

<b>Ecteinascidin-743   ET-743             Yondelis(r)</b>




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General Considerations

Descriptive Information

Online Information for Patients

Clinical Trials Results

References

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<b>General Considerations


Date: Friday, May 25, 2001 12:19 PM
From:    G 
Subject: ET-743

Hi Jill

I have been away from the computer for a few days and am sorry for the late reply. The ET-743 works for about 1/2 of those that try it. You must have been on 2 previous chemos to be eligible I believe. Of those who do respond 85% get stabilization and 15% get   shrinkage. It has been easy for me to take.
I have about 40-50 tumors but all are small most under 2 cm and the largest is 3.5 cm. Because I have so many I am inoperable but am doing very well and still ride my exercise bike 10 miles about every day. If the drug does work there is apparently no limit on the # of treatments one could take. I understand that some have been on it every 4 weeks for over 2 years. I hope this is helpful.

Sincerely,
G 


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Descriptive Information</b>


Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinata, a tunicate growing in mangrove roots in Caribbean, which exhibits potent antitumor activity.  Future supplies of ecteinascidins will probably be available from synthesis or aquaculture.]  [3, 6]

It binds to the minor groove of DNA, distorting the shape of the molecule by bending the DNA toward the major groove. [10]  The binding of ET-743 to DNA was abolished when guanines were substituted with inosines.  This suggests that ecteinascidin 743 is a novel DNA minor groove, guanine-specific alkylating agent. [8]
It might also prevent DNA copying and reproduction in other ways.  A mode of action of ET-743 might be related to its ability to modify the interaction between some DNA binding proteins and DNA. [6].  Ecteinascidin 743 disorganizes the microtubule network as well.[7] Previous studies [in vitro and phase I] suggest potent cytotoxic activity of ET-743 in some mesenchymal tumors.  Because of this, phase II clinical trials have been instigated to look at the effectiveness of ET-743 against sarcomas. [4]

"6 of 10 evaluable pts (60%) in the upfront study have exhibited stable disease or minor response after 2 cycles of therapy, as have 4 of 12 evaluable pts (33%) with prior CT. Preliminary evidence of clinical activity has been observed in liposarcoma, leiomyosarcoma, and synovial sarcoma. ... We conclude from these ongoing trials that ET-743 represents an extremely promising agent for the management of several histologic subtypes of STS."[4] 
.
The EORTC phase trial with ET 743 treated GIST patients and advanced sarcoma patients.  
There were no responses in the GIST arm.  
There was an overall response rate of 11% in the 2nd line sarcoma arm The median time to progression was 3 months, and median survival 7 months.  This compares favorably with other drugs tested as second line chemotherapy agents. [2]

" We report the results of an ongoing multicenter Phase II study assessing activity and safety of ET-743 in [Pretreated ] STS pts, given at 1500 mcg/m² by [24 hour intravenous continuous infusion every] 3 weeks.  ["The pharmacology of ET-743 supports its use as a 3-h IV infusion, and that study is now active in STS."] [5, 9]

Since 2/98, 50 PSTS pts have been enrolled. ... Twenty-two pts (44%) had leiomyosarcoma (10 uterine origin) and 3 pts (6%) GIST. Thirteen pts (26%) had bulky disease (at least 1 mass greater than 10cm) and 14 pts (28%) had liver metastasis.   All but one had previously received anthracyclines (A).  20 pts (40%) were considered refractory to anthracycline treatment (A-R) (PD as best response under last A regimen). Median number of prior chemotherapies: 2 (2-5)."  [5] 


48 pts were evaluable for response.  6% had a partial response, 12% had a minor response [tumor reduction between 25 and 50%, and 34% had stable disease, all were clinically significant.
Median duration of Partial Response was 7.6 months.
Median duration of Minor Response was 3.8 months.
Median duration of Stable Disease was 5.1 months.
Responses were seen in liver, bulky tumors and anthracycline resistant tumors, as well.
52% of this group had some degree of nonprogression of the disease.
Median overall time to progression was 2.6 months and median overall survival was 10.7 months.

Progression free survival rate was 18% and overall survival rates at 1 year were 49% for the first-line study, and 11% and 55% for the prior chemotherapy study. The conclusion was that "ET-743            yields durable disease control and objective responses in a subset of pts with a variety of STS histologies."  [9]  

"... a randomized study is planned to assess the survival benefit associated with ET-743 therapy." [9]



 
<b>Side effects</b>: [1, 2, 4, 5, 9]


no hair loss, no severe GI toxicity.  Nausea has been essentially eliminated by incorporating dexamethasone into a prophylactic antiemetic regimen 
Liver transaminases enzymes had a grade 3 to 4 temporary elevation in 32% of subjects
Low white count with fever in <5% of subjects
Low white count grade 3 to 4  in  45% of subjects
Low platelet count grade 3 to 4   in 27% of subjects
Nausea grade 2-3 in 17%
Vomiting grade 2-3 in 11%
Fatigue grade 2-3 in 32%
Toxic Deaths of 4 subjects, possibly related to low level cholangitis [gall bladder inflammation]




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<b>Online Information for Patients</b>



ET-743   Yondelis

http://www.pharmamar.es/en/prosci/facts_001.cfm 

http://www.esmo.org/reference/abstracts00/ms/574.htm

 http://dtp.nci.nih.gov/docs/static_pages/pharm_data/648766.html 

 http://www.slip.net/~mcdavis/database/cr971477.htm 

 http://www3.oup.co.uk/antcan/hdb/Volume_14/Issue_03/140179.sgm.abs.html 

http://www-schreiber.chem.harvard.edu/people/owa.html 

 http://www.infobiogen.fr/agora/journals/cancer/articles/10-6/avil.htm 

PUBMED
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=ET-743

ASCO 2002
http://www.asco.org/ac/1,1003,_12-002330-00_18-0025536-00_19-0025537,00.asp


