This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Taamma, A. Articles by Cvitkovic, E. Search for Related Content PubMed PubMed Citation Articles by Taamma, A. Articles by Cvitkovic, E. Social Bookmarking                            What's this?

Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors

From the Hôpital Paul Brousse, Villejuif; Cvitkovic et Associés Consultants, Bicêtre; and Centre René Huguenin, Saint Cloud, France; Pharma Mar S.A. Clinical Research and Development, Madrid, Spain; and Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaaart Hospital, Masteram, the Netherlands.

Address reprint requests to E. Cvitkovic, Hôpital Paul Brousse, 12-14 Boulevard Paul Vaillant Couturier, 94800 Villejuif, France; email: e.cvitkovic{at}cvitkovic-ac.fr

PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors.

PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 µg/m².

RESULTS: The MTD was defined as 1,800 µg/m² (DL 9), and the phase II RD was 1,500 µg/m² (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 µg/m²) in 94% and 25% of cycles, respectively. At the RD (1,500 µg/m²), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood.

CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 µg/m², with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.

Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998; the European Society of Medical Oncology Meeting, November 1998; and the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				F. Grosso, R. Sanfilippo, E. Virdis, C. Piovesan, P. Collini, P. Dileo, C. Morosi, J. C. Tercero, J. Jimeno, M. D'Incalci, et al. Trabectedin in myxoid liposarcomas (MLS): a long-term analysis of a single-institution series Ann. Onc., August 1, 2009; 20(8): 1439 - 1444. [Abstract] [Full Text] [PDF]

				M. K. Chuk, F. M. Balis, and E. Fox Trabectedin Oncologist, August 1, 2009; 14(8): 794 - 799. [Full Text] [PDF]

				B. Forouzesh, M. Hidalgo, Q. Chu, A. Mita, M. Mita, G. Schwartz, J. Jimeno, J. Gomez, V. Alfaro, C. Lebedinsky, et al. Phase I and Pharmacokinetic Study of Trabectedin as a 1- or 3-hour Infusion Weekly in Patients with Advanced Solid Malignancies Clin. Cancer Res., May 15, 2009; 15(10): 3591 - 3599. [Abstract] [Full Text] [PDF]

				J.-Y. Blay, M. von Mehren, B. L. Samuels, M. P. Fanucchi, I. Ray-Coquard, B. Buckley, L. Gilles, C. Lebedinsky, Y. A. Elsayed, and A. Le Cesne Phase I Combination Study of Trabectedin and Doxorubicin in Patients with Soft-Tissue Sarcoma Clin. Cancer Res., October 15, 2008; 14(20): 6656 - 6662. [Abstract] [Full Text] [PDF]

				M. von Mehren, R. J. Schilder, J. D. Cheng, E. Temmer, T. M. Cardoso, F. G. Renshaw, E. Bayever, P. Zannikos, Z. Yuan, and R. B. Cohen A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies Ann. Onc., October 1, 2008; 19(10): 1802 - 1809. [Abstract] [Full Text] [PDF]

				M. Biscardi, R. Caporale, F. Balestri, S. Gavazzi, J. Jimeno, and A. Grossi VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia Ann. Onc., October 1, 2005; 16(10): 1667 - 1674. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero, J.G. Supko, R.G. Maki, J. Manola, D.P. Ryan, D. Harmon, T.A. Puchalski, G. Goss, M.V. Seiden, A. Waxman, et al. Ecteinascidin-743 (ET-743) for Chemotherapy-Naive Patients With Advanced Soft Tissue Sarcomas: Multicenter Phase II and Pharmacokinetic Study J. Clin. Oncol., August 20, 2005; 23(24): 5484 - 5492. [Abstract] [Full Text] [PDF]

				C. Sessa, F. De Braud, A. Perotti, J. Bauer, G. Curigliano, C. Noberasco, F. Zanaboni, L. Gianni, S. Marsoni, J. Jimeno, et al. Trabectedin for Women With Ovarian Carcinoma After Treatment With Platinum and Taxanes Fails J. Clin. Oncol., March 20, 2005; 23(9): 1867 - 1874. [Abstract] [Full Text] [PDF]

				A. Le Cesne, J.Y. Blay, I. Judson, A. Van Oosterom, J. Verweij, J. Radford, P. Lorigan, S. Rodenhuis, I. Ray-Coquard, S. Bonvalot, et al. 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 J. Clin. Oncol., January 20, 2005; 23(3): 576 - 584. [Abstract] [Full Text] [PDF]

				L. Lau, J. G. Supko, S. Blaney, L. Hershon, N. Seibel, M. Krailo, W. Qu, D. Malkin, J. Jimeno, M. Bernstein, et al. A Phase I and Pharmacokinetic Study of Ecteinascidin-743 (Yondelis) in Children with Refractory Solid Tumors. A Children's Oncology Group Study Clin. Cancer Res., January 15, 2005; 11(2): 672 - 677. [Abstract] [Full Text] [PDF]

