Trabectedin (Yondelis) approved by the FDA for unresectable or metastatic liposarcoma or leiomyosarcoma

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October 24, 2015 –  The Amrican Food and Drug Administration approved Trabectedin (Yondelis) for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received a prior anthracycline-containing regimen.
The approval of trabectedin is based on improvement in progression-free survival (PFS) in a multicenter, randomized, open‑label, active‑controlled trial. Patients were randomized (2:1) to receive trabectedin 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (n=345) or dacarbazine 1000 mg/m2 administered as an intravenous infusion over 20 to 120 minutes once every 3 weeks (n=173).  Randomization was stratified by soft tissue sarcoma subtype Trabceptin(leiomyosarcoma vs. liposarcoma), ECOG performance status, and number of prior chemotherapy regimens.  The efficacy outcome measures were investigator‑assessed PFS per Response Evaluation Criteria in Solid Tumors (RECIST v1.1), overall survival, confirmed objective response rate, and response duration.  Patients randomized to the dacarbazine arm were not offered trabectedin at the time of disease progression. The median age was 56 years (range: 17 to 81); 30% were male; 76% White, 12% Black, and 4% Asian; 73% leiomyosarcoma and 27% liposarcoma; 49% had an ECOG PS of 0; and 89% received 2 or more prior chemotherapy regimens.  The most common drugs administered as prior therapy were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%).  Approximately 10% of patients had received pazopanib.
Trabectedin (Yondelis) comes with a series of rather serious averse events. The most serious risks of trabectedin are neutropenic sepsis, rhabdomyolysis, cardiomyopathy, hepatotoxicity, anaphylaxis, and extravasation leading to tissue necrosis.  Among the 378 patients who received at least one dose of trabectedin in the randomized trial, the most common (greater than or equal to 20% of patients) adverse reactions were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache.  The most common treatment-emergent, grade 3 or 4 laboratory abnormalities (greater than or equal to 5% of patients) were neutropenia, increased ALT, thrombocytopenia, anemia, increased AST, and increased creatine phosphokinase.
The recommended dose and schedule for trabectedin is 1.5 mg/m2 as a 24-hour intravenous infusion through a central venous line every 3 weeks in patients with normal bilirubin and with AST and ALT less than or equal to 2.5 times the upper limit of normal. Premedicate with dexamethasone 20 mg intravenously 30 minutes prior to each dose of trabectedin. There is no recommended dose of trabectedin for patients with serum bilirubin levels above the institutional upper limit of normal.
The mode of action of  Trabectedin is not yet completely understood. Recently however, it has been shown that Trabectedin blocks DNA binding of the oncogenic transcription factor FUS-CHOP and reverses the transcriptional program in myxoid liposarcoma. By reversing the genetic program created by this transcription factor, Trabectedin promotes differentiation and reverses the oncogenic phenotype in these cells. The compound is known to bind and alkylate DNA at the N2 position of guanine. It is known from in vitro work that this binding occurs in the minor groove, spans approximately 3 to 5 bp and is most efficient with CGG sequences. Additional favorable binding sequences are TGG, AGC, or GGC. Once bound, this reversible covalent adduct bends DNA toward the major groove, interferes directly with activated transcription, poisons the transcription-coupled nucleotide excision repair (TCR) complex, promotes degradation of RNA polymerase II, and generates DNA double-strand breaks.

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Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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