Sirolimus + Chemotherapy for Refractory Pediatric Cancer

(AflacST1502 Trial)

Not currently recruiting at 6 trial locations

Overseen By Thomas Cash, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Corticosteroids, Anticonvulsants, CYP3A4 drugs, others

Disqualifiers: Pregnancy, Breastfeeding, Infection, 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: Unknown

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment plan for children with difficult-to-treat or relapsed cancers. Researchers aim to assess the effectiveness of combining sirolimus (Rapamune) and celecoxib with two chemotherapy drugs, etoposide and cyclophosphamide. Eligible participants have cancers unresponsive to standard treatments or that have recurred, with no other curative options available. Participants will take these medications in cycles for up to two years to determine if this approach can better manage their cancer. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group, offering hope for improved cancer management.

Do I need to stop taking my current medications to join the trial?

Yes, you may need to stop some medications. You cannot take corticosteroids unless on a stable dose for 7 days, enzyme-inducing anticonvulsants, potent CYP3A4 inducers or inhibitors, other investigational drugs, or anti-cancer agents. Cannabis oil is not allowed during the first 2 cycles and must be stopped 3 days before enrollment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as corticosteroids if not on a stable dose for at least 7 days, enzyme-inducing anticonvulsants, potent CYP3A4 inducers or inhibitors, other investigational drugs, and any other anti-cancer agents. Additionally, cannabis oil must be stopped 3 days before enrollment.

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

Studies have shown that using sirolimus with metronomic chemotherapy, which involves small, frequent doses of cancer drugs, is well tolerated in children. This suggests that combining sirolimus with celecoxib, etoposide, and cyclophosphamide could be safe for children with difficult-to-treat tumors.

Other research has found that this drug combination had positive effects on some brain tumors in children. No major side effects were reported, which is encouraging.

While these findings are promising, individual reactions can vary. Always consult a healthcare professional before joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pediatric cancer?

Unlike the standard treatments for refractory pediatric cancer, which often involve traditional chemotherapy, this investigational treatment combines sirolimus, celecoxib, etoposide, and cyclophosphamide to offer a potentially more effective approach. Sirolimus is an mTOR inhibitor, which means it targets a specific pathway that cancer cells use to grow and multiply, offering a new mechanism of action. Celecoxib, typically used as a pain reliever, may help reduce inflammation that supports cancer growth. Researchers are excited because this combination could enhance the effectiveness of chemotherapy and improve outcomes for young patients with difficult-to-treat cancers.

What evidence suggests that this trial's treatments could be effective for refractory pediatric cancer?

In this trial, participants will receive a combination of oral sirolimus, celecoxib, etoposide, and cyclophosphamide. Research has shown that sirolimus can help treat difficult-to-treat childhood cancers. One study reported that 60% of patients experienced tumor reduction or disappearance, while 40% maintained stable disease. Celecoxib has shown promise in shrinking tumors, with some patients achieving complete remission when combined with other treatments. Etoposide is effective for children with recurrent or hard-to-treat cancer, though prolonged use has not proven superior to intermittent use. Cyclophosphamide, when combined with other drugs, has controlled the disease in 39% of certain childhood cancers. These findings suggest that combining these treatments might offer hope for children with challenging tumors. ^{6 7 8 9 10}

Who Is on the Research Team?

Thomas Cash, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for children with recurrent or refractory solid tumors and CNS (central nervous system) cancers, including brain tumors (except DIPG). Participants must have no known curative therapy available, be recovered from previous cancer treatments' side effects, and have measurable disease. They need to function at a certain level physically and have adequate organ function. Pregnant individuals, those on certain drugs like CYP3A4 inducers/inhibitors or cannabis oil during early treatment cycles, or with uncontrolled infections cannot join.

Inclusion Criteria

Your cancer diagnosis needs to be confirmed by a tissue sample, except in certain cases.

I have a brain tumor, but it is not DIPG.

My cancer returned after initial treatment or didn't respond to it, and there's no known cure.

Exclusion Criteria

Pregnant or breastfeeding women

I am not currently taking any experimental drugs or cancer treatments.

I will not use cannabis oil during the first 2 treatment cycles.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral sirolimus and celecoxib, with cycles of oral etoposide and cyclophosphamide for up to two years

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Celecoxib
• Cyclophosphamide
• Etoposide
• Sirolimus

Trial Overview The study tests the effectiveness of daily sirolimus combined with celecoxib plus low-dose etoposide alternating with cyclophosphamide in pediatric patients. The goal is to see how well this regimen works for kids whose cancer has come back after treatment or hasn't responded to initial therapies.

