Sirolimus + Chemotherapy for High-Risk Pediatric Cancers

(AflacST1903 Trial)

Recruiting at 5 trial locations

Overseen By Kathryn Sutton, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must be taking: Metronomic chemotherapy

Must not be taking: Anticonvulsants, CYP3A4 inducers

Disqualifiers: Pregnancy, Uncontrolled 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: 12 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding sirolimus (Rapamune) to a standard chemotherapy regimen can help children with high-risk solid tumors remain cancer-free longer after standard treatment. The chemotherapy includes cyclophosphamide and etoposide, and participants will alternate these with sirolimus over a year. Children or young adults who have completed initial cancer treatment and are in complete remission or have minimal abnormalities on scans may qualify if they have certain solid tumors, such as osteosarcoma or Ewing sarcoma. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant findings.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications. You cannot be on enzyme-inducing anticonvulsants, potent CYP3A4 inducers or inhibitors, other investigational drugs, or any other anti-cancer agents. If you're on corticosteroids, the dose must be stable or decreasing for the prior 7 days.

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

Research shows that the drugs used in this trial—sirolimus, celecoxib, etoposide, and cyclophosphamide—have been studied for safety.

Sirolimus has been used for bone cancer and demonstrated benefits with manageable side effects, even in children. Celecoxib has been researched for its ability to slow tumor growth, with no major safety issues identified. Etoposide has proven effective against tumors in sarcomas and is considered relatively safe, as it doesn't cause severe side effects. Cyclophosphamide, when combined with other drugs, has been effective against certain sarcomas and is generally well-tolerated by patients.

Overall, research suggests these treatments are usually well-tolerated with manageable side effects. Participants should consult their healthcare provider about any potential risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it combines sirolimus with a maintenance chemotherapy regimen to tackle high-risk pediatric cancers differently. Unlike standard therapies, which typically involve high doses of chemotherapy, this regimen uses low-dose oral etoposide and cyclophosphamide, alternating every 21 days, with continuous sirolimus and celecoxib. Such a combination aims to maintain remission while potentially reducing side effects associated with higher doses. Sirolimus, in particular, is notable for its ability to inhibit a key protein involved in cancer cell growth, offering a targeted approach that could improve outcomes for young patients with aggressive cancers.

What evidence suggests that this trial's treatments could be effective for high-risk pediatric cancers?

Research shows that sirolimus, when combined with treatments like cyclophosphamide, may help treat certain high-risk childhood cancers. Studies have found that it can slow tumor growth and stabilize sarcomas for several months. In this trial, participants will receive a maintenance chemotherapy regimen including sirolimus, celecoxib, etoposide, and cyclophosphamide. Celecoxib has been shown to slow cancer cell growth, particularly in bone cancer (osteosarcoma) and muscle cancer (rhabdomyosarcoma), by affecting specific cell processes. Etoposide has proven effective in shrinking tumors in cases of recurring Ewing sarcoma. Cyclophosphamide, when combined with other drugs, has shown success in controlling difficult-to-treat tumors like osteosarcoma. This trial studies these treatments together to determine if they can improve outcomes for children with these challenging cancers. ^{1 2 3 6 7}

Who Is on the Research Team?

Kathryn Sutton, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

Children and young adults aged 1 to 30 with high-risk solid tumors, such as osteosarcoma or Ewing sarcoma, who have completed standard therapy and are in remission. They must have good performance status, adequate organ function (liver, kidney), normal blood sugar levels, not be pregnant or breastfeeding, and agree to use contraception.

Inclusion Criteria

I am mostly able to care for myself and carry out daily activities.

My kidney function is good based on tests.

I have a specific type of advanced sarcoma or tumor.

Exclusion Criteria

I am not currently taking medication for seizures that affects enzymes.

I am not pregnant or breastfeeding, and if capable of having children, I agree to use contraception during and for 3 months after treatment.

I do not have any infections that are currently uncontrolled.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 12-month course of maintenance chemotherapy with continuous sirolimus, celecoxib, and alternating low-dose oral etoposide and cyclophosphamide

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Celecoxib
• Cyclophosphamide
• Etoposide
• Sirolimus
• VP-16

Trial Overview The trial is testing whether a maintenance regimen of sirolimus combined with low-dose chemotherapy can improve the progression-free survival for children with high-risk solid tumors compared to just observation after completing standard therapy.

How Is the Trial Designed?

