Advertisement

Investigational New Drugs

, Volume 31, Issue 5, pp 1236–1243 | Cite as

Phase I clinical and pharmacokinetic study of trabectedin and cisplatin given every three weeks in patients with advanced solid tumors

  • Cristiana SessaEmail author
  • Gianluca Del Conte
  • Alexandre Christinat
  • Sara Cresta
  • Antonella Perotti
  • Elisa Gallerani
  • Pilar Lardelli
  • Carmen Kahatt
  • Vicente Alfaro
  • Jorge L. Iglesias
  • Carlos Fernández-Teruel
  • Luca Gianni
PHASE I STUDIES

Summary

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m2 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m2). The immediately lower dose (trabectedin 0.60 mg/m2) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.

Keywords

Phase I Trabectedin Cisplatin Antitumor Cytotoxic Dose-limiting toxicities 

Notes

Acknowledgments

This study was supported by PharmaMar, S.A., and preliminary results were presented at the American Society of Clinical Oncology (ASCO) 47th Annual Meeting, Jun 3–7, 2011. Chicago, Illinois: Phase I Dose-Finding Study of Trabectedin in combination with Cisplatin in Patients with Advanced Solid Tumors. Sessa, C.; Gallerani, E.; Del Conte, G.; Christinat, A.; Perotti, A.; Lardelli, P.; Kahatt, C.; Flórez, A.; Fernández, C.; Gianni, L. J Clin Oncol 29:2011 (suppl: abstract 2517).

Conflict of interest

Pilar Lardelli, Carmen Kahatt, Vicente Alfaro, Jorge L. Iglesias, and Carlos Fernández-Teruel are employees in PharmaMar.

References

  1. 1.
    Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, D’Incalci M, Damia G (2008) Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer 44:609–618CrossRefGoogle Scholar
  2. 2.
    Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D’Incalci M (2001) Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer 37:97–105CrossRefGoogle Scholar
  3. 3.
    Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A (2009) Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 27:4188–4196CrossRefGoogle Scholar
  4. 4.
    Garcia-Carbonero R, Supko JG, Manola J, Seiden MV, Harmon D, Ryan DP, Quigley MT, Merriam P, Canniff J, Goss G, Matulonis U, Maki RG, Lopez T, Puchalski TA, Sancho MA, Gomez J, Guzman C, Jimeno J, Demetri GD (2004) Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 22:1480–1490CrossRefGoogle Scholar
  5. 5.
    Yovine A, Riofrio M, Blay JY, Brain E, Alexandre J, Kahatt C, Taamma A, Jimeno J, Martin C, Salhi Y, Cvitkovic E, Misset JL (2004) Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 22:890–899CrossRefGoogle Scholar
  6. 6.
    Le Cesne A, Blay JY, Judson I, Van Oosterom A, Verweij J, Radford J, Lorigan P, Rodenhuis S, Ray-Coquard I, Bonvalot S, Collin F, Jimeno J, Di Paola E, Van Glabbeke M, Nielsen OS (2005) 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 23:576–584CrossRefGoogle Scholar
  7. 7.
    Sessa C, De Braud F, Perotti A, Bauer J, Curigliano G, Noberasco C, Zanaboni F, Gianni L, Marsoni S, Jimeno J, D’Incalci M, Dall’o E, Colombo N (2005) Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J Clin Oncol 23:1867–1874CrossRefGoogle Scholar
  8. 8.
    Del Campo JM, Roszak A, Bidzinski M, Ciuleanu TE, Hogberg T, Wojtukiewicz MZ, Poveda A, Boman K, Westermann AM, Lebedinsky C (2009) Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer. Ann Oncol 20:1794–1802CrossRefGoogle Scholar
  9. 9.
    Krasner CN, McMeekin DS, Chan S, Braly PS, Renshaw FG, Kaye S, Provencher DM, Campos S, Gore ME (2007) A phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens. Br J Cancer 97:1618–1624CrossRefGoogle Scholar
  10. 10.
    Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Lisyanskaya AS, Makhson AN, Rolski J, Gorbounova VA, Ghatage P, Bidzinski M, Shen K, Ngan HY, Vergote IB, Nam JH, Park YC, Lebedinsky CA, Poveda AM (2010) Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 28:3107–3114CrossRefGoogle Scholar
  11. 11.
    Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia F, Pujade-Lourraine E, Zintl P, Parekh TV, Poveda A (2011) Final survival results of the randomized phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer. J Clin Oncol 29:suppl15s; abstr 5046CrossRefGoogle Scholar
  12. 12.
    Pommier Y, Kohlhagen G, Bailly C, Waring M, Mazumder A, Kohn KW (1996) 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. Biochemistry 35:13303–13309CrossRefGoogle Scholar
  13. 13.
    Zewail-Foote M, Hurley LH (1999) Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 42:2493–2497CrossRefGoogle Scholar
  14. 14.
    Giese B, McNaughton D (2003) Interaction of anticancer drug cisplatin with guanine: density functional theory and surface-enhanced Raman spectroscopy study. Biopolymers 72:472–489CrossRefGoogle Scholar
  15. 15.
    D’Incalci M, Galmarini CM (2010) A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther 9:2157–2163CrossRefGoogle Scholar
  16. 16.
    Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, Foiani M, D’Incalci M (2001) Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 92:583–588CrossRefGoogle Scholar
  17. 17.
    D’Incalci M, Colombo T, Ubezio P, Nicoletti I, Giavazzi R, Erba E, Ferrarese L, Meco D, Riccardi R, Sessa C, Cavallini E, Jimeno J, Faircloth GT (2003) The combination of yondelis and cisplatin is synergistic against human tumor xenografts. Eur J Cancer 39:1920–1926CrossRefGoogle Scholar
  18. 18.
    Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, De Braud F, Zucchetti M, D’Incalci M, Locatelli A, Marsoni S, Corradino I, Minoia C, Zintl P, Gianni L (2009) Phase I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours. Eur J Cancer 45:2116–2122CrossRefGoogle Scholar
  19. 19.
    Vidal L, Magem M, Barlow C, Pardo B, Florez A, Montes A, Garcia M, Judson I, Lebedinsky C, Kaye SB, Salazar R (2012) Phase I clinical and pharmacokinetic study of trabectedin and carboplatin in patients with advanced solid tumors. Invest New Drugs 30:616–628CrossRefGoogle Scholar
  20. 20.
    Chu Q, Mita A, Forouzesh B, Tolcher AW, Schwartz G, Nieto A, Soto-Matos A, