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

Cesne, Axel Le; Blay, Jean‐Yves; Judson, Ian; Oosterom, Allan Van; Verweij, Jaap; Radford, John; Lorigan, Paul; Rodenhuis, S.; Ray‐Coquard, Isabelle; Bonvalot, Sylvie; Collin, Françoise; Jimeno, J.; Paola, ED Di; Glabbeke, M. van; Nielsen, Ole Steen

doi:10.1200/jco.2005.01.180

Cited by 397 publications

(257 citation statements)

References 28 publications

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“…Gemcitabine has also shown activity in phase II trials as a single agent and in combination with docetaxel in patients with advanced sarcomas, particularly leiomyosarcoma [13,19,20,23]. Trabectedin has demonstrated efficacy as a single agent in patients with sarcoma [7,8,17,26,39] and has shown promise in phase I trials against a variety of malignancies when given in combination with capecitabine [9], doxorubicin [1] or pegylated liposomal doxorubicin [3], but nearly all previous studies have used an every-3-week schedule. Although dose level 3 contained an approved gemcitabine dose of 1,000 mg/m 2 per week, the highest dose of trabectedin evaluated in combination with this gemcitabine dose was 0.4 mg/m 2 per week.…”

Section: Discussionmentioning

confidence: 99%

“…In clinical trials, single-agent trabectedin in a variety of administration schedules has achieved clinical responses in patients with a variety of tumor types, including ovarian cancer, osteosarcoma, soft tissue sarcoma, and breast cancer [7,8,11,16,17,21,30,39,40]. Recent data suggest that single-agent trabectedin may become a standard of care in advanced pre-treated sarcomas, with clinical benefit observed in patients with liposarcoma and leiomyosarcoma following failure of all conventional treatment options [26].…”

Section: Introductionmentioning

confidence: 99%

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Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Messersmith

Jimeno

Ettinger

et al. 2008

Cancer Chemother Pharmacol

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Purpose-To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.Methods-Patients with ECOG performance status 0-1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m 2 ) followed by trabectedin (starting dose, 0.3 mg/m 2 ). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.Results-Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1-10). The most common drug-related toxicity was hepatic. Dose reductions were required for $watermark-text $watermark-text $watermark-text trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m 2 and gemcitabine 1,000 mg/m 2 , which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.Conclusions-Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Messersmith

Jimeno

Ettinger

et al. 2008

Cancer Chemother Pharmacol

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“…5 The only truly new treatment approved for sarcoma failing standard therapy is trabectedin (approved by the European Medicines Agency in 2007). 6,7 Gemcitabine with dacarbazine or docetaxel [8][9][10] and paclitaxel for angiosarcoma 11 seem to improve progression-free and overall survival in non-randomised and adaptively randomised trials.…”

Section: Introductionmentioning

confidence: 99%

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial

et al. 2012

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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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confidence: 99%

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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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

Cited by 397 publications

References 28 publications

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial

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

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