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<b>Clinical Trials Results</b>

ASCO   Search Conference Abstracts [Reports]
http://www.asco.org/ac/1,1003,_12-002328,00.asp

PUBMED  
ET-743 and clinical trials for sarcoma
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=ET-743%20AND%20clinical%20trial%20AND%20sarcoma

         
        

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<b> References</b>


[1] ASCO #727-2000 
Identification of Biochemical Parameters That Predict the Onset of Severe Toxicities in Patients Treated with ET-743.   ET 743 Phase I group. 

[2] ASCO #1407-2001 
ET-743 is an Active Drug in Adult Soft-Tissue Sarcoma (STS): a STBSG-EORTC Phase II Trial. Axel Le Cesne, Jean-Yves Blay, Ian Judson, Allan Van Oosterom, Jaap 
            Verweij, John Radford, Paul Lorigan, Sjoerd Rodenhuis, Eugenio 
            Donato Di Paola, Martine Van Glabbeke, Jose Jimeno, Ole Nielsen, 
            Institut Gustave Roussy, Villejuif, France; Centre Léon Bérard, 
            Lyon, France; Royal Marsden Hospital, London, UK; U.Z. Gasthuisberg, 
            Leuven, Belgium; A.Z. Rotterdam, Rotterdam, Netherlands; Christie 
            Hospital, Manchester, UK; Weston Park Hospital, Sheffield, UK; 
            Antoni Van Leeuwenhoekhuis, Amsterdam, Netherlands; EORTC, 
            Bruxelles, Belgium; Pharma-Mar, Madrid, Spain; Aarhus 
            Kommunehospital, Aarhus, Denmark.

[3] Med Res Rev 2000 Jan;20(1):1-27
Antitumor compounds from tunicates.
Rinehart KL.
Department of Chemistry, University of Illinois, 454 Roger Adams Laboratory, 600
So. Mathews Avenue, Urbana, Illinois 61801, USA.
	PMID: 10608919

[4] ASCO #2177-2000  Ecteinascidin (ET-743) Shows Promising Activity in Distinct Populations
of Sarcoma Patients: Summary of 3 U.S.-Based Phase II Trials. George D.
Demetri, Michael Seiden, Rocio Garcia-Carbonero, Jeffrey Supko, David
Harmon, Geraldine Goss, Lucette Robinson, Priscilla Merriam, Alison
Waxman, M T Quigley, Jose Jimeno, David P Ryan, Dana-Farber Cancer
Institute and Harvard Medical Sch, Boston, MA; MA Gen Hosp
(Dana-Farber/Partners CancerCare), Boston, MA; Dana Farber Cancer
Institute, Boston, MA; PharmaMar, Inc, Cambridge, MA. 

[5]  #1449-2001 
Ecteinascidin (ET-743) Given as a 24 Hour (H) Intravenous Continuous           Infusion (IVCI) Every 3 Weeks: Results of a Phase II Trial in Patients (pts) with Pretreated Soft Tissue Sarcomas (PSTS). 
            Alejandro Yovine, Mauricio Riofrío, Etienne Brain, Jean Yves Blay, C 
            Kahatt, Suzette Delaloge, Lucille Beautier, P Cottu, José Jimeno, 
            Esteban Cvitkovic, Jean Louis Misset, Hopital Paul Brousse, Paris, 
            France; Institut Gustave Roussy, Paris, France; Centre René 
            Huguenin, Paris, France; Centre Leon Berard, Lyon, France; Cvitkovic 
            Associés Consultants, Paris, France; Hopital Saint Louis, Paris, 
            France; Pharma Mar, Tres Cantos, Spain.

[6] Anticancer Drug Des 1999 Jun;14(3):179-86
Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA.  Bonfanti M, La Valle E, Fernandez Sousa Faro JM, Faircloth G, Caretti G, Mantovani R, D'Incalci M.  Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.  PMID: 10500494

[7] Br J Cancer 1996 Apr;73(8):875-83  
Characterisation of antimitotic products from marine organisms that disorganise the microtubule network: ecteinascidin 743, isohomohalichondrin-B and LL-15.  
Garcia-Rocha M, Garcia-Gravalos MD, Avila J.    
Centro de Biologia Molecular Severo Ochoa, Universidad Autonoma de Madrid, Spain. PMID: 8611420

[8] Biochemistry 1996 Oct 15;35(41):13303-9     
DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor  
groove by ecteinascidin 743, a potent antitumor compound from the Caribbean
tunicate Ecteinascidia turbinata.
Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW.
Laboratory of Molecular Pharmacology, National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892-4255, USA.
PMID: 8873596

[9] ASCO #1406-2001 
Ecteinascidin-743 (ET-743) Induces Durable Responses and Promising 1-Year Survival Rates in Soft Tissue Sarcomas (STS): Final Results of Phase II and Pharmacokinetic Studies in the U.S.A.     from Dana Farber and MSKCC
             
10.Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove.
Zewail-Foote M, Hurley LH.
Department of Chemistry and Biochemistry and College of Pharmacy, Drug Dynamics
Institute, The University of Texas at Austin, Austin, Texas 78712, USA.
PMID: 10411470 

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compiled by doctordee
March 2003          

