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DRUG RECORD

 

TRABECTEDIN

OVERVIEW
Trabectedin

 

Introduction

Trabectedin is natural product derived from the Caribbean sea squirt which has antineoplastic activity and is used to treat soft tissue sarcoma.  Trabectedin therapy is associated with a high rate of transient serum enzyme elevations during treatment and with occasional instances of clinically apparent liver injury with jaundice.

 

Background

Trabectedin (tra bek' te din) is a novel antineoplastic agent initially derived from extracts of the Caribbean sea squirt, Ecteinascideia turbinata or mangrove tunicate.  It was the first drug to be isolated from a sea animal.  Trabectedin binds to the minor groove of DNA, allowing for alkylation of guanine and resulting in DNA damage.  Biosynthesis of the active product allowed for clinical trials of trabectedin which demonstrated evidence of cytotoxic activity against soft tissue sarcomas.  Trabectedin was approved for use in the United States in 2014 as therapy of advanced, refractory liposarcoma and leiomyosarcoma.  Trabectedin is given intravenously and is available as 1 mg of lyophilized powder in single use vials under the brand name Yondelis.  The typical dose is 1.5 mg/m2 body surface area as a 24 hour infusion every 3 weeks.  It is usually given after premedication with 20 mg of dexamethasone.  Side effects are common and include bone marrow suppression, nausea, vomiting, diarrhea, anorexia, fatigue, peripheral edema, dyspnea, and headache.  Serious adverse events include neutropenic sepsis, rhabdomyolysis, cardiomyopathy and embryo-fetal toxicity.

 

Hepatotoxicity

Elevations in serum aminotransferase levels arise in almost all patients treated with trabectedin and elevations above 5 times the upper limit of normal occur 20% to 50% of patients.  Pretreatment with dexamethasone appears to decrease the degree and frequency of enzyme elevations.  The elevations arise within 2 to 5 days of the intravenous infusion, rise to maximal levels between 5 and 9 days and generally fall to baseline values within 3 to 4 weeks.  Minor elevations in serum alkaline phosphatase and bilirubin are also common.  However, clinically apparent liver injury with jaundice from trabectedin is rare.  On the other hand, patients with underlying liver disease appear to be at increased risk for septicemia and multiorgan failure, and monitoring of liver tests before and during therapy is recommended.  The liver injury typically mimics acute decompensation of an underlying cirrhosis with modest elevations in serum enzymes and worsening jaundice and hepatic synthetic dysfunction.  Immunoallergic and autoimmune features are uncommon.  Fatalities are generally due to sepsis and multiorgan failure.

Likelihood score: C[HD] (probable cause of clinically apparent liver injury, generally in the setting of preexisting liver disease and use of high doses)

 

Mechanism of Injury

The transient serum aminotransferase elevations that occur with trabectedin therapy are most likely due to direct hepatotoxicity.  Trabectedin is extensively metabolized by the hepatic cytochrome P450 system, predominant CYP 3A4 and is susceptible to drug-drug interactions with agents that induce or inhibit CYP 3A activity.

 

Outcome and Management

The severity of liver injury from trabectedin ranges from mild elevations in liver enzymes to marked aminotransferase elevations to clinically apparent liver injury with jaundice and hepatic failure.  Most severe cases occur in patients with preexisting liver disease.  For these reasons, patients should be monitored with routine liver tests before and during therapy and therapy delayed or stopped if liver test abnormalities persist.  In animal models, hepatotoxicity is lessened by pretreatment with dexamethasone and pretreatment with 30 mg of dexamethasone 30 minutes before each infusion is recommended.


Drug Class:  Antineoplastic Agents, Alkylating Agents

 

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PRODUCT INFORMATION
Trabectedin

 

REPRESENTATIVE TRADE NAMES
Trabectedin – Yondelis®

 

DRUG CLASS
Antineoplastic Agents, Alkylating Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Trabectedin 114899-77-3 C39-H43-N3-O11-S Trabectedin Chemical Structure

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REFERENCES
Trabectedin

 

References updated: 12 March 2017

  1. Zimmerman HJ. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.  (Expert review of hepatotoxicity of cancer chemotherapeutic agents published in 1999 before the availability of trabectedin).

  2. DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 541-68.  (Review of hepatotoxicity of cancer chemotherapeutic agents; trabectedin is listed as causing serum enzyme elevations and rare instances of liver failure when given in high doses).

