NK Cell Infusion + Chemotherapy for Neuroblastoma

(STING Trial)

Overseen By Melinda Triplet, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Nationwide Children's Hospital

Must not be taking: Steroids, CYP3A4 drugs

Disqualifiers: Pregnancy, Other malignancy, others

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

Compensation: Varies

Number of Visits: 21

Duration: 18 weeks

31 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for neuroblastoma, a cancer that primarily affects young children. Researchers aim to determine if adding natural killer (NK) cells, known as Vactosertib, to chemotherapy can enhance cancer treatment. The study's first phase will ensure the treatment's safety, while the second phase will assess its effectiveness. Individuals diagnosed with neuroblastoma, especially those whose disease has returned or not responded to previous treatments, may be suitable candidates for this trial. As a Phase 1/Phase 2 trial, this research seeks to understand the treatment's effects and measure its effectiveness in an initial, smaller group, offering participants a chance to benefit from this innovative approach.

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 must not have taken certain medications like systemic steroids or CYP3A4 inducers/inhibitors for at least 7 days before enrolling.

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

Research shows that the treatments in this trial have different safety profiles.

For irinotecan, studies have found significant side effects. Some patients, especially children, experienced high toxicity levels, leading to serious issues such as severe digestive problems and low blood cell counts.

Temozolomide has also been studied in similar situations. It is generally tolerated but can cause side effects like low blood counts, increasing the risk of infections.

Natural Killer (NK) cells, used in this trial, have shown promise in fighting tumors like neuroblastoma. Importantly, research has not reported significant toxicities specifically related to NK cells. They appear safe and well-tolerated by patients in trials so far.

While each of these treatments has its own safety concerns, the combination used in this trial is still under study to fully understand their safety when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the NK cell infusion combined with chemotherapy for neuroblastoma because it offers a novel approach by incorporating natural killer (NK) cells. Unlike standard treatments that primarily rely on chemotherapy, this approach harnesses the body's own immune system to target and kill cancer cells more effectively. Irinotecan and temozolomide, well-known chemotherapy agents, are supercharged by the addition of NK cells, which are designed to boost the immune response. This combination has the potential to improve tumor response rates and minimize the side effects commonly associated with traditional chemotherapy.

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

Research has shown that the drug irinotecan can effectively treat neuroblastoma, a type of cancer, with all tested tumor samples responding completely. In past treatments, combining irinotecan with another drug, temozolomide, improved outcomes in 19% of patients. Temozolomide alone has also been somewhat effective for neuroblastoma that has recurred or is resistant to other treatments, with a small number of patients showing improvement. In this trial, participants will receive a combination of irinotecan, temozolomide, dinutuximab, sargramostim, and natural killer (NK) cells. Early research suggests that adding NK cells to treatment plans might enhance their effectiveness against this cancer, as NK cells have shown potential in attacking and destroying neuroblastoma cells. ^{2 6 7 8 9}

Who Is on the Research Team?

Mark Ranalli

Principal Investigator

Nationwide Children's Hospital

Are You a Good Fit for This Trial?

This trial is for individuals under 30 years old with neuroblastoma or ganglioneuroblastoma, not just bone marrow disease. They must have adequate organ function and no recent treatments that conflict with the study drugs. Pregnant or breastfeeding individuals, those on certain medications, or with uncontrolled infections cannot participate.

Inclusion Criteria

It's been over 2 weeks since my last strong chemotherapy.

I have had previous cancer treatment but followed the required waiting periods.

My liver is working well.

Exclusion Criteria

I have not been diagnosed with any cancer other than the one I am seeking treatment for.

I do not have any major illnesses that could affect the study treatment or make its side effects worse.

I haven't taken any CYP3A4 affecting drugs in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 6 cycles of 21 days each of irinotecan, temozolomide, dinutuximab, sargramostim, and NK cells

18 weeks

Visits every 21 days for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Dinutuximab
• Irinotecan
• Natural Killer Cells
• Sargramostim
• Temozolomide

Trial Overview The trial tests how safe and tolerable it is to give universal donor NK cells combined with irinotecan, temozolomide, and dinutuximab to patients. It aims to see how well these patients respond after establishing safety in Phase 1 during the expanded Phase 2 cohort.

How Is the Trial Designed?

Group I: Treatment Experimental Treatment 5 Interventions

The planned therapy will involve 6 cycles of 21 days each consisting of irinotecan, temozolomide, dinutuximab, sargramostim, and natural killer (NK) cells. Treatment cycles will be repeated every 21 days based upon disease response and toxicity criteria. Tumor response will be assessed after Cycles 2, 4 and 6. Patients who do not experience dose-limiting toxicities and achieve complete response, partial response or stable disease may continue to receive the assigned therapy.

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

Approved in United States as Camptosar for:

• Colorectal cancer

Approved in European Union as Irinotecan for:

• Colorectal cancer

Approved in Japan as Topotecin for:

• Colorectal cancer
• Small cell lung cancer

Approved in Canada as Irinotecan for:

• Colorectal cancer

Who Is Running the Clinical Trial?

Nationwide Children's Hospital

Lead Sponsor

Trials

354

Recruited

5,228,000+

Published Research Related to This Trial

In a Phase I trial involving three children with advanced neuroblastoma, the maximum tolerated dose (MTD) of irinotecan hydrochloride (CPT-11) was determined to be 180 mg/m2 administered over three days, with manageable myelosuppression as a side effect.

