Sirolimus + Chemotherapy for High-Risk Pediatric Cancers
(AflacST1903 Trial)
Recruiting in Palo Alto (17 mi)
+4 other locations
Overseen ByKathryn Sutton, MD
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Emory University
Must be taking: Metronomic chemotherapy
Must not be taking: Anticonvulsants, CYP3A4 inducers
Disqualifiers: Pregnancy, Uncontrolled infection, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
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.
12345What 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.
46789How 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.
12346Eligibility 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.
+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.
+6 more
Trial 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
Participant Groups
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.
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:
๐บ๐ธ Approved in United States as Cytoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
๐ช๐บ Approved in European Union as Endoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
๐จ๐ฆ Approved in Canada as Neosar for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
- Rheumatoid arthritis
๐ฏ๐ต Approved in Japan as Endoxan for:
- Breast cancer
- Ovarian cancer
- Multiple myeloma
- Leukemia
- Lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Texas Children's Cancer CenterHouston, TX
Aflac Cancer & Blood Disorders CentersAtlanta, GA
Children's Healthcare of AtlantaAtlanta, GA
Washington University School of MedicineSaint Louis, MO
More Trial Locations
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Who Is Running the Clinical Trial?
Emory UniversityLead Sponsor
PeachBowl LegACy FundCollaborator
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]Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children.
EVE/cyclosporin (etoposide, vincristine, epirubicin with high-dose cyclosporin)-chemotherapy selected for multidrug resistance modulation. [2019]Sixteen children and young adults were treated with high-dose cyclosporin combined with a combination of cytotoxics (epirubicin, vincristine and etoposide) (EVE) known to be influenced by P-glycoprotein-mediated multidrug resistance (MDR). Tumour types were neuroblastoma 3, Ewing's sarcoma 2, rhabdomyosarcoma 5, osteosarcoma 3, desmoplastic small round cell tumour 1, nephroblastoma 1, T-acute lymphoblastic leukaemia (ALL) 1. All had progressed or relapsed following at least two of the drug types included in EVE. Acute reactions to cyclosporin and myelosuppression were the major toxicities documented. Renal and hepatic toxicity was rarely severe and always transient. Partial responses (PR) were observed in 2 patients (1 rhabdomyosarcoma, 1 Ewing's sarcoma). We conclude that this combination is tolerable in heavily pretreated patients and may be suitable for further evaluation in untreated poor risk tumours.
Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. [2021]Rapamycin demonstrated broad-spectrum tumor growth inhibition activity against the in vivo panels of childhood tumors used in the Pediatric Preclinical Testing Program (PPTP). Here we have evaluated rapamycin combined with agents used frequently in the treatment of childhood malignancies. Rapamycin was tested in vitro against 23 cell lines alone or in combination with melphalan, cisplatin, vincristine, or dexamethasone (leukemic models only). In vivo, the impact of combining rapamycin with a cytotoxic agent was evaluated using two measures: 1) the therapeutic enhancement measure, and 2) a linear regression model for time-to-event to formally evaluate for sub- and supraadditivity for the combination compared to the agents used alone. Combining rapamycin with cytotoxic agents in vitro gave predominantly subadditive or additive effects, except for dexamethasone in leukemia models for which supra-additive activity was observed. In vivo testing demonstrated that therapeutic enhancement was common for rapamycin in combination with cyclophosphamide and occurred for 4 of 11 evaluable xenografts for the rapamycin and vincristine combination. The combinations of rapamycin with either cyclophosphamide or vincristine were significantly more effective than the respective standard agents used alone at their maximum tolerated doses (MTD) for most evaluable xenografts. The combination of rapamycin and cisplatin produced excessive toxicity requiring cisplatin dose reductions, and therapeutic enhancement was not observed for this combination. Addition of rapamycin to either cyclophosphamide or vincristine at their respective MTDs appears promising, as these combinations are relatively well tolerated and as many of the pediatric preclinical models evaluated demonstrated therapeutic enhancement for these combinations.
Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. [2021]To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.
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 AcSรฉ-ESMART trial. [2021]Arms E and F of the AcSรฉ-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962).
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]This pilot study of the Australia and New Zealand Childhood Cancer Study Group investigated the effectiveness and toxicity of a regimen incorporating vincristine (VCR), etoposide, and divided-dose, escalating cyclophosphamide (CPA) (VETOPEC) in 23 patients aged 1 to 20 years with solid tumors.
Oral etoposide for recurrent/progressive sarcomas of childhood. [2013]Etoposide (VP-16) is a topoisomerase II inhibitor that is effective in a broad spectrum of pediatric and adult malignancies. Chronic, low-dose, oral VP-16 has also been shown to be active in some recurrent malignancies mostly in adults. The aim of this prospective, single institution study is to assess the efficacy and toxicity of oral VP-16 in children with progressive or recurrent (P/R) sarcomas.
Ifosfamide and etoposide in recurrent childhood acute lymphoblastic leukemia. [2019]The activity of the drug combination ifosfamide and etoposide (VP16) in refractory and relapsed childhood acute lymphoblastic leukemia (ALL) was assessed in a phase II study.
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]The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.