Thalidomide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Thalidomide: From Plasma Cell Myeloma to Ganglioneuroblastoma
One-Sentence Summary
Thalidomide was originally used to treat plasma cell myeloma (multiple myeloma). The TxGNN model's top-ranked prediction is ganglioneuroblastoma, but no clinical trials or publications were found for it, so this prediction rests on model score and biological plausibility alone. Better-supported alternatives among the other predictions are neuroblastoma (3 trials, 12 publications), myeloid leukemia (6 trials, 20 publications) and rheumatoid arthritis (1 indirect trial, 19 publications).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Plasma cell myeloma (the Singapore licence has no indication text on record) |
| Predicted New Indication | Ganglioneuroblastoma (top-ranked prediction) |
| TxGNN Prediction Score | 98.96% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. From the published literature, thalidomide is known to have anti-angiogenic, immunomodulatory and TNF-alpha-inhibiting effects. It also acts through cereblon, a protein that targets other proteins for degradation. These properties underlie its use in multiple myeloma.
Ganglioneuroblastoma is a tumour of neural crest origin, closely related to neuroblastoma. Thalidomide has shown anti-angiogenic activity in a neuroblastoma xenograft model, so a plausible biological link exists. This is an inference only. No trials or publications were found for ganglioneuroblastoma itself, and the high score may reflect knowledge-graph relationships rather than demonstrated benefit.
Several other predicted indications have more support:
- Neuroblastoma: completed early-phase trials of multi-drug anti-angiogenic regimens, plus preclinical data.
- Myeloid leukemia: small Phase 2 trials, mostly combinations and partly in myelodysplastic syndromes.
- Rheumatoid arthritis: historical open studies from the 1980s and 1990s.
- Indolent plasma cell myeloma: an extension within the original disease area.
Several other top-ranked predictions are developmental syndromes: vertebral anomalies with endocrine and T-cell dysfunction, brachydactyly-syndactyly syndrome, and colobomatous microphthalmia-rhizomelic dysplasia syndrome. They likely reflect thalidomide's known teratogenic phenotype, not therapeutic potential, and should not be pursued.
Clinical Trial Evidence
Currently no related clinical trials are registered for ganglioneuroblastoma. The closest related disease with registered trials is neuroblastoma:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00357500 | Phase 2 | Completed | 101 | Oral 5-drug anti-angiogenic regimen (thalidomide, celecoxib, fenofibrate, etoposide, cyclophosphamide) in relapsed or progressive cancer |
| NCT00098865 | Phase 2 | Completed | 15 | Thalidomide with temozolomide in relapsed or progressive brain tumours or neuroblastoma |
| NCT00049296 | Phase 1 | Completed | 26 | Pharmacokinetics of thalidomide with docetaxel in advanced cancer (safety and dosing) |
In all three, thalidomide is one component of a combination, so its individual contribution cannot be separated.
Literature Evidence
No literature was found for ganglioneuroblastoma. For neuroblastoma, the most relevant publications are:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24123865 | 2014 | Phase 2 trial | Pediatr Blood Cancer | Multi-agent oral metronomic anti-angiogenic regimen in children with recurrent or progressive cancer |
| 14612937 | 2003 | Preclinical (xenograft) | Int J Oncol | Thalidomide is anti-angiogenic in a neuroblastoma xenograft model |
| 29423589 | 2018 | Preclinical (murine) | Pediatr Surg Int | Thalidomide potentiates etoposide-induced apoptosis in murine neuroblastoma by suppressing NF-κB |
| 18024879 | 2007 | Case report | J Clin Oncol | Successful anti-angiogenic therapy for neuroblastoma with thalidomide |
| 10882863 | 2000 | Review | Eur J Cancer | Thalidomide as an "accidental" anti-angiogenic drug |
| 12033499 | 2002 | Preclinical (CAM assay) | Biol Pharm Bull | Hydroxylated thalidomide metabolites and blood vessel density, tumour and endothelial cell proliferation |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16362P | DOMIDE CAPSULES 50mg | Capsule | Not stated in the available record |
The product is a single-ingredient oral capsule, manufactured by TTY Biopharm Company Limited (Chungli Factory).
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Immunomodulatory / anti-angiogenic agent (not a conventional cytotoxic) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions. The knowledge graph links thalidomide to neutropenia and agranulocytosis |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count with differential; assessment for peripheral neuropathy and thromboembolism |
| Handling Protection | Please refer to the package insert warnings and precautions. Thalidomide is a known teratogen, so exposure by women who are or may become pregnant should be avoided |
Safety Considerations
- Contraindication-related disease associations (from the knowledge graph, not label text): multiple system atrophy, postural orthostatic tachycardia syndrome, orthostatic hypotension, epilepsy, neutropenia, agranulocytosis, peripheral nervous system disease, peripheral neuropathy, pulmonary embolism.
- Teratogenicity: thalidomide is a well-known cause of severe birth defects. This is a major barrier for any new indication, especially for the developmental syndromes in the prediction list.
- Peripheral neuropathy: reported in the literature as a dose-limiting adverse effect, including in rheumatoid arthritis patients.
- Drug interactions: 100 interactions were found in the DDI screening. The major-level ones listed here are all corticosteroids: hydrocortisone, triamcinolone, dexamethasone, betamethasone and prednisone. Moderate-level interactions include H2 blockers (famotidine, ranitidine, cimetidine, nizatidine), antiemetics (ondansetron, dolasetron, palonosetron, metoclopramide), morphine, metronidazole, clarithromycin, levofloxacin, dronabinol, nabilone and picosulfuric acid.
The package insert warnings and contraindications for the Singapore product were not available, so please refer to the package insert for the full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: Ganglioneuroblastoma has a very high model score but no trials or publications, so the evidence level is L5 and the link is inferred only. The related disease neuroblastoma has more support, but only from early-phase combination-regimen trials and preclinical data. There is no Phase 3 RCT and no way to isolate thalidomide's effect. Teratogenicity and neuropathy add significant safety constraints.
To proceed, the following is needed:
- Mechanism of action data for thalidomide
- The Singapore package insert, covering warnings, contraindications and approved indication text
- Direct preclinical or clinical evidence in ganglioneuroblastoma, for example by extending neuroblastoma data
- Consideration of neuroblastoma, myeloid leukemia or indolent myeloma as the lead candidate, since each has more supporting evidence
- A risk-management plan covering teratogenicity (pregnancy prevention), neuropathy monitoring and thromboembolism risk
- Review of the interactions with corticosteroids and other major-level combinations
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.