  3. Chabner BA, Bertino J, Clearly J, Ortiz T, Lane A, Supko JG, Ryan DP. Trabectedin. Cytotoxic agents. Chemotherapy of neoplastic diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1719-21.  (Textbook of pharmacology and therapeutics).

  4. Brain EG. Safety and efficacy of ET-743: the French experience. Anticancer Drugs 2002; 13 Suppl 1: S11-4. PubMed Citation  (Among 54 patients with advanced, refractory soft tissue sarcoma treated with trabectedin [1500 mg/m2 intravenously every 3 weeks], 3 [6%] had a partial response, and side effects included asymptomatic and reversible neutropenia and aminotransferase elevations in 60% of patients and 2 cases of rhabdomyolysis).

  5. van Kesteren Ch, de Vooght MM, López-Lázaro L, Mathôt RA, Schellens JH, Jimeno JM, Beijnen JH. Yondelis(trabectedin, ET-743): the development of an anticancer agent of marine origin. Anticancer Drugs 2003; 14: 487-502. PubMed Citation  (Review of the development, chemistry, mode of action and preclinical and clinical studies of trabectedin suggests that it acts by binding to the minor groove of DNA, thereby interfering with transcription factor binding to DNA and blocking transcription).

  6. Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, Taamma A, et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 2004; 22: 890-9. PubMed Citation  (Among 54 patients with advanced, refractory soft tissue sarcoma treated with trabectedin [1-20 cycles], 6 had a partial or minor response, and side effects included ALT or AST elevations above 5 times ULN in 50% of patients with 2 treatment related deaths, one from rhabdomyolysis and one from febrile neutropenia which resulted in decompensation of a preexisting alcoholic cirrhosis).

  7. Beumer JH, Schellens JH, Beijnen JH. Hepatotoxicity and metabolism of trabectedin: a literature review. Pharmacol Res 2005; 51: 391-8. PubMed Citation  (Review of trabectedin hepatotoxicity in preclinical and clinical studies; mentions that hepatotoxicity is seen in mice, rats, dogs, and rhesus monkeys and is partially abrogated by dexamethasone pretreatment; the ALT elevations in humans start to rise 2-5 days after an infusion, reach at maximum at 5-9 days, and resolve within 4 weeks, the abnormalities often lessening with repeated cycles).

  8. Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, et al. Phase II study of ET-743 in advanced soft tissue sarcomas: a European Organisation for the Research and Treatment of Cancer (EORTC) soft tissue and bone sarcoma group trial. J Clin Oncol 2005; 23: 576-84 PubMed Citation  (Among 104 patients with soft tissue or bone sarcoma treated with trabectedin [1500 mg/m2 every 3 weeks], ALT elevations above 5 times ULN arose in 45%, bilirubin elevations in 42%, Alk P in 63% and neutropenia in 52%, while 4 patients died usually of multiorgan failure, but correlating best with preexisting liver abnormalities, particularly any elevation in Alk P).

  9. Grosso F, Dileo P, Sanfilippo R, Stacchiotti S, Bertulli R, Piovesan C, Jimeno J, et al. Steroid premedication markedly reduces liver and bone marrow toxicity of trabectedin in advanced sarcoma. Eur J Cancer 2006; 42: 1484-90. PubMed Citation  (Among 54 patients with advanced, refractory sarcomas treated with trabectedin, 31 did and 23 did not receive pretreatment with oral dexamethasone [4 mg twice daily for the 24 hours before infusions], and adverse events were less with pretreatment including aminotransferase elevations [above 5 times ULN] in 2% vs 34%, neutropenia in 2% vs 24% and thrombocytopenia in none vs 25%, while objective response rates and progression free survival appeared unaffected).

  10. Krasner CN, McMeekin DS, Chan S, Braly PS, Renshaw FG, Kaye S, Provencher DM, et al. A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens. Br J Cancer 2007; 97: 1618-24. PubMed Citation  (Among 147 women with recurrent ovarian carcinoma after platinum based therapy who were treated with trabectedin [0.58 mg/m2 every week], ALT elevations occurred in 28% and were above 5 times ULN in 11%, but all were self-limited in course).

  11. Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, et al. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 2009; 27: 4188-96. PubMed Citation  (Among 270 patients with advanced or metastatic, refractory soft tissue sarcoma treated with 1 of 2 regimens of trabectedin [weekly or every 3rd week], response rates were higher with every 3 week dosing as were adverse events including ALT elevations above 5 times ULN [45% vs 9%], but there were no instances of hepatic failure).

