Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study

Abstract

ET-743 demonstrates clinical activity as first-line therapy against STS with acceptable toxicity. Additional studies to establish empirical dosing guidelines may be necessary to improve the safety of the drug in patients with varying degrees of hepatic dysfunction and definitively establish the role of ET-743 for patients with these malignancies.

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

“…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.…”

“…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].…”

“…Experience in patients with compromised liver function is limited to date. Interestingly, liver toxicity has been ameliorated by premedication with steroids in animal models [5]; dexamethasone has been employed as an antiemetic premedication in some phase II studies [7], and dexamethasone co-treatment has been associated with a decreased incidence of severe trabectedin-associated toxicities [28]. Phase I and II studies with trabectedin have evaluated a number of treatment schedules, the most extensive being every 3 weeks given over 3 or 24 h. The results of preclinical studies of trabectedin administered in combination with other agents suggested that additive or synergistic effects may be achieved [22,33,34].…”

Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: A Gynecologic Oncology Group phase II study

“…Single agents that show moderate activity in leiomyosarcoma include ifosfamide (response rate 17.2%), doxorubicin (response rate 25%), and gemcitabine (bolus infusion achieved a 20% response rate among women with uterine leiomyosarcoma who had received 0-1 prior cytotoxic regimen) [15][16][17]. Trabectedin achieved a response rate of 8% among patients with prior treatment, and 17% as first-line therapy, in patients with soft tissue sarcoma [18][19].…”

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

“…The tetrahydroisoquinoline alkaloids ecteinascidins, isolated mainly from the Caribbean ascidian Ecteinascidia turbinata, are probably the most useful anticancer agents found to date in a marine source [63,64]. The lead compound, trabectedin (ET-743, 84), is regarded as a successful story of modern marine drug research: it is indeed the first representative of a marine natural product to receive marketing authorization for the treatment of patients with advanced or metastatic soft tissue sarcomas (STS) and relapsed platinum-sensitive ovarian cancer under the brand name Yondelis (87), and ET 770 (88), was reported by the Rinehart group in 1990, of which ET-743 was the most abundant representative [67].…”