Lenalidomide + Dinutuximab +/- Isotretinoin for Neuroblastoma

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and assess the side effects of combining three drugs—lenalidomide (Revlimid), dinutuximab (a chimeric anti-GD2 monoclonal antibody), and possibly isotretinoin—to treat young patients with neuroblastoma. This type of cancer affects nerve cells and either hasn't responded to treatment or has returned. The combination therapy might more effectively stop the growth and spread of cancer cells. Patients with high-risk neuroblastoma that is recurrent, persistent, or refractory (not responding to standard treatment) might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking therapy.

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.

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

Research has shown that lenalidomide has been safely used in children with solid tumors. These studies found that patients can tolerate the drug, though side effects like tiredness, low blood counts, and rash may occur.

Dinutuximab, a monoclonal antibody, has been widely used to treat neuroblastoma. Some studies suggest it can help patients live longer, but it may cause side effects such as pain, fever, and allergic reactions.

Isotretinoin, often used for severe acne, also aids in cancer treatments. In cancer therapy, it might cause side effects like dry skin and lips, as well as mood changes.

This trial tests how these drugs work together and what side effects might occur. As this is an early stage of testing, researchers are still determining the best doses and potential side effects when these drugs are combined. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment combining lenalidomide, dinutuximab, and isotretinoin for neuroblastoma because it offers a unique approach compared to existing therapies. Unlike standard treatments that often focus on chemotherapy and radiation, this combination targets the cancer in multiple ways. Lenalidomide enhances the immune system, dinutuximab is an antibody that specifically attacks neuroblastoma cells, and isotretinoin helps to stop cancer cell growth. This multi-pronged strategy could potentially improve outcomes by attacking the cancer from different angles, making it a promising option for patients.

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

In this trial, participants will receive a combination of lenalidomide, dinutuximab, and isotretinoin. A previous study showed that dinutuximab, a medicine targeting neuroblastoma cells, helped patients with high-risk neuroblastoma live longer. Lenalidomide, when combined with dinutuximab, might enhance the immune system's ability to fight cancer. Research has shown that isotretinoin, often used in cancer treatment, can help stop cancer cells from growing and spreading. These treatments work together to attack neuroblastoma cells in different ways, potentially increasing their effectiveness. Early findings suggest that using these drugs together could offer new hope for patients whose cancer hasn't responded to other treatments. ^{1 3 6 7 8}

Who Is on the Research Team?

Araz Marachelian

Principal Investigator

New Approaches to Neuroblastoma Treatment (NANT)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01711554

Lenalidomide and Dinutuximab With or Without Isotretinoin ... This phase I trial studies the side effects and best dose of lenalidomide when given together with dinutuximab with or without isotretinoin in treating ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10527563/

Treatment of High-Risk Neuroblastoma with Dinutuximab ... The prognosis of high-risk neuroblastoma improved significantly with the addition of an anti-GD2 monoclonal antibody (dinutuximab) ...

3. asco.org asco.org/abstracts-presentations/ABSTRACT228803

A phase I NANT study of lenalidomide with ch14.18 and ... Background: Ch14.18 (dinutuximab) increases event free and overall survival in patients with high-risk NB when given in a regimen with GM-CSF/IL-2.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02573896

Immunotherapy of Relapsed Refractory Neuroblastoma ... Dinutuximab is a chimeric antibody against GD2, which is expressed on a majority of neuroblastoma cells. It has been shown to increase EFS and OS in ...

5. withpower.com withpower.com/trial/phase-1-neuroblastoma-1-2013-6d848

Lenalidomide + Dinutuximab +/- Isotretinoin for ... This trial studies the best dose and side effects of a combination of three drugs for young patients with difficult-to-treat neuroblastoma.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6306059/

Spotlight on dinutuximab in the treatment of high-risk ... This review summarizes the development of GD2 antibody-targeted therapy, the use of dinutuximab in both up-front and salvage therapy for high-risk NB,

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6082365/

Anti-GD2 immunotherapy for neuroblastomas - PMC Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory ...

8. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT02573896

Immunotherapy of Relapsed Refractory Neuroblastoma With ... Lenalidomide has been studied in children with solid tumors and can safely be given to patients based on 2 prior trials in children. It was also ...