Trabectedin for Women With Ovarian Carcinoma After Treatment With Platinum and Taxanes Fails

Sessa, Cristiana; Braud, Filippo de; Perotti, Antonella; Bauer, Jean; Curigliano, Giuseppe; Noberasco, Cristina; Zanaboni, Flavia; Gianni, Luca; Marsoni, Silvia; Jimeno, J.; D’Incalci, Maurizio; Dall'O', E.; Colombo, Nicoletta

doi:10.1200/jco.2005.09.032

Cited by 163 publications

(104 citation statements)

References 23 publications

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“…Confirmation of these early results has been seen in the recently completed every 3 week regimen two arm randomised ET-743:B-026 study (Del Campo et al, 2006;McMeekin et al, 2007). The results of the present study and those reported by Sessa et al (2005), Del Campo et al (2006), andMcMeekin et al (2007) demonstrate the effectiveness of trabectedin as a single agent in the platinum-sensitive patient population with respect to ORR and disease stabilisation. The most common TEAE in the three studies was a self-limiting reversible elevation in liver enzymes, with noncumulative myelosuppression being a secondary common adverse event.…”

Section: Discussionsupporting

confidence: 86%

“…The efficacy results seen in all platinum-sensitive patients treated every 3 weeks with trabectedin in the SENDO study (Sessa et al, 2005) showed a response rate of 43.5% (95% CI: 23 -65%) with TTP of 7.9 months (95% CI: 7.5 -14.1 months). Similarly, the ET-743:B-026 study (Del Campo et al, 2006) showed a response rate of 37.4% (95% CI: 28.2 -47.3%) with TTP of 6.8 months (95% CI: 5.5 -7.4 months).…”

Section: Discussionmentioning

confidence: 99%

“…In a similar Phase II trial of trabectedin administered every 3 weeks in advanced ovarian cancer Sessa et al (2005) showed promising results with limited toxicities. Confirmation of these early results has been seen in the recently completed every 3 week regimen two arm randomised ET-743:B-026 study (Del Campo et al, 2006;McMeekin et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…A Phase II study conducted by the Southern Europe New Drugs Organization Foundation (SENDO) evaluated the use of trabectedin in 59 patients with advanced disease including refractory or relapsing ovarian cancer following a platinum-taxane regimen (Sessa et al, 2005). An initial dose of 1.65 mg m À2 (reduced to 1.3 mg m À2 ) was administered as a 3-h infusion every 3 weeks.…”

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A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

et al. 2007

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The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis s ) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m À2) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (X6 months TFI) or platinum-resistant disease (o6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2 -41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8 -6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1 -14.2%). Median PFS was 2.0 months (95% CI: 1.7 -3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (X2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

et al. 2007

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“…ET-743 is a tetrahydroisoquinoline alkaloid isolated from the Caribbean sea squirt Ecteinascidia turbinata (12), pointing to marine products as a potential new source of molecules with original chemical structures and activities. ET-743 shows a broad activity spectrum toward tumor cell lines at pM and low nM concentrations (6,13) and has clinical activity toward ovarian cancer as well as soft tissue and bone sarcomas in heavily pretreated patients (14)(15)(16). In particular, ET-743 treatment is associated with a striking, long-term response in a subset of patients with otherwise chemoresistant soft tissue sarcomas (reviewed in ref.…”

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Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

Soares

Escargueil

Poindessous

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

144

111

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Adducts induced by the antitumor alkylator ecteinascidin 743 (ET-743, Yondelis, trabectedin) represent a unique challenge to the DNA repair machinery because no pathway examined to date is able to remove the ET adducts, whereas cells deficient in nucleotide excision repair show increased resistance. We here describe the processing of the initial ET adducts into cytotoxic lesions and characterize the influence of cellular repair pathways on this process. Our findings show that exposure of proliferating mammalian cells to pharmacologically relevant concentrations of ET-743 is accompanied by rapid formation of DNA double-strand breaks (DSBs), as shown by the neutral comet assay and induction of focalized phosphorylated H2AX. The ET adducts are stable and can be converted into DSBs hours after the drug has been removed. Loss of homologous recombination repair has no influence on the initial levels of DSBs but is associated with the persistence of unrepaired DSBs after ET-743 is removed, resulting in extensive chromosomal abnormalities and pronounced sensitivity to the drug. In comparison, loss of nonhomologous end-joining had only modest effect on the sensitivity. The identification of DSB formation as a key step in the processing of ET-743 lesions represents a novel mechanism of action for the drug that is in agreement with its unusual potency. Because loss of repair proteins is common in human tumors, expression levels of selected repair factors may be useful in identifying patients particularly likely to benefit, or not, from treatment with ET-743.cancer therapy ͉ natural products ͉ lesion processing ͉ DNA repair ͉ response prediction

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Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

Berek

Friedlander

Bast

2017

Holland‐Frei Cancer Medicine

222

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Overview Ovarian cancer is one of the most treatable solid tumors, as the majority will respond temporarily to surgery and cytotoxic agents. The disease, however, frequently persists and recurs in 70% of cases, having the highest fatality‐to‐case ratio of all the gynecologic cancers. Ovarian cancer is neither a common nor a rare disease, with a lifetime risk of 1 in 70 and a prevalence in the postmenopausal population in the United States of 1 in 2500, which impact strategies for early detection and prevention. Germ line mutations of BRCA1 and BRCA2 are associated with 10–15% of ovarian cancers and increase the risk of ovarian cancer dramatically. Factors that contribute to persistent ovulation increase the risk in women with sporadic disease, whereas use of oral contraceptives decreases the risk of disease post menopause. While epithelial ovarian cancers have been thought to arise from the ovarian surface epithelium or in the lining of inclusion cysts beneath the ovarian surface, many high‐grade serous “ovarian” carcinomas as well as peritoneal cancers are now believed to arise in the fimbriae of fallopian tube, rather than the ovary or peritoneum. Epithelial ovarian cancers can exhibit serous, endometrioid, mucinous, or clear cell histotypes. Low‐grade type I ovarian cancers grow slowly, can evolve from tumors of low malignant potential, bear Ras mutations in a majority of cases, express wild type TP53, often are detected in early stage (I–II), and respond less frequently to platinum‐ and taxane‐based therapy. High‐grade type II ovarian cancers grow rapidly, arise from precursors with TP53 mutations, are driven by DNA copy number changes, are diagnosed in late stage (III–IV), and frequently respond to combination chemotherapy. Owing to a lack of specific symptoms or an effective screening strategy, more than 70% of ovarian cancers are diagnosed in an advanced stage (III–IV). Primary treatment of epithelial ovarian cancer involves cytoreductive surgery and 6–8 cycles of carboplatin and paclitaxel. For those women with small volumes of disease after surgery, intraperitoneal administration of chemotherapy improves survival. Recurrent disease cannot be cured with currently available agents, but survival can be prolonged with combinations of cytotoxic agents including retreatment with paclitaxel and carboplatin. Palliative agents include liposomal doxorubicin, gemcitabine, topotecan, bevacizumab, pemetrexed, and etoposide. Experimental therapy for low‐grade cancers involves MEK inhibitors, whereas trials of PI3K pathway inhibitors and PARP inhibitors are underway in patients with high‐grade epithelial ovarian cancers. Combinations of targeted agents will be required.

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Trabectedin for Women With Ovarian Carcinoma After Treatment With Platinum and Taxanes Fails

Cited by 163 publications

References 23 publications

A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

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