Sirolimus
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Sirolimus: From Renal Cell Carcinoma and Lymphangioleiomyomatosis to Liposarcoma
One-Sentence Summary
Sirolimus is an mTOR inhibitor, listed in the knowledge graph for renal cell carcinoma (including clear cell subtypes) and lymphangioleiomyomatosis (LAM). The TxGNN model predicts it may be effective for Liposarcoma, with 1 clinical trial (a single-arm Phase 2 study of a combination regimen) and 7 publications (mostly reviews) currently supporting this direction. The evidence is indirect.
Note: The top-ranked prediction (liposarcoma) has only limited support. The strongest evidence in this dataset is for lymphangiomyoma (LAM), which is already an original indication and is covered in the additional-predictions section below.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Renal cell carcinoma (including clear cell and nonpapillary subtypes); lymphangioleiomyomatosis (from the knowledge graph; no approved indication text in the US license records) |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.89% |
| Evidence Level | L2 (one completed Phase 2 trial; single-arm, combination therapy) |
| US Market Status | Cancelled only (all licenses cancelled) |
| Number of NDAs | 11 authorizations in total (2 NDAs, 9 ANDAs) |
| Recommended Decision | Hold (research question) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, sirolimus is an mTOR inhibitor (mTORC1), and its activity in renal cell carcinoma and LAM is linked to mTOR pathway activation.
PI3K/AKT/mTOR pathway activation has been reported in soft tissue sarcomas, including liposarcoma. Mechanistically, blocking mTORC1 could slow tumour growth. Preclinical mouse models cited in the trial description show that mTOR inhibition can prevent tumour growth in chondrosarcoma and liposarcoma.
The limitation is that the only trial combines sirolimus with cyclophosphamide, so the effect of sirolimus alone cannot be separated. The literature is mostly reviews of targeted sarcoma therapy and transplant cancer-risk studies, which give only indirect support.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02821507 | Phase 2 | Completed | 70 | Single-arm, multicentre trial of sirolimus plus cyclophosphamide in metastatic or unresectable myxoid liposarcoma and chondrosarcoma (2014-06 to 2021-12). No randomized control; the liposarcoma subgroup size is not stated. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 39796641 | 2024 | Review | Cancers | Overview of novel therapeutics and recent regulatory approvals in soft tissue sarcoma |
| 37222206 | 2023 | Review | Current Opinion in Oncology | Rationale and results of recent trials of molecular-targeted agents in advanced sarcomas |
| 16434506 | 2006 | RCT (secondary analysis) | J Am Soc Nephrol | In renal transplant recipients, sirolimus after early cyclosporine withdrawal reduced cancer risk (430 patients randomized) |
| 20497911 | 2010 | Review | Bulletin du Cancer | Targeted treatments for rare connective tissue tumours and sarcomas |
| 26093731 | 2015 | Review | Transplantation Proceedings | Effects of immunosuppressive drugs on malignancy development in renal transplant patients |
| 32711543 | 2020 | Case report | Diagnostic Pathology | Three cases of fibro-adipose vascular anomaly with emphasis on the mTOR pathway |
| 42753013 | 2026 | Cohort | Familial Cancer | Retrospective cohort describing the phenotype and malignancy spectrum of PTEN hamartoma tumor syndrome |
US Market Information
All 11 US authorizations are cancelled; none are currently valid. Approved indication text is not available in the license records.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA021110 | Sirolimus (Mylan) | Tablet, sugar coated | Not available |
| NDA213478 | HYFTOR (Nobelpharma America) | Gel | Not available |
| ANDA201676 | Sirolimus (Zydus) | Tablet, film coated | Not available |
| ANDA214753 | Sirolimus (Ascend) | Tablet, film coated | Not available |
| ANDA208691 | Sirolimus (Northstar Rx) | Tablet, film coated | Not available |
The other six authorizations are generic sirolimus solutions or tablets (Amneal, VistaPharm, Apotex, Novadoz, Camber, American Health Packaging). A topical gel (HYFTOR) exists among the licenses.
Cytotoxicity
Sirolimus is a targeted mTOR inhibitor and is not a conventional cytotoxic agent. It is relevant here because some of its original and predicted indications are neoplastic.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (mTOR inhibitor) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
- Disease-level cautions (knowledge graph, not label text): The knowledge graph links sirolimus to caution in several conditions, including hypertension, kidney disease, liver disease, hyperglycemia and diabetes, hyperlipidemia and hypertriglyceridemia, interstitial lung disease, infections (including pneumocystosis and cytomegalovirus infection), stroke and cerebrovascular disorders, hyperbilirubinemia, pericardial effusion, progressive multifocal leukoencephalopathy, and certain cancers. These are knowledge-graph associations, not verified label contraindications.
- Drug Interactions: 100 interactions were identified; the 20 shown in the data include:
- Major: amphotericin B (including the lipid complex), mesalazine, balsalazide, clarithromycin
- Moderate: antidiabetic drugs (acarbose, metformin, pioglitazone, alogliptin, albiglutide, canagliflozin, dapagliflozin, chlorpropamide), corticosteroids (hydrocortisone, dexamethasone, betamethasone, budesonide, triamcinolone), aprepitant, cimetidine
Please refer to the package insert for authoritative warnings and contraindications; the label text could not be retrieved for this report.
Other Predicted Indications (Context)
| Rank | Predicted Indication | Score | Evidence Level | Key Point | Suggested Decision |
|---|---|---|---|---|---|
| 5 | Lymphangiomyoma (LAM) | 99.79% | L1 | Phase 3 MILES trial (NCT00414648, n=89, completed) and Phase 3 MILED (NCT03150914, n=60, active); already an original indication | Proceed with Guardrails |
| 9 | Lung PEComa | 99.63% | L2 | Evidence transferred from LAM, not specific to lung PEComa | Research question |
| 4 | Benign PEComa | 99.80% | L4 | Case reports of sirolimus/nab-sirolimus response; no registered trials | Research question |
| 3, 6-8, 10, 2 | Uterine PEComa, unclassified RCC, Xp11.2/TFE3 RCC, RCC with neuroblastoma, vulva sarcoma, ovarian myxoid liposarcoma | 99.6-99.85% | L5 | Prediction only; no specific trials or publications | Hold |
Conclusion and Next Steps
Decision: Hold (research question) for liposarcoma
Rationale: The only supporting trial is a single-arm Phase 2 study of a sirolimus plus cyclophosphamide combination, and the literature is indirect (reviews and transplant cancer-risk data). Efficacy of sirolimus alone in liposarcoma cannot be established from the available evidence. By contrast, the LAM prediction has direct randomized Phase 3 evidence and merits Proceed with Guardrails.
To proceed, the following is needed:
- Liposarcoma-specific subgroup results from NCT02821507, and ideally a randomized or sirolimus-monotherapy study
- Mechanism of action data (DrugBank) to support the mechanistic-link analysis
- FDA package insert warnings and contraindications (a blocking gap for safety screening)
- Clarification of product availability, since all US licenses are cancelled
- A drug-interaction management plan (high interaction burden, including major interactions with clarithromycin and amphotericin B)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.