A Comprehensive Safety Evaluation of Trabectedin and Drug–Drug Interactions of Trabectedin-Based Combinations

Abstract

Trabectedin (Yondelis(®)) is a potent marine-derived antineoplastic drug with high activity against various soft tissue sarcoma (STS) subtypes as monotherapy, and in combination with pegylated liposomal doxorubicin (PLD) for the treatment of patients with relapsed platinum-sensitive ovarian cancer. This article reviews the safety and pharmacokinetic profiles of trabectedin. Records were identified using predefined search criteria using electronic databases (e.g. PubMed, Cochrane Library Database of Systematic Reviews). Primary peer-reviewed articles published between 1 January 2006 and 1 April 2014 were included. The current safety and tolerability profile of trabectedin, based on the evaluation in clinical trials of patients treated with the recommended treatment regimens for STS and recurrent ovarian cancer, was reviewed. Trabectedin as monotherapy or in combination with PLD, was not associated with cumulative and/or irreversible toxicities, such as cardiac, pulmonary, renal, or oto-toxicities, often observed with other common chemotherapeutic agents. The most common adverse drug reactions (ADRs) were myelosuppression and transient hepatic transaminase increases that were usually not clinically relevant. However, trabectedin administration should be avoided in patients with severe hepatic impairment. Serious and fatal ADRs were likely to be related to pre-existing conditions. Doxorubicin or PLD, carboplatin, gemcitabine, or paclitaxel when administered before trabectedin, did not seem to influence its pharmacokinetics. Cytochrome P450 (CYP) 3A4 has an important role in the metabolism of trabectedin, suggesting a risk of drug-drug interactions with trabectedin used in combination with other CYP3A4 substrates. Trabectedin has a favorable risk/efficacy profile, even during extended treatment in pretreated patients.

Trabectedin: Supportive care strategies and safety profile

“…Nevertheless, in a phase I trial posttreatment liver biopsies from eight patients treated with trabectedin/PLD showed no evidence of serious, unusual or persistent pathological liver abnormalities [4,14]. In accordance with the experience in several studies, liver enzyme elevation is usually reversible and non-cumulative and is not usually accompanied with a clinically relevant liver dysfunction [15].…”

“…The complete mechanism of action for trabectedin is complex and still not fully understood with anti-inflammatory effects within the tumor microenvironment are still under investigation [2]. Trabectedin is cleared mainly by hepatic metabolism involving the CYP3A4 system, therefore, co-administration of trabectedin with potent inhibitors of the enzyme CYP3A4 should be avoided and caution should be taken if medicinal products associated with hepatotoxicity are administered concomitantly with trabectedin, since the risk of hepatotoxicity may be increased [3,4].…”

“…The main dose-limiting very common toxicities associated with trabectedin are neutropenia and elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The area of potential cumulative toxicities is very important in light of the data from a large retrospective trial that revealed that patients with non-progressive disease after 6 cycles may benefit from a further maintenance treatment [4,8]. ONCH-1950; This review of trabectedin will not compare the different trials but will focus on the reported incidence of side effects in order to provide clearly expressed suggestions that systematically and pragmatically cover supportive care issues and management of toxicities in order to maximize the benefits of trabectedin therapy.…”

Tumour‐associated macrophages correlate with microvascular bed extension in colorectal cancer patients

“…In this context, due to the sensitivity of CRC to anti‐angiogenic therapy, novel drugs killing TAMs, such as trabectedin, anti‐PD‐L1 antibodies, a pro‐apoptotic peptide M2 and PLX3397 (CSF‐1R tyrosine kinase inhibitor), might be evaluated in clinical trials as a new anti‐angiogenic strategy .…”

Real-World Management of Trabectedin/Pegylated Liposomal Doxorubicin in Platinum-Sensitive Recurrent Ovarian Cancer Patients: A National Survey

“…14 It is, however, well recognized that clinical outcome of cancer patients may differ whether they are treated in or out a clinical trial not only because of the higher heterogeneity of real-world patients, who often result unselected compared with those enrolled in investigational studies, but also because of the different background of each practice setting and the individual physician's experience/familiarity with therapeutic options and related toxicities. 15Y17 Therefore, despite the recommendations and guidelines, 11,18,19 variations in managing T/PLD administration in routine clinical practice across different centers/institutions cannot be excluded.…”