How Is the Trial Designed?

Group I: Oral sirolimus, celecoxib, etoposide, and cyclophosphamide Experimental Treatment 4 Interventions

Participants in this group will receive oral sirolimus and celecoxib in addition to cycles of oral etoposide and cyclophosphamide for up to two years.

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

Approved in United States as Celebrex for:

• Pain relief
• Inflammation
• Osteoarthritis
• Rheumatoid arthritis
• Menstrual cramps
• Colorectal polyps prevention

Approved in European Union as Celebrex for:

• Symptomatic relief in osteoarthritis
• Symptomatic relief in rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea
• Adenomatous polyposis coli

Approved in Canada as Celebrex for:

• Symptomatic relief of osteoarthritis
• Symptomatic relief of rheumatoid arthritis
• Ankylosing spondylitis
• Acute pain
• Primary dysmenorrhea

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Cannonball Kids' Cancer Foundation

Collaborator

Trials

6

Recruited

140+

Cannonball Kids' Cancer Foundation

Collaborator

Trials

4

Recruited

110+

Hyundai Hope On Wheels

Collaborator

Trials

7

Recruited

620+

Published Research Related to This Trial

The maximum tolerated dose (MTD) for the combination of sirolimus, cyclophosphamide, and topotecan in pediatric patients with relapsed/refractory solid tumors was established, with sirolimus levels targeted at 8-12.0 ng/mL, indicating a safe dosing strategy for this population.

While no objective responses were observed, the treatment was well tolerated, and biomarker analyses showed significant reductions in angiogenesis-related factors, suggesting potential modulation of tumor growth pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. Vo, KT., Karski, EE., Nasholm, NM., et al.[2021]

The VETOPEC regimen, which includes vincristine, etoposide, and escalating doses of cyclophosphamide, showed a high response rate of 95% in 20 patients with solid tumors, indicating its potential effectiveness for treating recurrent or advanced childhood cancers.

However, the treatment was associated with significant toxicity, particularly myelosuppression, with 98% of cycles resulting in grade IV neutropenia and a notable increase in grade IV thrombocytopenia, highlighting the need for further research to mitigate these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-intensive cyclophosphamide with etoposide and vincristine for pediatric solid tumors: a phase I/II pilot study by the Australia and New Zealand Childhood Cancer Study Group. White, L., McCowage, G., Kannourakis, G., et al.[2017]

The study involved 18 pediatric patients with recurrent and refractory solid and brain tumors, testing the combination of sirolimus and metronomic chemotherapy, which was found to be well tolerated with a recommended phase II dose of 2 mg/m2.

While the best response observed was stable disease in eight patients and a partial response in one, the treatment effectively inhibited a key cancer-related pathway, as indicated by the inhibition of phospho-S6 kinase in all patients during the first cycle.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors. Qayed, M., Cash, T., Tighiouart, M., et al.[2020]

In a study involving 13 pediatric patients with refractory or relapsed brain tumors, a combination chemotherapy regimen showed an objective tumor response rate of 38.5%, with some patients achieving complete and long-term responses.

The treatment was generally well-tolerated, with no severe grade III or IV toxicities reported, although some patients experienced mild side effects like thrombocytopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. Kim, H., Kang, HJ., Lee, JW., et al.[2021]

In a phase 1 study involving 15 children with recurrent solid tumors, the maximum tolerated dose of the combination treatment with bevacizumab and everolimus was established at 8 mg/kg and 4 mg/m2, respectively, with manageable toxicity levels.

The treatment showed some efficacy, with 30.8% of patients achieving stable disease, and significant inhibition of the mTOR pathway was observed, indicated by decreased levels of the biomarker phospho-4EBP1 in blood samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. Santana, VM., Sahr, N., Tatevossian, RG., et al.[2021]

The combination of temsirolimus and vinblastine in children with recurrent or refractory tumors showed significant toxicity, with grade 3 mucositis and hematologic issues being common, indicating a need for careful dose management.

Despite the toxicity, the treatment resulted in prolonged stable disease in four patients for a median of 5.0 months, suggesting potential efficacy in managing pediatric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218. Deyell, RJ., Wu, B., Rassekh, SR., et al.[2019]

In a phase II study involving 117 children and young adults with recurrent or refractory solid tumors, the combination of intravenous vinorelbine and oral cyclophosphamide showed a notable response rate of 36% in rhabdomyosarcoma, indicating potential efficacy for this specific cancer type.