				R. Garcia-Carbonero, J.G. Supko, J. Manola, M.V. Seiden, D. Harmon, D.P. Ryan, M.T. Quigley, P. Merriam, J. Canniff, G. Goss, et al. Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy J. Clin. Oncol., April 15, 2004; 22(8): 1480 - 1490. [Abstract] [Full Text] [PDF]

				A. Yovine, M. Riofrio, J.Y. Blay, E. Brain, J. Alexandre, C. Kahatt, A. Taamma, J. Jimeno, C. Martin, Y. Salhi, et al. Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients J. Clin. Oncol., March 1, 2004; 22(5): 890 - 899. [Abstract] [Full Text] [PDF]

				S. Donald, R. D. Verschoyle, P. Greaves, T. W. Gant, T. Colombo, M. Zaffaroni, R. Frapolli, M. Zucchetti, M. D'Incalci, D. Meco, et al. Complete Protection by High-Dose Dexamethasone against the Hepatotoxicity of the Novel Antitumor Drug Yondelis (ET-743) in the Rat Cancer Res., September 15, 2003; 63(18): 5902 - 5908. [Abstract] [Full Text] [PDF]

				K. Scotlandi, S. Perdichizzi, M. C. Manara, M. Serra, S. Benini, V. Cerisano, R. Strammiello, M. Mercuri, G. Reverter-Branchat, G. Faircloth, et al. Effectiveness of Ecteinascidin-743 against Drug-sensitive and -resistant Bone Tumor Cells Clin. Cancer Res., December 1, 2002; 8(12): 3893 - 3903. [Abstract] [Full Text] [PDF]

				A. Kanzaki, Y. Takebayashi, X.-Q. Ren, H. Miyashita, S. Mori, S.-i. Akiyama, and Y. Pommier Overcoming Multidrug Drug Resistance in P-Glycoprotein/MDR1-overexpressing Cell Lines by Ecteinascidin 743 Mol. Cancer Ther., December 1, 2002; 1(14): 1327 - 1334. [Abstract] [Full Text] [PDF]

				D. P. Ryan, T. Puchalski, J. G. Supko, D. Harmon, R. Maki, R. Garcia-Carbonero, C. Kuhlman, J. Winkelman, P. Merriam, T. Quigley, et al. A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors Oncologist, December 1, 2002; 7(6): 531 - 538. [Abstract] [Full Text] [PDF]

				J. M. Reid, M. J. Kuffel, S. L. Ruben, J. J. Morales, K. L. Rinehart, D. P. Squillace, and M. M. Ames Rat and Human Liver Cytochrome P-450 Isoform Metabolism of Ecteinascidin 743 Does Not Predict Gender-dependent Toxicity in Humans Clin. Cancer Res., September 1, 2002; 8(9): 2952 - 2962. [Abstract] [Full Text] [PDF]

				S. Donald, R. D. Verschoyle, R. Edwards, D. J. Judah, R. Davies, J. Riley, D. Dinsdale, L. L. Lazaro, A. G. Smith, T. W. Gant, et al. Hepatobiliary Damage and Changes in Hepatic Gene Expression Caused by the Antitumor Drug Ecteinascidin-743 (ET-743) in the Female Rat Cancer Res., August 1, 2002; 62(15): 4256 - 4262. [Abstract] [Full Text] [PDF]

				B. A. Chabner Cytotoxic Agents in the Era of Molecular Targets and Genomics Oncologist, August 1, 2002; 7(90003): 34 - 41. [Abstract] [Full Text] [PDF]

				M. D'Incalci, E. Erba, G. Damia, E. Galliera, L. Carrassa, S. Marchini, R. Mantovani, G. Tognon, R. Fruscio, J. Jimeno, et al. Unique Features of the Mode of Action of ET-743 Oncologist, June 1, 2002; 7(3): 210 - 216. [Abstract] [Full Text] [PDF]

				M. A. Villalona-Calero, S. G. Eckhardt, G. Weiss, M. Hidalgo, J. H. Beijnen, C. van Kesteren, H. Rosing, E. Campbell, M. Kraynak, L. Lopez-Lazaro, et al. A Phase I and Pharmacokinetic Study of Ecteinascidin-743 on a Daily x 5 Schedule in Patients with Solid Malignancies Clin. Cancer Res., January 1, 2002; 8(1): 75 - 85. [Abstract] [Full Text] [PDF]

				S. Delaloge, A. Yovine, A. Taamma, M. Riofrio, E. Brain, E. Raymond, P. Cottu, F. Goldwasser, J. Jimeno, J. L. Misset, et al. Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients--Preliminary Evidence of Activity J. Clin. Oncol., March 1, 2001; 19(5): 1248 - 1255. [Abstract] [Full Text] [PDF]