Trabectedin
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Trabectedin: From Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Trabectedin is a marine-derived cytotoxic agent, originally used to treat ovarian cancer (in combination with pegylated liposomal doxorubicin for relapsed, platinum-sensitive disease). The TxGNN model predicts it may be effective for female breast carcinoma, with 1 clinical trial (a QT-interval safety study, not an efficacy trial) and 20 publications currently associated with this direction. Phase 2 breast cancer data show limited single-agent activity.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ovarian cancer (the approved indication text in the Singapore licence record is blank; the original indication comes from the knowledge graph) |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L2 (as scored in the compiled data; see the note under Clinical Trial Evidence) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold (research question; consider a biomarker-selected study) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the compiled data. The following comes from the literature compiled for this report. Trabectedin binds the DNA minor groove and causes DNA double-strand breaks that depend on transcription-coupled nucleotide excision repair. Tumours with BRCA or other homologous recombination deficiencies are therefore especially sensitive. It also reduces tumour-associated macrophages, which changes the tumour microenvironment.
Ovarian and breast cancers share a biological link through BRCA1/2 deficiency. A phase 2 study in germline BRCA1/2-mutated metastatic breast cancer was built on this reasoning. Preclinical work also shows that trabectedin enhances IL-12 antitumour effects in triple-negative breast cancer.
Clinical results, however, are modest. Phase 2 data in anthracycline- and taxane-pretreated advanced breast cancer show limited single-agent activity. Any benefit is likely restricted to molecularly selected subgroups, such as BRCA-deficient disease.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, placebo-controlled study of the effect of a single trabectedin dose on the ECG QT interval in advanced solid tumours. This is a safety/pharmacology study and gives only indirect support. The title in the record is truncated and should be checked against the registry entry. |
The registered trial does not test efficacy in breast cancer. The "L2" score therefore overstates the direct evidence, and the evidence base for efficacy is better described as small phase 2 studies.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | Phase 2 randomized (2 regimens) | Clin Breast Cancer | Single-agent trabectedin in advanced breast cancer after anthracycline and taxane; compared 2 administration regimens |
| 24692579 | 2014 | Phase 2 | Ann Oncol | First-in-class phase 2 trial in germline BRCA1/2-mutated metastatic breast cancer, based on the hypersensitivity of homologous recombination-defective tumours |
| 27266804 | 2016 | Phase 2 | Clin Breast Cancer | Trabectedin 1.3 mg/m² in HR-positive, HER2-negative advanced breast cancer, stratified by XPG expression |
| 19114300 | 2009 | Phase 1 | Eur J Cancer | Trabectedin plus doxorubicin in advanced soft tissue sarcoma and breast cancer (9 breast patients) |
| 26592307 | 2016 | Review | Expert Opin Investig Drugs | Overview of trabectedin in breast cancer, including effects on tumour-associated macrophages |
| 27710871 | 2016 | Review | Cancer Treat Rev | Trabectedin as a chemotherapy option in BRCA-deficient patients |
| 39777457 | 2025 | Preclinical | Cancer Immunol Res | Trabectedin enhances the antitumour effects of IL-12 in triple-negative breast cancer |
| 24941346 | 2014 | Preclinical | Eur Cytokine Netw | Anti-angiogenic effects of trabectedin on breast cancer cells |
| 23792433 | 2013 | Preclinical | Toxicol Lett | Apoptosis induction in MCF-7 and MDA-MB-453 breast cancer cells |
| 18410797 | 2008 | Review | Semin Oncol | Emerging agents for anthracycline- and taxane-refractory metastatic breast cancer |
The abstracts compiled for this report do not report efficacy figures for these studies, so the table does not state response rates.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN13661P | YONDELIS Powder for Injection 1mg/vial (Baxter Oncology GmbH) | Injection, powder, for solution | Not stated in the compiled licence record |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (marine-derived DNA minor-groove binder) |
| Myelosuppression Risk | High. The literature reports grade 3-4 neutropenia in about 50% and thrombocytopenia in about 20% of patients; hepatic toxicity is also common |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count with differential, liver function tests, renal function. A dedicated study assessed QT effects (see the trial above) |
| Handling Protection | Follow institutional cytotoxic drug handling regulations |
Safety Considerations
- Drug Interactions: The compiled data list 100 interacting drugs. Most are Moderate, and Clarithromycin is rated Major (the list reviewed here covers 20 entries). Moderate examples include dexamethasone, aprepitant, cimetidine, metronidazole, levofloxacin, miconazole, simvastatin and rosuvastatin. Clarithromycin and cimetidine are often discussed as CYP3A4-related interactions, and this would need confirming against the label.
Warnings and contraindications from the package insert are not available in the compiled data. Please refer to the package insert for these safety details.
Conclusion and Next Steps
Decision: Hold
Rationale: The only registered trial is a QT safety study, and published phase 2 breast cancer studies show limited single-agent activity. A plausible mechanistic link exists in BRCA/homologous recombination-deficient disease, but the evidence is not strong enough to support broader use. The other predicted indications (rank 2-10) have no or only preclinical evidence and also stay on Hold. The Singapore licence text does not list an approved indication, and package insert safety data are not yet available.
To proceed, the following is needed:
- Package insert warnings and contraindications from HSA (a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- Full review of the three phase 2 breast cancer studies (efficacy results, BRCA/XPG subgroup outcomes)
- Verification of NCT00786838 against the registry record
- A biomarker-selected study design (for example, BRCA-deficient breast cancer) before any further development
- A DDI management plan, particularly for strong CYP3A4 inhibitors such as clarithromycin
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.