The treatment was generally well-tolerated, with neutropenia being the most common severe side effect (38%), while other serious toxicities were rare, suggesting a manageable safety profile that warrants further investigation in larger phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). Minard-Colin, V., Ichante, JL., Nguyen, L., et al.[2018]

In a study involving 16 children and young adults with various relapsed or progressed tumors, high-dose cyclosporin combined with cytotoxic drugs showed tolerable safety, with major toxicities being acute reactions to cyclosporin and myelosuppression, while severe renal and hepatic toxicity was rare and transient.

The treatment resulted in partial responses in 2 patients, suggesting that this combination therapy may be effective and warrants further investigation in untreated patients with poor-risk tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation. Davidson, A., Dick, G., Pritchard-Jones, K., et al.[2019]

In a study of 87 pediatric heart transplant recipients, sirolimus (SRL) showed a greater improvement in kidney function (eGFR) and HDL cholesterol levels compared to everolimus (EVL) over a follow-up period of up to 2 years.

Both sirolimus and everolimus were well-tolerated with low rates of withdrawal due to adverse effects, but EVL may have a less favorable metabolic profile, as indicated by increases in triglycerides and glycosylated hemoglobin in the EVL cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the adverse effects of sirolimus versus everolimus in pediatric heart transplant recipients. Newland, DM., Rosete, BE., Law, YM., et al.[2023]

In a phase II study involving 20 heavily pretreated children with relapsed acute lymphoblastic leukemia (ALL), the combination of ifosfamide and etoposide (VP16) resulted in a 40% complete remission rate, demonstrating significant efficacy in this challenging patient population.

The treatment was generally well tolerated, with myelosuppression being the most common side effect, indicating that while the therapy is effective, careful monitoring for toxicity is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. Crooks, GM., Sato, JK.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9144744/

Cyclic Metronomic Chemotherapy for Pediatric Tumors In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some ...

2. nature.com nature.com/articles/s41416-023-02525-2

Phase 1 study of high-dose DFMO, celecoxib ... Children with relapsed or refractory neuroblastoma have dismal outcomes [1] and novel treatments are sought. Amplification of the MYCN gene ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10093481/

Phase I Study of a Combination of Fluvastatin and Celecoxib ... Celecoxib has been used in several cancer trials [24] including in pediatric LGG protocols [26]. Mercurio et al. demonstrated a synergistic effect of ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/13/3/1036/194487/Celecoxib-Prevents-Neuroblastoma-Tumor-Development

Celecoxib Prevents Neuroblastoma Tumor Development and ... Results showed that celecoxib had a significant effect of reducing tumor volume regardless of treatment (control, irinotecan, and doxorubicin: ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/pdi3.2512

Metronomic chemotherapy in pediatric neuroblastoma These findings suggest that oral MC has the potential to improve survival outcomes in high-risk neuroblastoma patients who achieve CR/very good ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31876107/

A phase I study of sirolimus in combination with metronomic ... The combination of sirolimus with metronomic chemotherapy is well tolerated in children. A phase II trial of this combination is ongoing.

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT02574728/

Clinical Trial: NCT02574728 This study aims to determine the efficacy of daily sirolimus and celecoxib, with low dose etoposide alternating with cyclophosphamide for ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.10024

A phase 2 study of sirolimus in combination with ... The combination of sirolimus with metronomic chemotherapy showed activity in pediatric patients with some R/R CNS tumors, producing objective responses.

9. withpower.com withpower.com/trial/sirolimus-chemotherapy-for-refractory-pediatric-cancer-91f01

Sirolimus + Chemotherapy for Refractory Pediatric Cancer This study aims to determine the efficacy of daily sirolimus and celecoxib, with low dose etoposide alternating with cyclophosphamide for pediatric participants ...

10. researchgate.net researchgate.net/publication/371301191_A_multicenter_phase_II_trial_of_maintenance_sirolimus_in_combination_with_metronomic_chemotherapy_in_children_and_adolescents_with_high-risk_solid_tumors

A multicenter, phase II trial of maintenance sirolimus in ... Methods: This is a phase II study of sirolimus in combination with celecoxib and alternating low-dose etoposide and cyclophosphamide delivered as maintenance ...