Trabectedin

Indications

Trabectedin is used for: Advanced soft tissue sarcoma, after failure of anthracyclines & ifosfamide. Relapsed platinum-sensitive ovarian cancer, in combination w/ pegylated liposomal doxorubicin (PLD).

Adult Dose

Soft Tissue Sarcoma Indicated for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen Premedicate with dexamethasone prior to each dose 1.5 mg/m² IV q3wk until disease progression or unacceptable toxicity Infuse over 24 hr via a central venous line Hepatic impairment Moderate hepatic impairment (bilirubin levels 1.5 times to 3 times upper limit of normal, and AST and ALT < 8 times upper limit of normal): 0.9 mg/ m²

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30-89 mL/min): No dose adjustment required Severe (CrCl <30 mL/min) or ESRD: Not studied

Administration

Contra Indications

Known hypersensitivity, including anaphylaxis, to trabectedin

Precautions

Hepatic or renal impairment, neutropenia & thrombocytopenia, nausea & vomiting, rhabdomyolysis & severe CPK elevations (>5 times ULN), hepatic function test abnormalities, inj site reactions; concomitant use w/ CYP3A4 inhibitors, drugs associated w/ hepatotoxicity, alcohol, phenytoin or live attenuated vaccines. May affect ability to drive or operate machinery. Pregnancy.

Pregnancy-Lactation

Pregnancy Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy There are no available data on trabectedin use during pregnancy Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats Contraception Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose Males: May damage spermatozoa, resulting in possible genetic and fetal abnormalities; advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose Infertility May result in decreased fertility in males and females Lactation Unknown if distributed in human breast milk Because of the potential for serious adverse reactions from trabectedin in breastfed infants, advise a nursing woman to discontinue nursing during treatment

Interactions

Potent CYP3A4 inhibitors (oral ketoconazole, fluconazole, ritonavir, clarithromycin, aprepitant; dexamethasone; potent CYP3A4 inducers (rifampicin, phenobarb, St. John's wort); P-gp inhibitors (cyclosporine, verapamil).

Adverse Effects

Side effects of Trabectedin : >10% Nausea, all grades (75%) Fatigue, all grades (69%) Vomiting, all grades (46%) Constipation, all grades (37%) Decreased appetite, all grades (37%) Diarrhea, all grades (35%) Peripheral edema, all grades (28%) Dyspnea, all grades (25%) Headache, all grades (25%) Arthralgia, all grades (15%) Insomnia, all grades (15%) Myalgia, all grades (12%)

Mechanism of Action

Alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix toward the major groove Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA-binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death