title: Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer.
abstract: The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60 mg/m(2) and T at escalating doses from 600 to 800 microg/m(2), which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose--given to 18 patients in total--was 700 microg/m(2) T with 60 mg/m(2) D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.
authors.affiliation: Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale San Giovanni, Via Ospedale, 6500 Bellinzona, Switzerland. Electronic address: cristiana.sessa@eoc.ch.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Perotti
authors.affiliation: European Institute of Oncology (EIO), Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Noberasco
authors.affiliation: European Institute of Oncology (EIO), Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Braud
authors.affiliation: Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale San Giovanni, Via Ospedale, 6500 Bellinzona, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Gallerani
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cresta
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zucchetti
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Viganò
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Locatelli
authors.affiliation: PharmaMar R&D, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Jimeno
authors.affiliation: Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale San Giovanni, Via Ospedale, 6500 Bellinzona, Switzerland.
authors.forename: J W
authors.initials: JW
authors.lastname: Feilchenfeldt
authors.affiliation: Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Capri
authors.affiliation: Southern Europe New Drug Organisation (SENDO), Milano, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Ielmini
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori (INT), Milano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D004149:Dioxoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004317:Doxorubicin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009503:Neutropenia / Q000139:chemically induced; D012509:Sarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077606:Trabectedin; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077606:Trabectedin