  12. Pick AM, Nystrom KK. Fatal hepatic and renal toxicity as a complication of trabectedin therapy for radiation-induced sarcoma. J Oncol Pharm Pract 2010; 16: 269-72. PubMed Citation  (79 year old man with sarcoma developed progressive renal and hepatic failure 1 week after a 2nd [every 3 weeks] intravenous infusion of trabectedin [bilirubin initially 2.4 and rising to 12 mg/dL, ALT 73 to 502 U/L, Alk P 473 U/L] and dying 3 weeks later [no autopsy]).

  13. Fayette J, Boyle H, Chabaud S, Favier B, Engel C, Cassier P, Thiesse P, et al. Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution. Anticancer Drugs 2010; 21: 113-9. PubMed Citation  (Among 92 patients with advanced sarcoma treated with trabectedin [1.5 mg/m2 every 3 weeks], adverse events included ALT or AST elevations above 5 times ULN in 37%, but no “toxic deaths” occurred).

  14. Le Cesne A, Yovine A, Blay JY, Delaloge S, Maki RG, Misset JL, et al. A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials. Invest New Drugs 2012; 30: 1193-202. PubMed Citation  (Among 1132 patients treated with trabectedin in various regimens in 19 trials, common side effects including nausea [65%], fatigue [58%], neutropenia [69%], ALT elevations [91%], ALT elevations above 5 times ULN [44%] and bilirubin elevations [21%]).

  15. Baruchel S, Pappo A, Krailo M, Baker KS, Wu B, Villaluna D, Lee-Scott M, et al. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. Eur J Cancer 2012; 48: 579-85. PubMed Citation  (Among 50 children with recurrent sarcomas who were treated with trabectedin [1.3 or 1.5 mg/m2 every 3 weeks], only one patient had a partial response and 3 others had stable disease, while adverse events were common including ALT elevations above 5 times ULN in 32%, but all were asymptomatic and resolved without dose adjustment).

  16. Monk BJ, Blessing JA, Street DG, Muller CY, Burke JJ, Hensley ML. A phase II evaluation of trabectedin in the treatment of advanced, persistent, or recurrent uterine leiomyosarcoma: a gynecologic oncology group study. Gynecol Oncol 2012; 124: 48-52. PubMed Citation  (Among 20 women with advanced uterine leiomyosarcoma treated with 2-29 cycles of trabectedin, the progression free survival rate was 5.8 months and adverse events included ALT elevations in 55% which were above 5 times ULN in 10%).

  17. Laurenty AP, Thomas F, Chatelut E, Bétrian S, Le Guellec C, Hennebelle I, Le Guellec S, et al. Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: a case report. Pharmacogenomics. 2013; 14: 1389-96. PubMed Citation  (66 year old man with pleiomorphic sarcoma developed liver injury 3 weeks after a second infusion of trabectedin [bilirubin 0.5 mg/dL, ALT 7 times ULN, Alk P 5 times ULN], with subsequent slow rise of bilirubin to 9.5 mg/dL and persistently high Alk P], liver biopsy showing cholangitis and jaundice persisting until his death from metastatic sarcoma 10 months later).

  18. Ploner F, Lamm W, Schur S, Eisterer W, Kühr T, Lindorfer A, Tinchon C, et al. The Austrian experience with trabectedin in non-selected patients with metastatic soft tissue sarcoma (STS). J Cancer Res Clin Oncol 2013; 139: 1337-42. PubMed Citation  (Among 101 adult Austrian patients with metastatic soft tissue sarcoma treated with trabectedin, the extent and severity of toxicity “were low and manageable”, including ALT elevations in 25% with values above 5 times ULN in 3%).

  19. Samuels BL, Chawla S, Patel S, von Mehren M, Hamm J, Kaiser PE, Schuetze S, et al. Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study. Ann Oncol 2013; 24: 1703-9. PubMed Citation  (Among 1895 adults with advanced soft tissue sarcomas treated with trabectedin [1.5 mg/m2 every 3 weeks], best results were achieved in leiomyosarcoma and liposarcoma, while ALT elevations arose in 19% and were above 5 times ULN in 11%; no mention of clinically apparent liver injury, although 23 patients [1%] died of suspected drug related complications).

