Introduction
Yondelis (trabectedin) is a marine-derived antineoplastic agent approved for the treatment of specific soft tissue sarcomas and ovarian cancer. Originally isolated from the Caribbean sea squirt Ecteinascidia turbinata, it represents a unique class of anticancer therapy with a distinct mechanism of action targeting DNA repair pathways.
Mechanism of Action
Trabectedin binds to the minor groove of DNA, forming covalent adducts that bend DNA toward the major groove. This interaction:
- Blocks transcription-coupled nucleotide excision repair (TC-NER)
- Induces double-strand DNA breaks
- Disrupts the interaction between DNA transcription factors and their target sequences
- Selectively targets cells with defective DNA repair pathways (particularly homologous recombination repair-deficient cells)
- Modulates the tumor microenvironment by depleting monocytes and tumor-associated macrophages
Indications
FDA-approved indications:1. Unresectable or metastatic liposarcoma or leiomyosarcoma in patients who received prior anthracycline-containing chemotherapy 2. Advanced or recurrent ovarian cancer (in combination with pegylated liposomal doxorubicin) after failure of platinum-based chemotherapy
EMA-approved indications:- Advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents
Dosage and Administration
Standard dosing:- Monotherapy (sarcoma): 1.5 mg/m² as a 24-hour continuous intravenous infusion every 3 weeks
- Combination therapy (ovarian cancer): 1.1 mg/m² as a 3-hour IV infusion every 3 weeks (with pegylated liposomal doxorubicin 30 mg/m²)
- Hepatic impairment: Reduce dose for bilirubin > ULN
- Renal impairment: No specific recommendation (use with caution)
- Hematologic toxicity: Delay treatment until ANC ≥ 1,500/mm³ and platelets ≥ 100,000/mm³
- Administer through a central venous line
- Premedicate with dexamethasone 20 mg IV 30 minutes prior to infusion
- Monitor for extravasation (vesicant properties)
Pharmacokinetics
Absorption: Administered IV only (no oral bioavailability) Distribution: Large volume of distribution (~5,000 L), high protein binding (~94%) Metabolism: Extensive hepatic metabolism primarily via CYP3A4 Elimination: Primarily fecal excretion (58%), with renal excretion accounting for <10% Half-life: Terminal elimination half-life ~180 hoursContraindications
1. History of severe hypersensitivity to trabectedin 2. Pregnancy and breastfeeding 3. Concurrent use with strong CYP3A4 inhibitors 4. Patients with pre-existing severe hepatic impairment (Child-Pugh Class C) 5. Patients with pre-existing severe bone marrow suppression
Warnings and Precautions
Boxed Warning:- Myelosuppression (neutropenia, thrombocytopenia)
- Hepatotoxicity (elevated transaminases, liver failure)
- Rhabdomyolysis and musculoskeletal toxicity
- Cardiac toxicity (cardiomyopathy, decreased LVEF)
- Extravasation risk (tissue necrosis)
- Embryo-fetal toxicity
- Capillary leak syndrome
Drug Interactions
Major interactions:- Strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin): ↑ trabectedin exposure → increased toxicity
- Strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): ↓ trabectedin exposure → reduced efficacy
- Other myelosuppressive agents: Additive bone marrow suppression
- Avoid concurrent use with strong CYP3A inhibitors/inducers
- If unavoidable, monitor closely and consider dose adjustments
Adverse Effects
Very common (>10%):- Neutropenia (42%), thrombocytopenia (32%), anemia (65%)
- Elevated AST (99%), ALT (87%), alkaline phosphatase (47%)
- Nausea (73%), vomiting (52%), fatigue (69%)
- Constipation (38%), diarrhea (25%)
- Febrile neutropenia (7%)
- Hepatotoxicity (2% severe)
- Rhabdomyolysis (1%)
- Cardiomyopathy (<1%)
- Capillary leak syndrome (rare)
Monitoring Parameters
Prior to each cycle:- Complete blood count with differential
- Liver function tests (AST, ALT, bilirubin)
- Renal function tests
- Creatine phosphokinase (CPK)
- Cardiac function assessment (baseline and periodic echocardiogram)
- Vital signs
- Signs of extravasation
- Symptoms of infection (fever, chills)
- Musculoskeletal symptoms (myalgia, weakness)
- Signs of hepatic dysfunction (jaundice, dark urine)
Patient Education
Key points to discuss:- Report fever ≥38°C or signs of infection immediately
- Importance of regular blood tests to monitor for side effects
- Avoid pregnancy; use effective contraception during and after treatment
- Report unusual muscle pain, weakness, or dark urine
- Notify healthcare team of all medications, including OTC and herbal products
- Potential for fatigue; avoid driving or operating machinery if affected
- Maintain adequate hydration unless contraindicated
- Treatment requires IV infusion over several hours
- Premedication with steroids is necessary to reduce side effects
- Central venous access is typically required
References
1. FDA Prescribing Information: Yondelis (trabectedin). 2015. 2. European Medicines Agency. Yondelis Assessment Report. 2007. 3. Demetri GD, et al. Efficacy and Safety of Trabectedin in Patients With Advanced Sarcoma. Journal of Clinical Oncology. 2009;27(25):4188-4196. 4. Monk BJ, et al. Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer. Journal of Clinical Oncology. 2010;28(19):3107-3114. 5. Le Cesne A, et al. Trabecetdin in patients with advanced soft tissue sarcoma: pooled analysis of five phase II trials. Cancer Chemotherapy and Pharmacology. 2020;85(1):37-45. 6. National Comprehensive Cancer Network (NCCN) Guidelines: Soft Tissue Sarcoma (Version 2.2023). 7. Garcia-Carbonero R, et al. Phase II and pharmacokinetic study of trabectedin 3-hour infusion every three weeks in patients with advanced soft tissue sarcoma. Cancer Chemotherapy and Pharmacology. 2013;72(3):531-539.