Trabectedin
| 證據等級: L5 | 預測適應症: 1 個 |
目錄
Trabectedin: From [Original Indication Unavailable] to Female Breast Carcinoma
One-Sentence Summary
Trabectedin (DrugBank DB05109) is a marine-derived cytotoxic agent that is not currently marketed in this jurisdiction, and its original approved indication text is not available in the current dataset. The TxGNN model predicts it may be effective for Female Breast Carcinoma, with 2 clinical trials and 20 publications currently identified as supporting or contextual evidence — though most of this evidence is indirect (safety studies, single-arm Phase 2 trials, and preclinical work) rather than confirmatory Phase 3 data.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in this dataset (drug not marketed here; internationally, trabectedin is approved for soft tissue sarcoma and platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin) |
| Predicted New Indication | Female Breast Carcinoma |
| TxGNN Prediction Score | 99.73% |
| Evidence Level | L2 |
| Market Status | Not Marketed |
| Number of NDAs | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data for trabectedin is not available in this dataset as a structured field. Based on the supporting literature, trabectedin is a DNA minor-groove alkylating agent that binds DNA and interferes with transcription-coupled nucleotide excision repair (TC-NER); it also modulates the tumour microenvironment by reducing tumour-associated macrophages and pro-inflammatory cytokine signalling. It is currently used internationally for soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for relapsed platinum-sensitive ovarian cancer.
The mechanistic rationale for breast cancer centers on a specific molecular subgroup rather than the disease as a whole: tumours with homologous recombination deficiency (HRD), particularly BRCA1/2-mutated tumours (which represent roughly 5–10% of breast cancers), are selectively sensitive to trabectedin’s DNA-repair-interfering mechanism. This is supported by preclinical and early clinical data (e.g., PMID 23792433, PMID 24692579) showing activity in BRCA-mutated and hormone receptor-positive/HER2-negative breast cancer models and patients. However, this mechanistic link applies to a molecular subtype, not to female breast carcinoma broadly, which should be considered when interpreting the TxGNN score.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03470805 | Phase 2 | Completed | 9 | Evaluated olaparib as maintenance therapy after response to trabectedin + pegylated liposomal doxorubicin in recurrent ovarian carcinoma (BRCA-relevant population); trabectedin used as prior/lead-in therapy, not the primary study drug. Indirect support only, very small sample. |
| NCT00786838 | Phase 2 | Completed | 76 | Single-blind, placebo-controlled QT/QTc cardiac safety study of trabectedin in advanced solid tumors — a safety/pharmacology trial, not an efficacy trial for breast cancer. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 25239225 | 2014 | Phase 2 (randomized, single-arm comparison) | Clinical Breast Cancer | Multicenter Phase 2 study of single-agent trabectedin in advanced breast cancer post-anthracycline/taxane, comparing two administration regimens; assessed efficacy and safety directly in breast cancer patients. |
| 27266804 | 2016 | Phase 2 single-arm trial | Clinical Breast Cancer | Phase 2 study of trabectedin in HR-positive/HER2-negative advanced breast cancer, stratified by XPG gene expression as a predictive biomarker. |
| 24692579 | 2014 | Phase 2, first-in-class | Annals of Oncology | International Phase 2 trial showing trabectedin activity specifically in germline BRCA1/2-mutated metastatic breast cancer. |
| 25722380 | 2015 | Exploratory analysis of Phase 3 (ovarian cancer, off-target) | Annals of Oncology | Exploratory biomarker analysis from the Phase 3 OVA-301 trial showing BRCA1/XPG mutation status predicts response to trabectedin + PLD; supports the DNA-repair-deficiency mechanistic rationale, though population is ovarian cancer. |
| 26592307 | 2016 | Review | Expert Opinion on Investigational Drugs | Reviews trabectedin’s mechanism (transcription regulation, tumour-associated macrophage modulation) and its investigational role in breast cancer. |
| 27710871 | 2016 | Review | Cancer Treatment Reviews | Reviews trabectedin as a chemotherapy option specifically for BRCA-deficient tumours, including breast cancer. |
| 39777457 | 2025 | Preclinical | Cancer Immunology Research | Trabectedin depletes immunosuppressive myeloid cells and enhances IL-12-driven NK-cell antitumor activity in triple-negative breast cancer models. |
| 23792433 | 2013 | Preclinical/in vitro | Toxicology Letters | Trabectedin induces apoptosis via distinct pathways in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) breast cancer cell lines. |
| 24941346 | 2014 | Preclinical | European Cytokine Network | Demonstrates anti-angiogenic effects of trabectedin on breast cancer cell lines and endothelial cells. |
| 19114300 | 2009 | Phase 1 (mixed sarcoma/breast population) | European Journal of Cancer | Phase 1 pharmacokinetic study of trabectedin + doxorubicin in soft tissue sarcoma and advanced breast cancer, showing feasibility and antitumor activity. |
US Market Information
No approved authorizations are on record for this drug in this jurisdiction (total_licenses: 0, market_status: 未上市 / Not Marketed). No product table is available.
Cytotoxicity
Trabectedin is a marine-derived cytotoxic antineoplastic agent (DNA minor-groove alkylator), meeting the criteria for this section.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (DNA minor-groove alkylating agent, marine-derived alkaloid) |
| Myelosuppression Risk | High — literature reports Grade 3–4 neutropenia in approximately 50% and thrombocytopenia in approximately 20% of patients (per soft tissue sarcoma experience, PMID 19496709) |
| Emetogenicity Classification | Moderate to High |
| Monitoring Items | CBC with differential, liver function tests (hepatotoxicity is common), renal function, creatine phosphokinase (rhabdomyolysis has been reported), cardiac monitoring (QT/QTc, per NCT00786838) |
| Handling Protection | Yes — cytotoxic drug handling precautions (closed-system transfer devices, PPE) apply per standard antineoplastic handling regulations |
Safety Considerations
Please refer to the package insert for safety information. Structured safety data (key warnings, contraindications, and drug-drug interactions) are currently marked as data gaps in this evidence pack; this is flagged as a Blocking data gap (DG001) that must be resolved before a formal safety (S1) evaluation can proceed.
Conclusion and Next Steps
Decision: Hold
Rationale: Evidence level is L2, supported only by single-arm Phase 2 trials and largely preclinical/review literature rather than confirmatory randomized data specific to breast cancer; combined with a Blocking data gap in TFDA/label safety information and the fact that the drug is not currently marketed in this jurisdiction, the evidence base is not yet sufficient to proceed.
To proceed, the following is needed:
- Resolve DG001: obtain official label warnings/contraindications (e.g., via TFDA or reference regulator such as EMA/FDA, since the drug is not locally marketed)
- Resolve DG002: confirm mechanism of action documentation via DrugBank API
- Additional randomized or larger-scale trial data specifically in breast cancer, ideally enriched for BRCA1/2-mutated or HRD-positive subgroups, given the mechanistic rationale points to this subtype rather than breast cancer broadly
- Formal route-of-administration compatibility assessment (currently marked “pending” in the evidence pack)
- Drug-drug interaction data, given trabectedin’s known hepatic metabolism and myelosuppressive profile
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.