Combination Chemotherapy for Neuroblastoma

Overseen By Shakeel Modak, MD

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: Severe organ dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new combination of chemotherapy drugs, called N9, is safe and effective for treating children with neuroblastoma, a cancer affecting nerve tissue. The trial uses three different sets of chemotherapy drugs, including Carboplatin, Cyclophosphamide, Doxorubicin, Etoposide, Ifosfamide, Topotecan, and Vincristine, administered at different times to evaluate their effectiveness. Children who may be suitable for this trial are those newly diagnosed with high-risk neuroblastoma and have not undergone more than one round of chemotherapy. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

In a previous study, carboplatin, one of the drugs in the treatment, caused mild nerve issues in about 4% of patients. Cyclophosphamide has been used safely in children, but it can lower blood cell counts, potentially leading to infections or bleeding. Doxorubicin may increase the risk of heart problems, either during treatment or years later. Etoposide can cause bone marrow suppression, resulting in low blood cell counts. Ifosfamide has been linked to an increased risk of developing other types of cancer. Topotecan can lead to serious drops in blood cells, increasing the risk of fever and infection. Vincristine, another drug in the combination, is known to affect nerves and should be used carefully with other drugs that might damage hearing.

These drugs have been used in cancer treatments before, and their side effects are known. However, since this trial is in its early phase, the full safety profile for this specific combination in treating neuroblastoma has not yet been established. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination chemotherapy treatment for neuroblastoma because it brings together multiple powerful drugs: Carboplatin, Cyclophosphamide, Doxorubicin, Etoposide, Ifosfamide, Topotecan, and Vincristine. This cocktail aims to tackle the cancer from different angles, potentially increasing effectiveness compared to using just one or two drugs alone. The unique aspect here is the strategic combination, which could improve outcomes for patients with high-risk neuroblastoma by attacking cancer cells in various ways. By targeting multiple pathways, this approach might also help overcome resistance that tumors can develop against single-agent therapies.

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

Studies have shown that the chemotherapy drugs used in this trial have promising effects against neuroblastoma, a type of cancer. Participants will receive a combination of these drugs. Carboplatin significantly slows the growth of neuroblastoma cells, leading to better survival rates. Cyclophosphamide, when combined with other drugs, has improved treatment outcomes for patients with neuroblastoma. Doxorubicin destroys neuroblastoma cells and increases survival chances in research models. Etoposide has resulted in complete or partial reduction of the cancer in some cases. Ifosfamide, when combined with carboplatin and etoposide, has led to cancer shrinking in many patients. Topotecan, when used with cyclophosphamide, shows good treatment results with few side effects. Vincristine is approved by the FDA for treating neuroblastoma and is an effective part of treatment plans. ^{4 6 7 8 9}

Who Is on the Research Team?

Brian Kushner, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for children aged 1 to less than 13 with neuroblastoma, who have had no more than one prior chemo treatment. They must have a certain level of heart function and kidney function, as well as adequate liver function. Children with severe organ dysfunction or inability to follow the study plan cannot participate.

Inclusion Criteria

Signed informed consent indicating awareness of the investigational nature of this treatment

My neuroblastoma diagnosis is confirmed by specific tests and criteria.

I have had only one round of chemotherapy.

Exclusion Criteria

I do not have severe problems with my kidneys, heart, liver, brain, lungs, blood, or stomach.

I am a pre-adolescent, so pregnancy is not applicable.

Inability to comply with protocol requirements

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive N9 chemotherapy regimen, including combinations of Cyclophosphamide, topotecan, vincristine (CTV), Ifosfamide, carboplatin, etoposide (ICE), and Cyclophosphamide, doxorubicin, vincristine (CDV)

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Cyclophosphamide
• Doxorubicin
• Etoposide
• Ifosfamide
• Topotecan
• Vincristine

Trial Overview The N9 study tests three combinations of chemotherapy drugs (CTV, ICE, CDV) in cycles to determine their safety and effectiveness against pediatric neuroblastoma. Each drug combo includes agents like Cyclophosphamide and Doxorubicin known for treating cancer.

How Is the Trial Designed?

Group I: Participants with newly-diagnosed HR-Neuroblastoma Experimental Treatment 8 Interventions

This pilot study of N9 as induction chemotherapy will enroll 30 patients with newly-diagnosed HR-NB. A first cohort of \>1 to 12-year old, and a second cohort of extended age \<19 years old. Both cohorts will be analyzed together.

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

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]

In a phase II study involving 47 children with metastatic neuroblastoma, the combination of etoposide and carboplatin showed a 43% response rate, including 4 complete remissions and 13 partial remissions, indicating potential efficacy as an alternative treatment.

The treatment was associated with significant hematologic toxicity, leading to a median delay of 39 days between courses, and some patients experienced notable kidney and hearing side effects, suggesting the need for careful monitoring and further evaluation in newly diagnosed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. Frappaz, D., Michon, J., Hartmann, O., et al.[2017]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/EDBK_349783

High-Risk and Relapsed Neuroblastoma: Toward More ... Patients treated during this trial had a 97% end-induction response rate and a 73.7% 3-year EFS rate, both of which compare favorably to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7586261/

The Inhibitory Effect of Carboplatin Injection on Human ... The results in all these aspects showed that carboplatin injection had a significant inhibitory effect on neuroblastoma SK-N-SH. Literature review found that ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8330963/

Improving Outcomes in Children With High-Risk ... Outcomes for children with newly diagnosed high-risk neuroblastoma have improved significantly over the past 20 years, but despite intensive ...

4. siope.eu siope.eu/media/documents/escp-high-risk-neuroblastoma-standard-clinical-practice-recommendations.pdf

escp-high-risk-neuroblastoma-standard-clinical-practice- ... These trials explored the impact on survival of consolidation regimens consisting of HD carboplatin- etoposide-melphalan (CEM) and total body irradiation ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S235246422500241X

Late effects after high-risk neuroblastoma (LEAHRN): a ... 18, 19 Several randomised clinical trials in high-risk neuroblastoma show improved survival with tandem SCT (versus single),6 carboplatin ...

6. mayoclinic.org mayoclinic.org/drugs-supplements/carboplatin-intravenous-route/description/drg-20062578

Carboplatin (intravenous route) - Side effects & uses Carboplatin is an antineoplastic agent (cancer medicine). It interferes with the growth of cancer cells, which are eventually destroyed by the ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2003/20-452.pdf_Paraplatin_Prntlbl.pdf

PARAPLATIN® (carboplatin aqueous solution) INJECTION PARAPLATINR (carboplatin aqueous solution) INJECTION should be administered under the supervision of a qualified physician experienced in the use of cancer ...

8. labeling.pfizer.com labeling.pfizer.com/showlabeling.aspx?id=4379

carboplatin injection, solution Hospira, Inc. Peripheral neuropathies have been observed in 4% of the patients receiving carboplatin (6% of pretreated ovarian cancer patients) with mild paresthesias ...

9. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/c/carboplatinEbeweinj.pdf

Carboplatin Ebewe 5.3 PRECLINICAL SAFETY DATA. Genotoxicity. Animal studies demonstrate that carboplatin is mutagenic and teratogenic. Patients should be advised of its ...