Aurora, CO

C.S Mott Children's Hospital Ann Arbor, MI

More Trial Locations

Who Is Running the Clinical Trial?

New Approaches to Neuroblastoma Therapy Consortium Lead Sponsor

Nationwide Children's Hospital Collaborator

United Therapeutics Industry Sponsor

Children's Neuroblastoma Cancer Fund Collaborator

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] Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.

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

Dinutuximab: first global approval. [2019] United Therapeutics Corporation and the National Cancer Institute are developing dinutuximab (Unituxin™; ch14.18), a monoclonal antibody targeting GD2, for the treatment of neuroblastoma. GD2 is a glycolipid found on the surface of tumour cells, which is overexpressed in neuroblastoma. Dinutuximab, an IgG1 human/mouse chimeric switch variant of murine monoclonal antibody 14G2a, binds to GD2 and induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The US FDA has recently approved the use of dinutuximab combination therapy for the treatment of high-risk neuroblastoma in paediatric patients. The marketing authorization application for dinutuximab is under regulatory review in the EU, and phase I-III development is underway in several other countries. This article summarizes the milestones in the development of dinutuximab leading to this first approval for use (in combination with granulocyte macrophage colony-stimulating factor, interleukin-2 and 13-cis retinoic acid) in the treatment of paediatric patients with high-risk neuroblastoma who achieve at least partial response to prior first-line multiagent, multimodality therapy.

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] An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.

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] The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF.

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] Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma.

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] Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.

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] Label="PURPOSE">Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with ex vivo-activated human natural killer (aNK) cells.