| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Massachusetts General Hospital [D. P R., J. G. S., M. V. S., T. J. L., A. J. F., J. D., J. W. C.] and Dana-Farber Cancer Institute [J. P. E., G. D.], Harvard Medical School, Boston, Massachusetts 02115, and Clinical Research and Development, Pharma Mar, S. A., Madrid, Spain [J. J.]
Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline
alkaloid that covalently binds to DNA in the minor groove. The
in vitro chemosensitivity of cancer cells to ET-743 is
markedly enhanced by prolonging the duration of exposure to the drug. A
Phase I study of ET-743 given as a 72-h continuous i.v. infusion every
21 days was performed. Characteristics of the 21 adult patients with
refractory solid tumors enrolled in the study were as follows:
(a) 12 men; (b) 9 women;
(c) median age, 59 years; (d) Eastern
Cooperative Oncology Group performance status 
1, 20 patients;
and (e) two prior regimens of chemotherapy, 7
patients. Dose limiting toxicity (DLT) was defined by typical
criteria, except that grade 3 transaminitis did not constitute a DLT.
There were no DLTs in the six patients evaluated at the first two dose
levels of 600 and 900 µg/m2. Reversible grade 4
transaminitis occurred in two of nine patients after treatment with the
first cycle of therapy at the third dose level of 1200
µg/m2. Another patient experienced grade 4
rhabdomyolysis, renal failure requiring hemodialysis, grade 4
neutropenia, and grade 3 thrombocytopenia during the second cycle of
therapy with this dose. The maximum tolerated dose was 1200
µg/m2, and an additional six patients were enrolled at an
intermediate dose level of 1050 µg/m2. This
well-tolerated dose was established as the recommended Phase II dose.
The disposition of ET-743 was distinctly biexponential, and a departure
from linear pharmacokinetic behavior was evident at the
1200-µg/m2 dose level. Pharmacokinetic parameters
determined at 1050 µg/m2 were (mean ± SD): maximum
plasma concentration, 318 ± 147 pg/ml; initial disposition phase
half-life, 9.0 ± 10.3 min; terminal phase half-life, 69.0 ±
56.7 h; and total plasma clearance, 28.4 ± 22.5
liters/h/m2. Prolonged systemic exposure to concentrations
of the agent that are cytotoxic in vitro were achieved.
Toxicity of the drug is clearly schedule-dependent, because increasing
the duration of infusion from 3 or 24 h to 72 h results in
decreased myelosuppression and comparable hepatotoxicity. Although
there were no objective responses to therapy, clear evidence of
antitumor activity was observed in a patient with epithelioid
mesothelioma, as confirmed by positron emission tomography studies. A
Phase II trial to assess the efficacy of ET-743 against this highly
refractory neoplasm has been initiated on the basis of this
observation. The therapeutically optimal administration schedule
remains to be established, inasmuch as there have been indications of
activity against a variety of tumors during Phase I studies when the
drug was infused over times ranging from 1 to 72 h. Characterizing
the pharmacokinetics of ET-743 during the course of Phase II trials and
Phase I combination studies is recommended to assure that this
promising new anticancer drug can be used with an acceptable
margin of safety.
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
 |
|
 J. A. Casado, P. Rio, E. Marco, V. Garcia-Hernandez, A. Domingo, L. Perez, J. C. Tercero, J. J. Vaquero, B. Albella, F. Gago, et al. Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin Mol. Cancer Ther., May 1, 2008; 7(5): 1309 - 1318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Verweij Ecteinascidin-743 (ET-743): Early Test or Effective Treatment in Soft Tissue Sarcomas? J. Clin. Oncol., August 20, 2005; 23(24): 5420 - 5423. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
