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1.
Eur J Cancer ; 39(13): 1842-51, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12932661

ABSTRACT

Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacokinetics , Dioxoles/pharmacokinetics , Isoquinolines/pharmacokinetics , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/adverse effects , Cohort Studies , Dioxoles/administration & dosage , Dioxoles/adverse effects , Dose-Response Relationship, Drug , Female , Hematologic Diseases/chemically induced , Humans , Infusions, Intravenous , Isoquinolines/administration & dosage , Isoquinolines/adverse effects , Male , Maximum Tolerated Dose , Middle Aged , Tetrahydroisoquinolines , Trabectedin
2.
Eur J Cancer ; 39(1): 70-7, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12504661

ABSTRACT

Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Antigens, Neoplasm/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Proteins/administration & dosage , Neoplasms/therapy , Adult , Aged , Cancer Vaccines/administration & dosage , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Transitional Cell/therapy , Female , Humans , Immunization , Lipid A/administration & dosage , Lipid A/analogs & derivatives , Lung Neoplasms/therapy , Male , Melanoma/therapy , Middle Aged , Neoplasm Metastasis , Neoplasms/pathology , Recombinant Proteins/administration & dosage , Saponins/administration & dosage , Skin Neoplasms/therapy , Survival Analysis , Treatment Outcome , Urinary Bladder Neoplasms/therapy
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