Efficacy and safety of trabectedin for the treatment of advanced uterine or ovarian carcinosarcoma: Results of a phase II multicenter clinical trial (MITO-26).

OBJECTIVE: This open-label phase II clinical trial evaluated the antitumor activity and safety of trabectedin in patients with advanced ovarian (OC) or uterine carcinosarcomas (UC). METHODS: Eligible patients were adults (≥18 years) with histologically proven recurrent OC/UC not amenable to surgery or radiotherapy who received up to two prior chemotherapy lines. Trabectedin 1.3 mg/m2 was administered as a 3-h infusion every three weeks. The primary endpoint was objective response rate (ORR) as per RECIST v.1.1. If at least 8 of 43 patients (18.6%) achieve an objective response, trabectedin would be declared worthy for further investigations. RESULTS: Forty-five patients with either OC (n = 32) or UC (n = 13) from seven MITO centers across Italy were enrolled. The ORR was 11.9% (90% CI: 6-23) and included two patients with a complete response and three with a partial response. Eight patients (19.0%) had disease stabilization for a disease control rate of 31.0% (90% CI: 20-44). Median progression-free survival was 2.01 months (95% CI: 1.78-2.30) and median overall survival was 4.64 months (95% CI: 3.19-8.29). Neutrophil count decreases (n = 8, 18.2%) and transaminase increases (n = 6, 13.6%) were the most common grade 3-5 adverse events related with trabectedin. Two patients died due to trabectedin-related grade 5 hematological toxicity. CONCLUSION: Although trabectedin did not meet the prespecified activity criteria, it confers modest but clinically meaningful benefit to patients with advanced OC/UC as being as effective as any other available treatment for this indication. The toxicity profile appears in line with that previously reported for the drug.

Experience with second-line trabectedin in daily clinical practice: case studies.

As a recommended second-line option for advanced soft tissue sarcoma, trabectedin can provide the necessary balance between long-term tumor control and preserved quality of life. Three case studies illustrate the long-lasting responses that patients can achieve with second-line trabectedin. A female patient with metastatic leiomyosarcoma maintained disease control for 2 years with trabectedin (× 41 cycles) with excellent tolerability and no relevant adverse events. At the time of writing, a male patient with a metastatic solitary fibrous tumor was asymptomatic after 30 cycles of trabectedin and treatment was ongoing. A young male patient with a recurrent, nonresectable, retroperitoneal myxoid/round cell liposarcoma was able to continue his sporting activities (triathlons) over 2 years with trabectedin (× 14 cycles) plus watchful waiting.

Trabectedin as second-line treatment in advanced soft tissue sarcoma: quality of life and safety outcomes.

The choice of second- and later-line options for advanced soft tissue sarcoma (aSTS) should always be considered from the patient's perspective, taking into account the potential impact of treatment on daily activities and quality of life. This review examines data on the safety of trabectedin in the management of patients with aSTS as reported in clinical trials and real-world studies. Evidence indicates that trabectedin exhibits an acceptable and manageable safety profile and is compatible with daily activities. Trabectedin is associated with low rates of toxicity-related discontinuations, few potentially life-threatening toxicities, a lack of apparent cumulative toxicities and low rates of grade 3/4 nausea, vomiting and fatigue. Trabectedin represents a valuable second-line option for aSTS, including in elderly patients.

Real-World Experience of Efficacy and Safety of Trabectedin in Patients with Soft Tissue Sarcoma: A Bicentric Retrospective Analysis.

INTRODUCTION: Soft tissue sarcomas (STSs) are a rare and heterogenous group of tumors, with poor prognostic, judging from their frequency to relapse. Few drugs are available after the conventional first-line regimen. Since 2007, trabectedin got approval after failure of anthracyclines and ifosfamide, for advanced or metastatic STS. This led to a FDA approval in 2015, but real-world evidence is still required, complementary to the pivotal phase II and III trials. METHODS: One hundred twenty-six patients with STS, treated by trabectedin between 2002 and 2019, were analyzed in this retrospective study, in two French centers. The effects of trabectedin on survival, response, and toxicity were described. All patients were tested for toxicities, and efficacy was assessed in patients exposed to at least 2 cycles of trabectedin. RESULTS: Three median cycles were administered per patient (1-79). Among the 113 patients analyzed for efficacy, the median progression-free survival was 3.0 months (95% CI: 2.3-4.8), with an overall survival of 12.3 months (95% CI: 10.2-16.9). The rate of disease control was 46% at the end of treatment. Myxoid liposarcoma (n = 11) was the histology subtype that benefited most from this chemotherapy with median progression-free survival and overall survival of 13.3 months (95% CI: 2.3-18.7) and 27.8 months (95% CI: 3.2-64.7), respectively. Adverse events were manageable. DISCUSSION AND CONCLUSION: Efficacy of trabectedin is confirmed in terms of clinical benefit and low toxicity, especially for myxoid liposarcoma. Combinatory regimens are under clinical trials to optimize the place of this chemotherapy.

Trabectedin and Durvalumab Combination Is Feasible and Active in Relapsing Ovarian Cancer.

The combination of chemotherapy and immune therapies still promises to synergize for prolonged tumor control. However, the quest for optimal combinations tailored for tumor histology remains ongoing. A recent study provides evidence on the feasibility of the trabectedin/durvalumab combination and reports on interesting preliminary efficacy. See related article by Toulmonde et al., p. 1765.

Single-Center Experience with Trabectedin for the Treatment of Non-L-sarcomas.

INTRODUCTION: The effectiveness of trabectedin for the treatment of leiomyosarcoma and liposarcoma (commonly referred to as L-sarcomas) has been widely evidenced in clinical trials and real-world studies. Nevertheless, available literature on non-L-sarcomas is less abundant. The objective of the present study is to evaluate the effectiveness and safety of trabectedin in a cohort of patients with non-L-sarcomas in the real-world setting. METHODS: This retrospective, observational study included 34 patients who received trabectedin in the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) between October 2013 and July 2020. RESULTS: The most frequent histologic subtypes were undifferentiated spindle cell/pleomorphic sarcoma (n = 11, 32.4%), synovial sarcoma (n = 6, 17.7%), myxofibrosarcoma (n = 5, 14.7%), and malignant peripheral nerve sheath tumor (n = 4, 11.8%). The mean number of cycles with trabectedin was 5.5 (range 2-28). Three patients achieved partial response (8.8%) and eight patients showed stable disease (23.5%). The objective response rate and disease control rate were 8.8% (95% confidence interval (CI), 95% CI 1.9-23.7) and 32.4% (95% CI 17.4-50.5), respectively. Overall, progression-free survival was 2.9 months (95% CI 2.1-3.4). The overall survival was 7.3 months (95% CI 4.7-12.8). The most common trabectedin-related grade 3 adverse events were observed in 10 patients (26.5%), mostly being neutropenia (14.7%) and elevated transaminases (5.9%), whereas one patient (2.9%) reported grade 4 febrile neutropenia that required hospitalization. CONCLUSIONS: The findings of this real-life study consistently support that trabectedin is an effective and safe option for the treatment of patients with non-L-sarcoma after failure of anthracyclines and ifosfamide, or in patients who are unsuited to receive these agents.

Comparative Transcriptome Profiling of Young and Old Brown Adipose Tissue Thermogenesis.

Brown adipose tissue (BAT) is a major site for uncoupling protein 1 (UCP1)-mediated non-shivering thermogenesis. BAT dissipates energy via heat generation to maintain the optimal body temperature and increases energy expenditure. These energetic processes in BAT use large amounts of glucose and fatty acid. Therefore, the thermogenesis of BAT may be harnessed to treat obesity and related diseases. In mice and humans, BAT levels decrease with aging, and the underlying mechanism is elusive. Here, we compared the transcriptomic profiles of both young and aged BAT in response to thermogenic stimuli. The profiles were extracted from the GEO database. Intriguingly, aging does not cause transcriptional changes in thermogenic genes but upregulates several pathways related to the immune response and downregulates metabolic pathways. Acute severe CE upregulates several pathways related to protein folding. Chronic mild CE upregulates metabolic pathways, especially related to carbohydrate metabolism. Our findings provide a better understanding of the effects of aging and metabolic responses to thermogenic stimuli in BAT at the transcriptome level.

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

A randomized phase III trial comparing trabectedin to best supportive care in patients with pre-treated soft tissue sarcoma: T-SAR, a French Sarcoma Group trial.

BACKGROUND: The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/m2 every 3 weeks or BSC, stratified into L-STS (liposarcoma/leiomyosarcoma) and non-L-STS groups (other histotypes). Patients from the BSC arm were allowed to cross over to trabectedin at progression. The primary efficacy endpoint was progression-free survival (PFS) confirmed by blinded central review and analyzed in the intention-to-treat population. RESULTS: Between 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P < 0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin. CONCLUSION: Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.

Trabectedin for the therapy of ovarian cancer.

Trabectedin is a marine-derivate antitumor drug with a relevant cytotoxic activity and good safety profile. It has been investigated for the treatment of solid diseases, including ovarian cancer (OC), breast cancer, and soft-tissue sarcoma. In 2009, results from the pivotal trial OVA-301 led the European Medicines Agency (EMA) to the approval of trabectedin in combination with PEGylated liposomal doxorubicin for the treatment of platinum-sensitive recurrent OC; further studies revealed an additional benefit also in the subgroup of patients with partially platinum-sensitive disease and in those with a BRCA-mutated status. Additionally, trabectedin demonstrated to prolong the time interval to the subsequent chemotherapy line. Recently, the improved understanding of the antitumor action exerted by trabectedin paved the way to new investigational trials exploring its combination with targeted therapies.

Effects of Fludioxonil on the Cell Growth and Apoptosis in T and B Lymphocytes.

Fludioxonil is fungicide used in agriculture, which is present in fruits and vegetables. In this study, the effects of fludioxonil on human immune cell viability, apoptosis, cell cycle arrest, and mitochondrial membrane potential were examined in human immune cells, such as Jurkat T cells and Ramos B cells. To examine the cell viability, Jurkat T cells and Ramos B cells were treated with fludioxonil (10-9-10-5 M) for 24 h and 48 h. Water soluble tetrazolium salt assay showed that fludioxonil decreased Jurkat T cell and Ramos B cell viability. Jurkat T cell viability decreased at 24 and 48 h, but Ramos B cell viability decreased only at 48 h. JC-1 dye revealed decreased mitochondrial membrane potential in fludioxonil-treated Jurkat T cells and Ramos B cells. To evaluate apoptosis, annexin-V conjugated FITC, AF488, and propidium iodide (PI) were used and to evaluate cell cycle arrest PI was used. Apoptosis and cell cycle arrest were induced by fludioxonil (10-7-10-5 M) in the Jurkat T cells at 24 and 48 h and Ramos B cells at 48 h. Moreover, the protein levels of pro-apoptotic proteins, such as p53, BAX, and cleaved caspase 3, were increased and anti-apoptotic protein Bcl-2 was decreased by fludioxonil. Expression of the Fas receptor related to the extrinsic apoptosis pathway was increased by fludioxonil. Additionally, cyclin D1 and cyclin E1 were decreased by fludioxonil. In the present study, fludioxonil induced immunotoxicity in human T cells and B cells through apoptosis and cell cycle arrest. Therefore, the present study suggests that fludioxonil induces the cellular toxicity in immune cells.

Study of the antitumor mechanisms of apiole derivatives (AP-02) from Petroselinum crispum through induction of G0/G1 phase cell cycle arrest in human COLO 205 cancer cells.

BACKGROUND: Apiole was isolated from the leaves of various plants and vegetables and has been demonstrated to inhibit human colon cancer cell (COLO 205 cells) growth through induction of G0/G1 cell cycle arrest and apoptotic cell death. This study further explored the antitumor effects of apiole derivatives AP-02, 04, and 05 in COLO 205 cancer cells. METHODS: Human breast (MDA-MB-231, ZR75), lung (A549, PE089), colon (COLO 205, HT 29), and hepatocellular (Hep G2, Hep 3B) cancer cells were treated with apiole and its derivatives in a dose-dependent manner. Flow cytometry analysis was subsequently performed to determine the mechanism of AP-02-induced G0/G1 cell cycle arrest. The in vivo antitumor effect of AP-02 (1 and 5 mg/kg, administered twice per week) was examined by treating athymic nude mice bearing COLO 205 tumor xenografts. The molecular mechanisms of AP-02-induced antitumor effects were determined using western blot analysis. RESULTS: AP-02 was the most effective compound, especially for inhibition of COLO 205 colon cancer cell growth. The cytotoxicity of AP-02 in normal colon epithelial (FHC) cells was significantly lower than that in other normal cells derived from the breast, lung or liver. Flow cytometry analysis indicated that AP-02-induced G0/G1 cell cycle arrest in COLO 205 cells but not in HT 29 cells (< 5 µM for 24 h, **p < 0.01). Tumor growth volume was also significantly inhibited in AP-02 (> 1 mg/kg)-treated athymic nude mice bearing COLO 205 tumor xenografts compared to control mice (*p < 0.05). Furthermore, G0/G1 phase regulatory proteins (p53 and p21/Cip1) and an invasion suppressor protein (E-cadherin) were significantly upregulated, while cyclin D1 was significantly downregulated, in AP-02-treated tumor tissues compared to the control group (> 1 mg/kg, *p < 0.05). CONCLUSIONS: Our results provide in vitro and in vivo molecular evidence of AP-02-induced anti-proliferative effects on colon cancer, indicating that this compound might have potential clinical applications.

Uncertainty surrounding the mechanism and safety of the post-harvest fungicide fludioxonil.

Fludioxonil is a phenylpyrrole pesticide that is applied to fruit and vegetable crops post-harvest to minimize losses to mold, both during transport and at point of sale. Its effectiveness is reflected in the dramatic increase in its production/usage since its introduction in 1994, an increase that has peaked in recent years as it became licenced for use abroad. Recently, doubts as to the nature of its mechanism of action have been raised. Given that the pesticide has long been known to induce stress intermediates in target and non-target organisms alike, the lack of a firmly established mechanism might be cause for concern. Troubling reports further delineate a capacity to disrupt hepatic, endocrine and neurological systems, indicating that fludioxonil may represent a health threat to consumers. In the absence of a clear, safe mechanism of action, fludioxonil should be re-evaluated for its potential to impact human health.

Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship.

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem. Rats treated s.c. for 2 weeks (0.3 and 1 mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs. Interscapular BAT increased in weight/volume. In contrast, local treatment into the IFP was not efficacious in terms of weight/volume, despite slight increases in UCP-1 staining and changes in histological features. After local treatment, the exposure of the IFP was lower than after systemic treatment. In turn higher local doses (0.5 and 5 mg/ml) were then tested which produced a strong trend for decreased volume of the IFP, a significant increase in UCP-1 staining, and also a decrease in adipocytes size but increased number. However, after this treatment the systemic exposure was in the same range as following systemic treatment. In conclusion, we saw no evidence for the possibility of converting inguinal WAT to a BAT-phenotype solely through local activation of ß3 receptors. This is in concert with our in vitro experiments which detected direct effects of PPARγ agonists at the gene/protein expression and functional level, but were unable to detect any effect of CL-316,243.

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

Body Mass Index as a Risk Factor for Toxicities in Patients with Advanced Soft-Tissue Sarcoma Treated with Trabectedin.

OBJECTIVES: Low body mass index (BMI) and/or low lean body mass have been shown to be risk factors for chemotherapy-related toxicities in a number of different cancers. However, no data are available regarding the role of BMI as a risk factor for developing toxicities related to the novel anticancer agent, trabectedin, in patients with soft-tissue sarcoma (STS). We evaluated the role of BMI as a risk factor for trabectedin-related toxicity in patients with STS. METHODS: Data from 51 patients with metastatic/advanced STS treated with trabectedin after progression on ≥1 anthracycline ± ifosfamide regimen were retrospectively reviewed. RESULTS: Eighteen patients (35.3%) were underweight, and the remainder were of normal bodyweight (45.1%) or overweight (19.6%). Neutropenia of any grade (77.8 vs. 33.3%) and grade 3-4 neutropenia (50.0 vs. 18.2%) occurred more frequently in the underweight versus normal/overweight patients (p = 0.025). Febrile neutropenia also occurred more frequently in underweight patients. Differences remained statistically significant after adjusting for other predictors of toxicity. There were no significant differences in other hematological and nonhematological toxicities between the groups. CONCLUSIONS: The data suggest for the first time that BMI should be considered a risk factor for neutropenia in patients with STS treated with trabectedin.

Effects of Dietary Supplementation of Astaxanthin and Sesamin on Daily Fatigue: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study.

Severe fatigue can negatively affect quality of life, and oxidative stress may play a role in its mechanism. The aim of this study was to evaluate the effect of dietary supplementation of astaxanthin and sesamin (AS), strong food-derived antioxidants, on fatigue. Twenty-four healthy volunteers were supplemented with AS and placebo, each for four weeks. After each supplementation period, participants underwent tasks inducing mental and physical fatigue (visual display terminal task and ergometer task, respectively). Subjective fatigue was evaluated using a visual analogue scale during and after the mental and physical tasks, and daily subjective fatigue was evaluated by the Chalder fatigue questionnaire. Secondary outcomes included other subjective feelings, work efficiency, autonomic nerve activity, levels of an oxidative stress marker (plasma phosphatidylcholine hydroperoxide (PCOOH)) and safety. AS supplementation was associated with significantly improved recovery from mental fatigue compared with placebo. Increased PCOOH levels during mental and physical tasks were attenuated by AS supplementation. No differences between AS and placebo were detected in secondary outcomes, and no adverse effects of AS supplementation were observed. In conclusion, AS supplementation may be a candidate to promote recovery from mental fatigue which is experienced by many healthy people.

A noninterventional, multicenter, prospective phase IV study of trabectedin in patients with advanced soft tissue sarcoma.

This prospective, noninterventional study is the first phase IV trial designed to evaluate trabectedin in patients with advanced soft tissue sarcoma in real-life clinical practice across Europe. To be included in the study, patients must have received more than or equal to one cycle of trabectedin and be currently on treatment. The primary endpoint was progression-free survival as defined by investigators. The secondary endpoints included objective response rate, disease control rate, time to progression and the growth modulation index (GMI), overall survival, and an assessment of the cancer-related symptoms and safety. A total of 218 patients from 41 European centers were evaluated. Patients received a median of six cycles per patient, mostly on an outpatient basis (n=132; 60.6%). The median progression-free survival was 5.9 months, with 70 and 49% of patients free from progression at 3 and 6 months after treatment, respectively. Three (1.4%) patients achieved a complete response and 55 (25.2%) patients achieved a partial response for an objective response rate of 26.6%. A total of 85 (39.0%) patients had disease stabilization for a disease control rate of 65.6%. The median GMI was 0.8, with 5.1 and 38.8% of patients with a GMI of greater than 1.1 to less than 1.33 and greater than or equal to 1.33, respectively. The median overall survival was 21.3 months. Febrile neutropenia (2.3% of patients), neutropenia, nausea, and pneumonia (1.4% each) were the most common trabectedin-related grade 3/4 serious adverse drug reactions. Trabectedin confers clinically meaningful long-term benefits to patients with multiple soft tissue sarcoma histotypes, being either comparable or better than those observed previously in clinical trials, and with a manageable safety profile.

FDA Approval Summary: Trabectedin for Unresectable or Metastatic Liposarcoma or Leiomyosarcoma Following an Anthracycline-Containing Regimen.

On October 23, 2015, the FDA approved trabectedin, a new molecular entity for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Approval was based on results of a single, randomized, active-controlled, 518-patient, multicenter study comparing the safety and efficacy of trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous (i.v.) infusion once every 3 weeks with dacarbazine 1,000 mg/m2 i.v. once every 3 weeks. Treatment with trabectedin resulted in a statistically significant improvement in progression-free survival (PFS), with a PFS of 4.2 months and 1.5 months for trabectedin and dacarbazine, respectively (HR, 0.55; 95% confidence interval, 0.44-0.70; unstratified log-rank test, P < 0.001). The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. Serious adverse reactions included anaphylaxis, neutropenic sepsis, rhabdomyolysis, hepatotoxicity, cardiomyopathy, and extravasation resulting in tissue necrosis. A postmarketing trial was required to evaluate the serious risk of cardiomyopathy. This approval provides another treatment option in a setting where no drug has been shown to improve overall survival. A key regulatory consideration during review of this application was the use of PFS as an endpoint to support regular approval of trabectedin. Clin Cancer Res; 23(24); 7448-53. ©2017 AACR.