The treatment showed promising efficacy, with one child achieving a complete response and two others showing partial responses, suggesting that CPT-11 could be a valuable option for treating this type of cancer, warranting further research into its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase I study with irinotecan hydrochloride (CPT-11) for advanced neuroblastoma]. Hirota, T., Kawai, N., Kitagawa, S., et al.[2018]

The combination of vincristine, irinotecan, and temozolomide (VIT) was found to be an effective treatment for relapsed or refractory neuroblastoma, achieving an overall objective response rate of 69.6% in a study of 46 patients.

The VIT regimen was well-tolerated, with most toxicities being manageable; while some patients experienced Grade 3-4 hematologic toxicity, the regimen was still considered active and safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vincristine, Irinotecan, and Temozolomide in Patients With Relapsed/Refractory Neuroblastoma. Zhu, J., Wang, J., Sun, F., et al.[2022]

In a study involving 35 children with relapsed or refractory neuroblastoma, the combination of irinotecan, temozolomide, and dinutuximab showed significant anti-tumor activity, with 53% of patients achieving an objective response, including complete responses.

In contrast, the combination of irinotecan, temozolomide, and temsirolimus had a much lower response rate, with only 6% of patients showing a partial response, indicating that the dinutuximab combination is more promising for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Mody, R., Naranjo, A., Van Ryn, C., et al.[2022]

In a phase 2 trial involving patients with high-risk neuroblastoma, the combination of irinotecan, temozolomide, and immunotherapy (dinutuximab and GM-CSF) showed a response rate of 53% in the initial cohort, indicating its potential efficacy for treating relapsed or refractory cases.

The study found that specific genotypes related to natural killer (NK) cell activity, particularly KIR and their ligands, were associated with clinical outcomes, highlighting the importance of genetic factors in the effectiveness of the chemoimmunotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KIR/KIR-ligand genotypes and clinical outcomes following chemoimmunotherapy in patients with relapsed or refractory neuroblastoma: a report from the Children's Oncology Group. Erbe, AK., Diccianni, MB., Mody, R., et al.[2023]

In a phase II study involving 55 children with relapsed/refractory neuroblastoma, the combination of irinotecan and temozolomide showed an objective response rate of 15%, indicating potential efficacy, especially in patients whose disease was assessable by MIBG or bone marrow analysis.

The treatment was well tolerated, with less than 6% of patients experiencing severe diarrhea and less than 10% developing infections during neutropenia, suggesting a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. Bagatell, R., London, WB., Wagner, LM., et al.[2022]

The combination treatment of irinotecan, temozolomide, dintuximab, and GM-CSF (I/T/DIN/GM-CSF) showed significant antitumor activity in patients with relapsed or refractory neuroblastoma, with an overall objective response rate of 41.5% across 53 patients.

The treatment was associated with a one-year progression-free survival rate of 67.9% and an overall survival rate of 84.9%, although it also resulted in notable grade ≥ 3 toxicities, including fever/infection and neutropenia.

NCBI (Pubmed)

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. Mody, R., Yu, AL., Naranjo, A., et al.[2021]

In a phase I trial involving 14 children with recurrent high-risk neuroblastoma, an all-oral regimen of irinotecan and temozolomide was found to be feasible and well tolerated, with 50% of patients showing a response or disease stabilization for three or more treatment courses.

The maximum-tolerated dose (MTD) was established at 60 mg/m2/d for oral irinotecan combined with 75 mg/m2/d of temozolomide, demonstrating similar plasma exposure levels to those seen with intravenous irinotecan, suggesting this oral combination could be a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of oral irinotecan and temozolomide for children with relapsed high-risk neuroblastoma: a new approach to neuroblastoma therapy consortium study. Wagner, LM., Villablanca, JG., Stewart, CF., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9815701/

Efficacy of systemic administration of irinotecan ... - PubMed Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/15126363/

In vivo treatment with CPT-11 leads to differentiation of ... Our data suggest that prolonged in vivo exposure to CPT-11 induces differentiation of NB xenografts, which is associated with truncation of the topo I enzyme.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S030438359700428X

Oral versus intraperitoneal administration of irinotecan in ... In the present study, we compared the plasma concentrations of CPT-11 and SN-38 in nude mice as well as their effectiveness against a human neuroblastoma ...

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Efficacy of systemic administration of irinotecan against ... Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.23.00458

Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial Patients receiving irinotecan or topotecan experienced more AEs than those receiving T alone (Data Supplement, Table S6). Patients receiving ...

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Safety evaluation of irinotecan - PubMed Central Submitter outcome data from FAERS (B) and JADER (C) were illustrated using donut plots to visually represent the distribution of reported clinical outcomes.

7. fda.gov fda.gov/files/drugs/published/N20-571S023-Irinotecan-Clinical-BPCA.pdf

N20-571S023 Irinotecan Clinical BPCA Primary Objectives: To determine the efficacy of irinotecan in the treatment of children with refractory neuroblastoma, sarcomas of soft tissue ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3112027/

Do pharmacokinetic polymorphisms explain treatment ... In the last few decades, improvement in treatment outcome for high-risk patients has not occurred, with an overall survival rate <30–40%. Many reasons may ...

9. researchgate.net researchgate.net/figure/Prevalence-of-CPT-11-Related-Toxicities-in-Children-with-Relapsed-Refractory-Solid-Tumors_tbl2_350295671

Prevalence of CPT-11-Related Toxicities in Children with... 17 In our center, it is observed that some patients displayed intolerable toxicity to standard dosing of irinotecan due to high incidence of grade 3-4 toxicity, ...