U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves YONDELIS (trabectedin)

FDA Approves YONDELIS^® (trabectedin) for Advanced Soft Tissue Sarcoma Subtypes, Liposarcoma, and Leiomyosarcoma, With Prior Chemotherapy

On October 23, 2015, the United States Food and Drug Administration (FDA) approved YONDELIS (trabectedin) for the treatment of patients with advanced soft tissue sarcoma (STS), liposarcoma, and leiomyosarcoma subtypes (L-type sarcoma), who have received prior chemotherapy, including an anthracycline regimen. The approved recommended dosage of YONDELIS lyophilized powder for injection is 1.5 mg/m2 administered as a 24-hour intravenous (IV) infusion once every three weeks (Q3W). Patients receiving YONDELIS will be premedicated with dexamethasone 20 mg IV or an equivalent dose of an IV corticosteroid on day 1 of each treatment cycle, 30 minutes before the infusion.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Trabectedin

• MOA: Trabectedin disrupts the cell cycle and inhibits cell proliferation.
• Dose proportionality: Exhibited dose-proportional increases in systemic exposure over the dose range of 0.024 mg/m2 to 1.8 mg/m2 (i.e., 0.016 times to 1.2 times the approved recommended dosage).
• Accumulation: No accumulation was observed at the approved recommended dosage.
• Plasma protein binding: Approximately 97%.
• Terminal half-life (mean): Approximately 175 hours in patients.
• Metabolism: Extensive. Primarily metabolized by CYP3A. 
• Excretion: Approximately 58% of the total recovered radio-labeled trabectedin dose was eliminated in the feces and 6% was eliminated in the urine. Unchanged trabectedin recovery was negligible.
• Exposure-safety: Adverse reactions (ARs), mainly neutropenia and elevation in transaminases, led to dose reductions in 35% of patients receiving trabectedin in the registration trial. The proposed dose adjustment from 1.5 mg/m2 to 1.2 mg/m2 and then to 1 mg/m2 due to toxicity was used in the registration trial. Exposure-response (E-R) relationships were identified for the common ARs in the registration trial, including neutropenia, elevation in transaminases, and hyperbilirubinemia, using data from Phase 1 and 2 studies. The proposed dose adjustments are likely to decrease toxicity based on the exposure-toxicity relationships.

Drug Interaction Potential

• Avoid strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. Administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion if short term strong CYP3A inhibitor use (i.e., less than 14 days) must be used. Coadministration of a strong CYP3A4 inhibitor (i.e., ketoconazole) increased the trabectedin dose normalized AUC by 66% and Cmax by 22%. 
• Avoid strong CYP3A inducers. Coadministration of a strong CYP3A4 inducer (i.e.., rifampicin) decreased trabectedin dose normalized AUC by 31% and Cmax by 21%. 

Use in Specific Populations

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), BSA (0.9 to 2.8 m2), mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment. The effect of any degree of hepatic impairment, severe renal impairment (CLcr 15 to 29 mL/min), or end stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis on trabectedin exposure is unknown.

Safety and Efficacy

Clinical effectiveness and safety of trabectedin were demonstrated at the recommended dose in a multicenter, randomized, open-label, active-controlled trial that enrolled 518 patients with L-type sarcoma who received prior chemotherapy, including an anthracycline regimen. The median progression-free survival was 4.2 months in trabectedin-treated patients compared to 1.5 months in those receiving dacarbazine [hazard ratio: 0.55 (0.4, 0.7, p < 0.0001)]. The most common ARs were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, fever, cough, increases in AST or ALT, neutropenia, and anemia.

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Full prescribing information is available at http://go.usa.gov/c344F.

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This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov