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Martin E. Blackstein - One of the best experts on this subject based on the ideXlab platform.
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Trabectedin for inoperable or recurrent soft tissue sarcoma in adult patients: a retrospective cohort study
BMC Cancer, 2016Co-Authors: Fernando A. Angarita, Amanda J. Cannell, Albiruni R. Abdul Razak, Brendan C. Dickson, Martin E. BlacksteinAbstract:Background Trabectedin is an antineoplastic agent used for patients with soft tissue sarcoma (STS) who fail standard-of-care treatment. Real-world data of its performance is scarce. This study evaluates the safety and effectiveness of Trabectedin for patients with advanced STS who were treated at a high-volume sarcoma center. Methods A retrospective chart review was performed on 77 patients treated with Trabectedin (24 h infusion q3w) between 01/2005 and 05/2014. Data regarding safety, objective radiological response, progression-free and overall survival were analyzed. Results Median age at treatment onset was 52y [interquartile range (IQR): 45-61y]. Tumors included leiomyosarcoma (41.6 %), liposarcoma (18.2 %), and synovial sarcoma (13 %). Trabectedin was provided as ≥ third-line chemotherapy in 71.4 %. Median number of cycles was 2 (range: 1–17). Dose reduction and treatment delays occurred in 19.5 and 40.3 %, respectively. Toxicities occurred in 78 %, primarily for neutropenia or elevated liver enzymes. Two patients died secondary to Trabectedin-induced rhabdomyolysis. Treatment was discontinued because of disease progression (84.7 %), toxicity (10 %), and patient preference (5 %). Partial response or stable disease occurred in 14.1 and 33.8 %, respectively, while 52.1 % developed progressive disease. Median progression-free survival was 1.3 m (IQR: 0.7–3.5 m) and was significantly higher in patients lacking severe toxicities or progressive disease. Median overall survival was 6.7 m (IQR: 2.3–12.7 m) and was significantly higher in patients with leiomyosarcoma or liposarcoma relative to other histologies. Conclusions Trabectedin has an acceptable safety profile as an anti-tumor agent. Our data further suggest there may be some benefit in using Trabectedin particularly in patients with leiomyo- or liposarcoma who failed standard-of-care agents.
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Trabectedin for inoperable or recurrent soft tissue sarcoma in adult patients a retrospective cohort study
BMC Cancer, 2016Co-Authors: Fernando A. Angarita, Amanda J. Cannell, Brendan C. Dickson, Martin E. Blackstein, Albiruni R A RazakAbstract:Trabectedin is an antineoplastic agent used for patients with soft tissue sarcoma (STS) who fail standard-of-care treatment. Real-world data of its performance is scarce. This study evaluates the safety and effectiveness of Trabectedin for patients with advanced STS who were treated at a high-volume sarcoma center. A retrospective chart review was performed on 77 patients treated with Trabectedin (24 h infusion q3w) between 01/2005 and 05/2014. Data regarding safety, objective radiological response, progression-free and overall survival were analyzed. Median age at treatment onset was 52y [interquartile range (IQR): 45-61y]. Tumors included leiomyosarcoma (41.6 %), liposarcoma (18.2 %), and synovial sarcoma (13 %). Trabectedin was provided as ≥ third-line chemotherapy in 71.4 %. Median number of cycles was 2 (range: 1–17). Dose reduction and treatment delays occurred in 19.5 and 40.3 %, respectively. Toxicities occurred in 78 %, primarily for neutropenia or elevated liver enzymes. Two patients died secondary to Trabectedin-induced rhabdomyolysis. Treatment was discontinued because of disease progression (84.7 %), toxicity (10 %), and patient preference (5 %). Partial response or stable disease occurred in 14.1 and 33.8 %, respectively, while 52.1 % developed progressive disease. Median progression-free survival was 1.3 m (IQR: 0.7–3.5 m) and was significantly higher in patients lacking severe toxicities or progressive disease. Median overall survival was 6.7 m (IQR: 2.3–12.7 m) and was significantly higher in patients with leiomyosarcoma or liposarcoma relative to other histologies. Trabectedin has an acceptable safety profile as an anti-tumor agent. Our data further suggest there may be some benefit in using Trabectedin particularly in patients with leiomyo- or liposarcoma who failed standard-of-care agents.
Erica Palesandro - One of the best experts on this subject based on the ideXlab platform.
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PARP1 expression drives the synergistic antitumor activity of Trabectedin and PARP1 inhibitors in sarcoma preclinical models
Molecular Cancer, 2017Co-Authors: Ymera Pignochino, Lorenzo D’ambrosio, Carmine Dell’aglio, Marco Basiricò, Marta Canta, Francesca Vignolo Lutati, Sandra Aliberti, Federica Capozzi, Annalisa Lorenzato, Erica PalesandroAbstract:BackgroundEnhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate Trabectedin-induced DNA damage in tumor cells leading finally to cell death.MethodsWe investigated Trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.ResultsTrabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with Trabectedin and we confirmed the antitumor and antimetastatic activity of Trabectedin/olaparib combination in mice models. However, we observed different degree of Trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to Trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in Trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, Trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.ConclusionsPARP1 inhibition potentiated Trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
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PARP1 expression drives the synergistic antitumor activity of Trabectedin and PARP1 inhibitors in sarcoma preclinical models
Molecular cancer, 2017Co-Authors: Ymera Pignochino, Marco Basiricò, Marta Canta, Sandra Aliberti, Federica Capozzi, Annalisa Lorenzato, Lorenzo D'ambrosio, Carmine Dell'aglio, Francesca Vignolo Lutati, Erica PalesandroAbstract:Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate Trabectedin-induced DNA damage in tumor cells leading finally to cell death. We investigated Trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with Trabectedin and we confirmed the antitumor and antimetastatic activity of Trabectedin/olaparib combination in mice models. However, we observed different degree of Trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to Trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in Trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, Trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. PARP1 inhibition potentiated Trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
Sarah Uboldi - One of the best experts on this subject based on the ideXlab platform.
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Identification of effective new drugs combinations exploiting the ability of Trabectedin to modulate transcription
2017Co-Authors: Sarah UboldiAbstract:Ewing’s sarcoma (ES) is the second most common malignant bone tumor of childhood, characterized by the chimeric protein EWS-FLI1 (hallmark of this pathology), that alters the transcription of different genes. The five-year overall survival of patients with localized disease is approximately 70%; unfortunately the majority of patients with a metastatic disease have a poor prognosis with a five-year overall survival around the 30%. Among the recently registered drugs for the therapy of sarcomas, Trabectedin could be of potential great interest as it seems very active in some “translocated sarcomas”. Trabectedin exerts its antitumor activity with different mechanisms of action. One of the most important is related to its ability to interfere with DNA repair mechanisms (NER and HR), that cause cell cycle perturbations. Furthermore Trabectedin is able to displace the oncogenic EWS-FLI1 chimera from its target promoters, modulating the transcription of these genes, in ES cells. Although Trabectedin has shown some activity against ES, the overall clinical results indicated only a marginally activity of Trabectedin given as single agent in ES. The thesis is aimed at using the available knowledge on Trabectedin mechanism of action to identify some effective combinations. Since Trabectedin induces cell cycle perturbations I speculated that its activity could be increased by checkpoint inhibitors. The studies performed on the combination of Trabectedin and the WEE1 inhibitor, AZD-1775, have shown that the inhibition of WEE1 enhances the Trabectedin activity, thus the combination is synergic. Since Trabectedin affects the transcription of several genes, I have developed a new approach based on the use of silencing RNA (siRNA) libraries to identify whether the downregulation of some genes was synthetically lethal when ES cells were pretreated with Trabectedin. An important part of the thesis was the development, validation and initial application of this approach.
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Increased sensitivity to platinum drugs of cancer cells with acquired resistance to Trabectedin.
British journal of cancer, 2015Co-Authors: Benedetta Colmegna, Sarah Uboldi, Roberta Frapolli, Simonetta Andrea Licandro, Nicolò Panini, Carlos M. Galmarini, Nadia Badri, Victoria J. Spanswick, John Bingham, Konstantinos KiakosAbstract:In order to investigate the mechanisms of acquired resistance to Trabectedin, Trabectedin-resistant human myxoid liposarcoma (402-91/T) and ovarian carcinoma (A2780/T) cell lines were derived and characterised in vitro and in vivo. Resistant cell lines were obtained by repeated exposures to Trabectedin. Characterisation was performed by evaluating drug sensitivity, cell cycle perturbations, DNA damage and DNA repair protein expression. In vivo experiments were performed on A2780 and A2780/T xenografts. 402-91/T and A2780/T cells were six-fold resistant to Trabectedin compared with parental cells. Resistant cells were found to be hypersensitive to UV light and did not express specific proteins involved in the nucleotide excision repair (NER) pathway: XPF and ERCC1 in 402-91/T and XPG in A2780/T. NER deficiency in Trabectedin-resistant cells was associated with the absence of a G2/M arrest induced by Trabectedin and with enhanced sensitivity (two-fold) to platinum drugs. In A2780/T, this collateral sensitivity, confirmed in vivo, was associated with an increased formation of DNA interstrand crosslinks. Our finding that resistance to Trabectedin is associated with the loss of NER function, with a consequent increased sensitivity to platinum drugs, provides the rational for sequential use of these drugs in patients who have acquired resistance to Trabectedin.
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Trabectedin efficacy in Ewing sarcoma is greatly increased by combination with anti-IGF signaling agents.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015Co-Authors: Ana Teresa Amaral, Sarah Uboldi, Roberta Frapolli, Silvana Di Giandomenico, Cecilia Garofalo, Maria Cristina Manara, Caterina Mancarella, José Luis Ordóñez, V. Sevillano, Roberta MalaguarneraAbstract:Purpose: Goal of this study was to identify mechanisms that limit efficacy of Trabectedin (ET-743, Yondelis) in Ewing sarcoma (EWS), so as to develop a clinical applicable combination therapy. Experimental Design: By chromatin immunoprecipitation, we analyzed EWS–FLI1 binding to the promoters of several target genes, such as TGFβR2 , CD99 , insulin-like growth factor receptor 1 ( IGF1R ), and IGF1 , both in vitro and in xenografts treated with Trabectedin or doxorubicin. Combined therapy with Trabectedin and anti-IGF1R agents (AVE1642 HAb ; OSI-906) was tested in vitro and in xenografts. Results: We confirm that both Trabectedin and doxorubicin were able to strongly reduce EWS–FLI1 (both type I and type II) binding to two representative target genes ( TGFβR2 and CD99 ), both in vitro and in xenografts. However, Trabectedin, but not doxorubicin, was also able to increase the occupancy of EWS–FLI1 to IGF1R promoters, leading to IGF1R upregulation. Inhibition of IGF1R either by the specific AVE1642 human antibody or by the dual IGF1R/insulin receptor inhibitor OSI-906 (Linsitinib) greatly potentiate the efficacy of Trabectedin in the 13 EWS cell lines here considered as well as in TC-71 and 6647 xenografts. Combined therapy induced synergistic cytotoxic effects. Trabectedin and OSI-906 deliver complementary messages that likely converge on DNA-damage response and repair pathways. Conclusions: We showed that Trabectedin may not only inhibit but also enhance the binding of EWS–FLI1 to certain target genes, leading to upregulation of IGF1R. We here provide the rationale for combining Trabectedin to anti-IGF1R inhibitors. Clin Cancer Res; 21(6); 1373–82. ©2015 AACR .
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antiangiogenic activity of Trabectedin in myxoid liposarcoma involvement of host timp 1 and timp 2 and tumor thrombospondin 1
International Journal of Cancer, 2014Co-Authors: Romina Dossi, Roberta Frapolli, Silvana Di Giandomenico, Lara Paracchini, Fabio Bozzi, Silvia Brich, Vittoria Castiglioni, Patrizia Borsotti, Dorina Belotti, Sarah UboldiAbstract:: Trabectedin is a marine natural product, approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. Clinical and experimental evidence indicates that Trabectedin is particularly effective against myxoid liposarcomas where response is associated to regression of capillary networks. Here, we investigated the mechanism of the antiangiogenic activity of Trabectedin in myxoid liposarcomas. Trabectedin directly targeted endothelial cells, impairing functions relying on extracellular matrix remodeling (invasion and branching morphogenesis) through the upregulation of the inhibitors of matrix metalloproteinases TIMP-1 and TIMP-2. Increased TIMPs synthesis by the tumor microenvironment following Trabectedin treatment was confirmed in xenograft models of myxoid liposarcoma. In addition, Trabectedin upregulated tumor cell expression of the endogenous inhibitor thrombospondin-1 (TSP-1, a key regulator of angiogenesis-dependent dormancy in sarcoma), in in vivo models of myxoid liposarcomas, in vitro cell lines and primary cell cultures from patients' myxoid liposarcomas. Chromatin Immunoprecipitation analysis showed that Trabectedin displaced the master regulator of adipogenesis C/EBPβ from the TSP-1 promoter, indicating an association between the up-regulation of TSP-1 and induction of adipocytic differentiation program by Trabectedin. We conclude that Trabectedin inhibits angiogenesis through multiple mechanisms, including directly affecting endothelial cells in the tumor microenvironment--with a potentially widespread activity--and targeting tumor cells' angiogenic activity, linked to a tumor-specific molecular alteration.
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role of macrophage targeting in the antitumor activity of Trabectedin
Cancer Cell, 2013Co-Authors: Giovanni Germano, Sarah Uboldi, Roberta Frapolli, Cristina Belgiovine, Achille Anselmo, Samantha Pesce, Manuela Liguori, Eugenio Erba, M Zucchetti, Fabio PasqualiniAbstract:There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that Trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, Trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using Trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
Ymera Pignochino - One of the best experts on this subject based on the ideXlab platform.
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PARP1 expression drives the synergistic antitumor activity of Trabectedin and PARP1 inhibitors in sarcoma preclinical models
Molecular Cancer, 2017Co-Authors: Ymera Pignochino, Lorenzo D’ambrosio, Carmine Dell’aglio, Marco Basiricò, Marta Canta, Francesca Vignolo Lutati, Sandra Aliberti, Federica Capozzi, Annalisa Lorenzato, Erica PalesandroAbstract:BackgroundEnhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate Trabectedin-induced DNA damage in tumor cells leading finally to cell death.MethodsWe investigated Trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.ResultsTrabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with Trabectedin and we confirmed the antitumor and antimetastatic activity of Trabectedin/olaparib combination in mice models. However, we observed different degree of Trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to Trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in Trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, Trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.ConclusionsPARP1 inhibition potentiated Trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
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PARP1 expression drives the synergistic antitumor activity of Trabectedin and PARP1 inhibitors in sarcoma preclinical models
Molecular cancer, 2017Co-Authors: Ymera Pignochino, Marco Basiricò, Marta Canta, Sandra Aliberti, Federica Capozzi, Annalisa Lorenzato, Lorenzo D'ambrosio, Carmine Dell'aglio, Francesca Vignolo Lutati, Erica PalesandroAbstract:Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate Trabectedin-induced DNA damage in tumor cells leading finally to cell death. We investigated Trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with Trabectedin and we confirmed the antitumor and antimetastatic activity of Trabectedin/olaparib combination in mice models. However, we observed different degree of Trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to Trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in Trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, Trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. PARP1 inhibition potentiated Trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
Robin L Jones - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of Trabectedin in elderly patients with sarcoma subgroup analysis from a phase iii randomized controlled study of Trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma
Annals of Oncology, 2018Co-Authors: Robin L Jones, Mohammed M Milhem, George Wang, George D Demetri, Scott M Schuetze, Anthony D Elias, B A Van Tine, John T Hamm, Sharon Anne Mccarthy, Trilok V ParekhAbstract:Abstract Background Treatment options for soft tissue sarcoma (STS) patients aged ≥65years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that Trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial. Patients and methods Patients were randomized 2 : 1 to Trabectedin (n=384) or dacarbazine (n=193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup. Results Among 131 (Trabectedin=94; dacarbazine=37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with Trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the Trabectedin arm (43% versus 23%, respectively; P=0.04). Elderly patients treated with Trabectedin showed significantly improved PFS [4.9 versus 1.5months, respectively; hazard ratio (HR)=0.40; P=0.0002] but no statistically significant improvement in OS (15.1 versus 8.0months, respectively; HR=0.72; P=0.18) or ORR (9% versus 3%, respectively; P=0.43). The safety profile for elderly Trabectedin-treated patients was comparable to that of the overall Trabectedin-treated study population. Conclusions This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from Trabectedin similar to that observed in younger patients. Trial registration www.clinicaltrials.gov, NCT01343277.
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efficacy and safety of Trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline based chemotherapy subgroup analysis of a phase 3 randomized clinical trial
Gynecologic Oncology, 2017Co-Authors: Martee L Hensley, Robin L Jones, Bradley J. Monk, Shreyaskumar Patel, Margaret Von Mehren, Kristen N Ganjoo, Arthur Staddon, Daniel A Rushing, Mohammed M Milhem, George WangAbstract:Abstract Objective Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of Trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). Methods Of 577 patients randomized 2:1 to receive Trabectedin 1.5mg/m 2 by 24-hour IV infusion or dacarbazine 1g/m 2 by 20–120-minute IV infusion once every three weeks, 232 had uLMS (Trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. Results PFS for Trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41–0.81; P =0.0012). OS was similar (Trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65–1.24; P =0.51) between groups. ORR was 11% with Trabectedin vs. 9% with dacarbazine ( P =0.82). CBR for Trabectedin was 31% vs. 18% with dacarbazine ( P =0.05); median DOR was 6.5months for Trabectedin vs. 4.1months for dacarbazine ( P =0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the Trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. Conclusions In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, Trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.
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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
Journal of Clinical Oncology, 2016Co-Authors: George D Demetri, Robin L Jones, Martee L Hensley, Kristen N Ganjoo, Arthur Staddon, Mohammed M Milhem, Scott M Schuetze, Anthony D Elias, Margaret Von Mehren, Hussein TawbiAbstract:PurposeThis multicenter study, to our knowledge, is the first phase III trial to compare Trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen.Patients and MethodsPatients were randomly assigned in a 2:1 ratio to receive Trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control—progression-free survival (PFS), time to progression, objective response rate, and duration of response—as well as safety and patient-reported symptom scoring.ResultsA total of 518 patients were enrolled and randomly assigned to either Trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, Trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for Trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); b...
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Advanced soft-tissue sarcoma and treatment options: critical appraisal of Trabectedin
Cancer management and research, 2016Co-Authors: Ingrid M.e. Desar, Robin L Jones, Anastasia Constantinidou, Suzanne E. J. Kaal, Winette T. A. Van Der GraafAbstract:Soft-tissue sarcomas (STS) are a heterogeneous group of rare solid tumors of mesenchymal origin. This paper reviews the current status of systemic treatment in advanced and metastatic soft tissue sarcomas, with an emphasis on Trabectedin. Trabectedin is a unique type of chemotherapeutic agent with multiple potential mechanisms of action. We discuss the putative mechanisms, as well as the toxicity and administration schedules of Trabectedin, followed by its efficacy in first-line systemic therapy and beyond first-line systemic therapy.
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clinical benefit of Trabectedin in uterine adenosarcoma
Medical Oncology, 2013Co-Authors: Brett A Schroeder, Elizabeth T. Loggers, Eve T. Rodler, Seth M. Pollack, Robin L JonesAbstract:Uterine adenosarcoma is an extremely rare uterine malignancy, and the utility of chemotherapy in this disease is not well defined. This study assessed the safety and efficacy of Trabectedin in patients with recurrent/metastatic uterine adenosarcoma with sarcomatous overgrowth. A retrospective search of a prospectively maintained database was performed to identify patients with adenosarcoma treated with Trabectedin between 2010 and 2012, within a compassionate use trial. Three patients with recurrent/metastatic uterine adenosarcoma treated with Trabectedin were identified. All three patients tolerated the drug well. Two patients obtained prolonged clinical benefit from treatment, one having received 17 cycles and another 11 cycles of therapy. Trabectedin is well tolerated and has clinical activity in recurrent/metastatic uterine adenosarcoma.
