Sirolimus + Chemotherapy for Refractory Pediatric Cancer

(AflacST1502 Trial)

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

46 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to determine the efficacy of daily sirolimus and celecoxib, with low dose etoposide alternating with cyclophosphamide for pediatric participants with relapsed or refractory tumors.

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.

What data supports the idea that Sirolimus + Chemotherapy for Refractory Pediatric Cancer is an effective drug?

The available research shows that combining sirolimus with chemotherapy drugs like cyclophosphamide and topotecan is being studied for its safety and effectiveness in children with difficult-to-treat solid tumors. While the studies focus on determining safe dosage levels and understanding side effects, they suggest potential benefits when sirolimus is used with other chemotherapy drugs. However, the research primarily aims to establish safety rather than directly proving effectiveness compared to other treatments. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Sirolimus combined with chemotherapy for refractory pediatric cancer?

Research shows that combining sirolimus with other chemotherapy drugs like cyclophosphamide and topotecan has been studied for safety and dosage in children with relapsed solid tumors. Additionally, similar treatments using mTOR inhibitors, like sirolimus, have shown potential benefits in improving outcomes for pediatric cancer patients. ^{1 2 3 4 5}

What safety data is available for Sirolimus + Chemotherapy in pediatric cancer?

The safety data for Sirolimus combined with chemotherapy in pediatric cancer can be inferred from several studies: 1) A Phase I study assessed the safety of temsirolimus (an mTOR inhibitor like Sirolimus) with vinblastine in children, indicating the exploration of mTOR inhibitors in pediatric cancer. 2) A study compared adverse effects of Sirolimus versus Everolimus in pediatric heart transplant recipients, providing insights into Sirolimus's safety profile. 3) A Phase II study evaluated the safety of vinorelbine and low-dose cyclophosphamide in children with solid tumors, showing a good tolerance profile. 4) A pilot study investigated the toxicity of a regimen including cyclophosphamide and etoposide in pediatric solid tumors. These studies collectively contribute to understanding the safety of Sirolimus and related chemotherapy regimens in pediatric settings. ^{2 3 6 7 8}

What safety data exists for Sirolimus + Chemotherapy in pediatric cancer treatment?

Studies have shown that sirolimus and chemotherapy drugs like cyclophosphamide and etoposide have been used in children with cancer, and while they can be effective, they may also cause side effects. For example, a study on cyclophosphamide and etoposide in children reported on the treatment's effectiveness and potential toxicity, indicating that these drugs can be tolerated but may have adverse effects. ^{2 3 6 7 8}

Is the drug combination of Celecoxib, Cyclophosphamide, Etoposide, and Sirolimus promising for treating refractory pediatric cancer?

The combination of these drugs shows promise because sirolimus, when combined with other chemotherapy drugs like cyclophosphamide and etoposide, has been studied for its potential to help treat difficult pediatric cancers. These studies aim to find the best dose and understand how the drugs work together, suggesting that this combination could be effective in treating cancers that have not responded to other treatments. ^{1 2 5 9 10}

What makes the drug combination of Sirolimus, Celecoxib, Cyclophosphamide, and Etoposide unique for treating refractory pediatric cancer?

This drug combination is unique because it includes Sirolimus, which is an mTOR inhibitor that can enhance the effects of chemotherapy drugs like Cyclophosphamide and Etoposide, potentially improving outcomes in children with difficult-to-treat cancers. The use of Sirolimus in combination with these drugs is novel, as it aims to exploit its ability to interfere with cancer cell growth pathways, which is different from traditional chemotherapy approaches. ^{1 2 5 9 10}

Research Team

Thomas Cash, MD

Principal Investigator

Emory University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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 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 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 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]

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 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]

References

1. United States 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. [2021]

2. United States 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. [2019]

3. United States 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. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors. [2021]

5. United States 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. [2020]

6. England 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). [2018]

7. Denmark pubmed.ncbi.nlm.nih.gov

Assessment of the adverse effects of sirolimus versus everolimus in pediatric heart transplant recipients. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. [2019]

9. England pubmed.ncbi.nlm.nih.gov

EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation. [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. [2021]