Lenalidomide + Dinutuximab +/- Isotretinoin for Neuroblastoma

Recruiting at 15 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Disqualifiers: Infection, Paraben allergy, Thrombosis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per course, up to 12 courses

27 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial studies the best dose and side effects of a combination of three drugs for young patients with difficult-to-treat neuroblastoma. The drugs work together to kill or stop the growth of cancer cells, with one drug specifically targeting the cancer cells. IBL-302 has shown promise in enhancing the effects of common treatments like cisplatin, doxorubicin, and etoposide in neuroblastoma treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting the study. You must stop myelosuppressive chemotherapy at least 2 weeks before, and any biologic agents, monoclonal antibodies, or cytokines at least 7 days before starting the trial. You cannot be on any other anti-cancer agents or radiotherapy during the study.

What data supports the effectiveness of the drug combination Lenalidomide + Dinutuximab +/- Isotretinoin for treating neuroblastoma?

Research shows that dinutuximab, when used with other drugs like isotretinoin, improves survival in patients with high-risk neuroblastoma. It has been approved for use in combination therapies for this condition, demonstrating benefits in event-free survival compared to isotretinoin alone. ^{1 2 3 4 5}

What safety data exists for the treatment of neuroblastoma with Lenalidomide, Dinutuximab, and Isotretinoin?

Dinutuximab, used in combination with other drugs like isotretinoin, has been shown to improve survival in high-risk neuroblastoma patients, but it can cause significant side effects such as pain, fever, and infections. Most patients experience some level of toxicity, with severe cases requiring dose adjustments or additional medical care, but no treatment-related deaths were reported. ^{1 2 6 7 8}

What makes the drug combination of Lenalidomide and Dinutuximab unique for treating neuroblastoma?

This drug combination is unique because it targets GD2, a molecule found on neuroblastoma cells, using dinutuximab, a monoclonal antibody, which helps the immune system attack the cancer cells. Lenalidomide, known for its immune-modulating effects, may enhance this immune response, making the combination potentially more effective than using isotretinoin alone. ^{1 2 4 5 7}

Research Team

Araz Marachelian

Principal Investigator

New Approaches to Neuroblastoma Treatment (NANT)

Eligibility Criteria

This trial is for young patients with neuroblastoma that's either not responding to treatment or has come back. They should have had some prior treatments, meet specific blood and organ function criteria, and not be on other cancer treatments. Females of childbearing age must test negative for pregnancy and both genders must use effective contraception.

Inclusion Criteria

I have been diagnosed with neuroblastoma confirmed by tests.

My blood, kidney, liver, heart, and metabolic health meet specific criteria.

I am using effective birth control and agree to regular pregnancy tests if applicable.

Exclusion Criteria

I had a blood clot before turning 40, not due to a central line.

I cannot swallow lenalidomide capsules whole.

I have chosen not to participate in the NANT 2004-05 study, or my institution is exempt.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive lenalidomide orally once daily on days 1-21, dinutuximab intravenously over 10 hours on days 8-11, and isotretinoin orally twice daily on days 15-28. Treatment repeats every 28 days for up to 12 courses.

28 days per course, up to 12 courses

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 3 years

Treatment Details

Interventions

• Dinutuximab
• Isotretinoin
• Lenalidomide

Trial Overview The study tests the safety and best dose of lenalidomide combined with dinutuximab, with or without isotretinoin in children with tough-to-treat neuroblastoma. It aims to see how these drugs can stop tumor growth by killing cells or preventing them from dividing or spreading.

Participant Groups

Group I: Treatment (lenalidomide, dinutuximab, isotretinoin) Experimental Treatment 5 Interventions

Patients receive lenalidomide PO QD on days 1-21, dinutuximab IV over 10 hours on days 8-11, and isotretinoin PO BID on days 15-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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, an antibody targeting the GD2 antigen on neuroblastoma cells, is FDA-approved for treating high-risk neuroblastoma in patients who have responded to initial therapy, showing significant clinical efficacy when combined with other treatments like cytokines and isotretinoin.

The effectiveness of dinutuximab can be limited by the presence of GD2-negative neuroblastoma cells and factors affecting the immune response, which may lead to resistance against this targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Keyel, ME., Reynolds, CP.[2023]

In a study of 25 patients with relapsed/refractory neuroblastoma, the combination of dinutuximab beta with chemotherapy regimens N5 and N6 showed an acceptable safety profile, with no unexpected severe toxicities reported.

The treatment resulted in a 48% objective response rate and a 1-year overall survival rate of 44%, indicating promising efficacy in heavily pretreated patients, suggesting the need for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. Lode, HN., Ladenstein, R., Troschke-Meurer, S., et al.[2023]

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]

References

1. France pubmed.ncbi.nlm.nih.gov

Dinutuximab: A Review in High-Risk Neuroblastoma. [2019]

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

Dinutuximab: first global approval. [2019]

3. 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]

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

Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Effect and Tolerance of N5 and N6 Chemotherapy Cycles in Combination with Dinutuximab Beta in Relapsed High-Risk Neuroblastoma Patients Who Failed at Least One Second-Line Therapy. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment of High-Risk Neuroblastoma with Dinutuximab and Chemotherapy Administered in all Cycles of Induction. [2023]

7. 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]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Treatment-Related Toxicities During Anti-GD2 Immunotherapy in High-Risk Neuroblastoma Patients. [2021]