  20. Vincenzi B, Stumbo L, Maltese G, Cerbone L, Spalato Ceruso M, Badalamenti G, Santini D, et al. Lack of correlation between liver tests abnormalities and trabectedin efficacy in the treatment of soft tissue sarcoma: a retrospective study. Sci Rep 2015; 5: 12077. PubMed Citation  (Among 113 patients with advanced sarcoma treated with trabectedin in 3 Italian oncology centers, 40% developed ALT or AST elevations above 5 times ULN, and retrospective analyses found no associations between ALT elevations and tumor response or progression free or overall survival).

  21. Bui-Nguyen B, Butrynski JE, Penel N, Blay JY, Isambert N, Milhem M, Kerst JM, et al.; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC/STBSG) and the Sarcoma Alliance for Research through Collaboration (SARC). A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: the TRUSTS trial. Eur J Cancer 2015; 51: 1312-20. PubMed Citation  (Among 133 patients with soft tissue sarcoma treated with trabectedin [as 3 or 24 hour infusions] vs doxorubicin [standard therapy], median progression free survival was less with trabectedin [2.8 and 3.1 vs 5.5 months] and side effects were more common, requiring discontinuation in 15% and 20% vs 3% and with ALT elevations above 5 times ULN in 67% and 49% vs 2.5%]).

  22. Kawai A, Araki N, Sugiura H, Ueda T, Yonemoto T, Takahashi M, Morioka H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol 2015; 16: 406-16. PubMed Citation  (Among 76 Japanese patients with advanced sarcoma treated with trabectedin [1.2 mg/kg every 3 weeks] vs supportive case, median progression-free survival was 5.6 vs 0.9 months and adverse events included nausea [89% vs 8%], anorexia [53% vs 5%], neutropenia [83% vs 0%] and elevated ALT [67% vs 0%]).

  23. Schack LH, Mouritsen LS, Elowsson C, Krarup-Hansen A, Safwat A. The Danish experience with trabectedin treatment for metastatic sarcoma: Importance of hyponatremia. Acta Oncol 2015; 54: 34-40. PubMed Citation  (Among 117 patients with metastatic sarcoma treated with trabectedin in 3 oncology centers in Denmark, adverse events were frequent including 22% with “elevated liver enzymes” and there were 3 deaths, all related to severe infections).

  24. Martin-Broto J, Pousa AL, de Las Peñas R, García Del Muro X, Gutierrez A, Martinez-Trufero J, Cruz J, et al. Randomized phase II study of trabectedin and doxorubicin compared with doxorubicin alone as first-line treatment in patients with advanced soft tissue sarcomas: a Spanish group for research on sarcoma study. J Clin Oncol 2016; 34: 2294-302. PubMed Citation  (Among 115 patients with soft tissue sarcoma treated with doxorubicin with or without trabectedin [1.1 mg/m2 every 3 weeks], progression- free survival was minimally longer with the combination [5.7 vs 5.5 months] and adverse events were more frequent including ALT elevations [71% vs 14%] and those greater than 5 times ULN [19% vs none]).

  25. In brief: Two Drugs for soft-tissue sarcoma. Med Lett Drugs Ther 2016; 58 (1494): e62. PubMed Citation  (Concise summary of the mechanism of action, efficacy and safety of trabectedin and eribulin shortly after their approval in the US as therapy of soft tissue sarcoma; mentions that trabectedin therapy is associated with serum aminotransferase elevations).

  26. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol 2016; 34: 786-93. PubMed Citation  (Among 518 patients with metastatic lipo- or leiomyosarcoma treated with trabectedin vs dacarbazine, progression-free survival was longer with trabectedin [4.2 vs 1.5 months], but overall survival similar [12.4 vs 12.9 months], while ALT elevations arose in 45% vs 6% and were above 5 times ULN in 26% vs 1%).

  27. Angarita FA, Cannell AJ, Abdul Razak AR, Dickson BC, Blackstein ME. Trabectedin for inoperable or recurrent soft tissue sarcoma in adult patients: a retrospective cohort study. BMC Cancer 2016; 16: 30. PubMed Citation  (Among 77 adults with advanced soft tissue sarcoma treated with trabectedin, elevations in liver enzymes occurred in 26% of subjects including values above 5 times ULN in 19%, but there were no serious liver related adverse events and two deaths attributed to therapy were both due to rhabdomyolysis).

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OTHER REFERENCE LINKS
Trabectedin
  1. PubMed logoRecent References on Trabectedin

  2. Clinical Trials logoTrials on Trabectedin

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