Group I: Maintenance Chemotherapy Regimen Experimental Treatment 4 Interventions

Participants with metastatic osteosarcoma, metastatic Ewing sarcoma, high-risk rhabdomyosarcoma, metastatic non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), desmoplastic small round cell tumor (DSRCT), and malignant rhabdoid tumor (MRT) in first complete remission (cohort 1) or participants with recurrent solid tumors (any histology) in second complete remission (cohort 2), receiving a maintenance chemotherapy regimen administered as a 12-month course of continuous sirolimus with celecoxib and low-dose oral etoposide alternating every 21 days with low-dose oral cyclophosphamide following the completion of "standard" therapy.

Group II: Historical Control Cohort Receiving Standard Therapy Active Control 1 Intervention

This study arm is a historical control cohort of patients matched with cohort 1 on diagnosis, age, metastatic site, and date of diagnosis. The matched historical controls will be obtained from the same treating institution as the corresponding case to account for institutional differences in treatment and supportive care. Patients in the historical control cohort received standard therapy.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

PeachBowl LegACy Fund

Collaborator

Trials

1

Recruited

50+

Published Research Related to This Trial

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]

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]

In a phase II trial involving 43 patients with relapsed or refractory sarcomas, the combination of the anti-IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus did not lead to any objective tumor responses, despite promising preclinical results.

The treatment was associated with dose-limiting toxicities in 16% of cycles, with common side effects including mucositis, electrolyte disturbances, and myelosuppression, indicating that while the drugs were safe to administer, they did not provide the expected therapeutic benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Children's Oncology Group. Wagner, LM., Fouladi, M., Ahmed, A., et al.[2022]

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]

Vistusertib, a dual mTORC1/2 inhibitor, was found to be safe and well tolerated in a small group of pediatric patients (14.3 years median age) with relapsed/refractory malignancies, with the main side effects being hematological.

Despite the safety of vistusertib, the study was terminated due to a lack of tumor responses and insufficient target engagement, indicating that while targeting the PI3K/AKT/mTOR pathway is promising, further exploration is needed in pediatric cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-child phase I/II study of the dual mTORC1/2 inhibitor vistusertib (AZD2014) as monotherapy and in combination with topotecan-temozolomide in children with advanced malignancies: arms E and F of the AcSé-ESMART trial. Morscher, RJ., Brard, C., Berlanga, P., et al.[2021]

In a study of 21 children with progressive or recurrent sarcomas, oral etoposide (VP-16) showed a modest efficacy with a 14% objective response rate, including one complete response and two partial responses after two treatment courses.

Oral VP-16 was found to be relatively nontoxic, with no major acute toxicities reported, making it a simple treatment option for children, although the cure rate is low and it may be more suitable for palliative care in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral etoposide for recurrent/progressive sarcomas of childhood. Kebudi, R., Görgün, O., Ayan, I.[2013]

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]

Rapamycin showed broad-spectrum tumor growth inhibition in childhood tumors and, when combined with cyclophosphamide or vincristine, demonstrated significant therapeutic enhancement in most cases, indicating a promising treatment strategy.

However, combining rapamycin with cisplatin resulted in excessive toxicity, necessitating dose reductions, highlighting the importance of careful combination strategies in pediatric cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Houghton, PJ., Morton, CL., Gorlick, R., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4673269/

ZD6474, a new treatment strategy for human osteosarcoma ... Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006291X1100386X

Celecoxib inhibits STAT3 phosphorylation and suppresses ... We found that celecoxib inhibits IL-6-induced and persistent STAT3 phosphorylation and inhibits cell viability in human rhabdomyosarcoma cells.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02727387?cond=sarcoma%20es&viewType=Table&checkSpell=&rank=1

Protocol for the Treatment of Metastatic Ewing Sarcoma Study Overview. Brief Summary. Study for the treatment of metastatic Ewing sarcoma with high doses chemotherapy, radiotherapy and maintenance therapy.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4583823/

A Pilot Study of Low-Dose Anti-angiogenic Chemotherapy in ... Patients with metastatic Ewing sarcoma family of tumors (ES) continue to have a poor outcome with a three year survival of 20% despite the use of dose- ...

5. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35537

Consensus recommendations for systemic therapies in the ... Treatment of relapsed/refractory ES (RR-ES) remains a clinical challenge; the 5-year survival rate is less than 15%, and the majority of ...

6. mdpi.com mdpi.com/2072-6694/17/17/2894

ESFT13: A Phase II Study Evaluating the Addition of ... In one study, patients with non-metastatic high-risk rhabdomyosarcoma demonstrated improved survival when maintenance chemotherapy was added to the standard ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/22703797/

Celecoxib inhibits invasion and metastasis via a ... Celecoxib significantly inhibits invasion of Ewing sarcoma cells in vitro. Prostaglandin E2, a downstream product of COX-2, did not reverse in vitro inhibition.