Immunotherapy + Chemotherapy for High-Risk Neuroblastoma

Recruiting at 9 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants

Disqualifiers: Bone marrow failure, Pregnancy, 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: 3

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II pilot trial studies the side effects and how well dinutuximab and sargramostim work when combined with chemotherapy in patients with high-risk neuroblastoma. 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. Sargramostim helps the body produce normal infection-fighting white blood cells. These cells also help the dinutuximab work better. Giving chemotherapy before a stem cell transplant, with drugs such as cisplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, thiotepa, melphalan, etoposide, carboplatin, topotecan, and isotretinoin, helps kill cancer cells that are in the body and helps make room in a patient's bone marrow for new blood-forming cells (stem cells). Giving dinutuximab and sargramostim with combination chemotherapy may work better than combination chemotherapy alone in treating patients with high-risk neuroblastoma.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude patients on immunosuppressive medications. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drugs used in the Immunotherapy + Chemotherapy for High-Risk Neuroblastoma trial?

Research shows that combining topotecan with other drugs like vincristine and doxorubicin can be effective in treating neuroblastoma. Additionally, combining topotecan with an anti-GD2 antibody has shown enhanced effectiveness in killing neuroblastoma cells, suggesting that combining chemotherapy with immunotherapy may improve treatment outcomes. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy generally safe for treating high-risk neuroblastoma?

Research suggests that combining immunotherapy with chemotherapy, such as topotecan, may improve the safety profile of treatments for neuroblastoma by using lower doses with no noticeable side effects. However, current therapies can still cause complications that affect quality of life, and more research is needed to further reduce toxicity. ^{1 2 3 6 7}

How is the Immunotherapy + Chemotherapy treatment for high-risk neuroblastoma different from other treatments?

This treatment combines immunotherapy with anti-GD2 (a type of protein found on neuroblastoma cells) and a multi-drug chemotherapy regimen, which includes drugs like carboplatin, cisplatin, and topotecan, known for their effectiveness in neuroblastoma. The inclusion of immunotherapy is a novel approach, as it aims to enhance the body's immune response against cancer cells, potentially improving outcomes compared to traditional chemotherapy alone. ^{3 4 6 8 9}

Research Team

Sara M Federico

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and young adults with high-risk neuroblastoma or ganglioneuroblastoma, confirmed by pathology analysis or bone marrow clumps with elevated urinary catecholamines. Participants must have certain heart function levels, adequate liver function, and kidney clearance rates. They should not have had extensive prior treatments except under specific circumstances and must be able to undergo stem cell collection. Pregnant females, patients over 18 months with non-amplified MYCN regardless of other features, those on immunosuppressants (except for allergies/adrenal therapy), breastfeeding females, and sexually active individuals not using contraception are excluded.

Inclusion Criteria

Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular) verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites. The following disease groups are eligible:

Patients with International Neuroblastoma Risk Group (INRG) stage M disease are eligible if found to have either of the following features: MYCN amplification (> 4-fold increase in MYCN signals as compared to reference signals), regardless of age or additional biologic features; OR Age > 547 days regardless of biologic features;

Creatinine clearance (CrCl) or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows: Age 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL); Age 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL); Age 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL); Age 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL); Age 6 to < 10 years (male 1 mg/dL, female 1 mg/dL); Age 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL); Age 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL); Age >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to enrollment).

Exclusion Criteria

Lactating females who plan to breastfeed their infants.

Female patients who are pregnant are ineligible since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.

Patients >18 months of age with INRG stage L2, MYCN non-amplified, regardless of additional biologic features.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive multi-agent chemotherapy and immunotherapy with dinutuximab and sargramostim during cycles 3-5

15 weeks

Multiple visits for chemotherapy administration

Consolidation

Patients undergo autologous stem cell transplant following high-dose chemotherapy

2-3 weeks

Radiation Therapy

Patients receive external beam radiation therapy daily for up to 20 days

3-4 weeks

Post-Consolidation

Patients receive sargramostim, dinutuximab, and isotretinoin in cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up visits at months 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60

Treatment Details

Interventions

• Autologous Hematopoietic Stem Cell Transplantation
• Carboplatin
• Cisplatin
• Cyclophosphamide
• Dinutuximab
• Doxorubicin
• Etoposide
• External Beam Radiation Therapy
• Melphalan
• Sargramostim
• Topotecan

Trial Overview The study tests the effectiveness of dinutuximab combined with sargramostim alongside a chemotherapy regimen before a stem cell transplant in treating high-risk neuroblastoma. The chemotherapy includes cisplatin, etoposide, vincristine, doxorubicin among others. This approach aims to improve immune response against cancer cells while making space in the bone marrow for new blood-forming cells.

Participant Groups

Group I: Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT) Experimental Treatment 15 Interventions

See Detailed Description

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a Phase II trial involving 25 children with advanced neuroblastoma, the combination of topotecan, vincristine, and doxorubicin showed a promising overall response rate of 64%, with 4 complete responses and 12 partial responses.

The treatment was generally well tolerated, with limited toxicity primarily affecting the hematopoietic system, and only one patient experiencing dose-limiting Grade 4 liver toxicity, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Garaventa, A., Luksch, R., Biasotti, S., et al.[2020]

In a study of 42 children with newly diagnosed stage III or IV neuroblastoma, the OPEC chemotherapy regimen resulted in a good partial response in 74% of patients, with an even higher response rate of 78% among those who strictly followed the treatment protocol.

The OPEC regimen was found to be at least as effective as the more toxic OPEC-D regimen, with significantly lower treatment-related complications, suggesting it could be a safer alternative for treating advanced neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. Shafford, EA., Rogers, DW., Pritchard, J.[2017]

References

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

A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. [2020]

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

Neuroblastoma chemotherapy can be augmented by immunotargeting O-acetyl-GD2 tumor-associated ganglioside. [2021]

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

Phase II study of cisplatinum and carboplatinum (CACIS) combination in advanced stage neuroblastomas. [2019]

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

Treatment with topotecan plus cyclophosphamide in children with first relapse of neuroblastoma. [2013]

5. England pubmed.ncbi.nlm.nih.gov

High-dose cyclophosphamide-irinotecan-vincristine for primary refractory neuroblastoma. [2018]

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

Current and future strategies for relapsed neuroblastoma: challenges on the road to precision therapy. [2021]

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

Camptothecin analogs (irinotecan or topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. [2021]

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

Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. [2017]

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

Use of combination adriamycin (NSC-123127) and DTIC (NSC-45388) in children with advanced stage IV neuroblastoma. [2016]