50 Participants Needed

Sirolimus + Chemotherapy for High-Risk Pediatric Cancers

(AflacST1903 Trial)

Recruiting at 4 trial locations
Kathryn Sutton | Faculty | People ...
Overseen ByKathryn Sutton, MD
Age: < 65
Sex: Any
Trial Phase: Phase 2
Sponsor: Emory University
Must be taking: Metronomic chemotherapy
No Placebo GroupAll trial participants will receive the active study treatment (no placebo)
Prior Safety DataThis treatment has passed at least one previous human trial

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to improve the 2-year progression-free survival in children with high-risk solid tumors who are administered a maintenance regimen with continuous sirolimus administered on a backbone of metronomic chemotherapy following the completion of "standard" therapy, as compared to high-risk solid tumor patients treated with observation alone following completion of "standard" therapy.

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.

What data supports the effectiveness of the drug combination Sirolimus + Chemotherapy for high-risk pediatric cancers?

Research shows that combining rapamycin (another name for sirolimus) with chemotherapy drugs like cyclophosphamide and vincristine can be more effective than using these drugs alone in treating childhood tumors. This combination was well-tolerated and showed promising results in preclinical models.12345

What safety data exists for Sirolimus combined with chemotherapy in pediatric cancers?

A study on sirolimus combined with oral cyclophosphamide and topotecan in children with relapsed solid tumors aimed to find the maximum tolerated dose and noted toxicities, indicating that safety was a key focus. Another study assessed the safety of oral etoposide in children with sarcomas, highlighting its toxicity profile.46789

How is the drug Sirolimus combined with chemotherapy unique for high-risk pediatric cancers?

The combination of Sirolimus with chemotherapy drugs like cyclophosphamide and etoposide is unique because it shows enhanced effectiveness compared to using these chemotherapy drugs alone, particularly in pediatric cancer models. This combination is relatively well tolerated and has shown promising results in preclinical studies, making it a novel approach for treating high-risk pediatric cancers.12346

Research Team

KS

Kathryn Sutton, MD

Principal Investigator

Emory University

Eligibility Criteria

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.
My child's cancer is in remission or nearly clear after initial treatment.
See 13 more

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.
See 6 more

Timeline

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

Treatment Details

Interventions

  • Celecoxib
  • Cyclophosphamide
  • Etoposide
  • Sirolimus
  • VP-16
Trial OverviewThe 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.
Participant Groups
2Treatment groups
Experimental Treatment
Active Control
Group I: Maintenance Chemotherapy RegimenExperimental Treatment4 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 TherapyActive Control1 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

Find a Clinic Near You

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+

Findings from Research

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

References

Phase I study of vinblastine and temsirolimus in pediatric patients with recurrent or refractory solid tumors: Canadian Cancer Trials Group Study IND.218. [2019]
EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation. [2019]
Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. [2021]
Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. [2021]
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. [2021]
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]
Oral etoposide for recurrent/progressive sarcomas of childhood. [2013]
Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. [2019]
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. [2022]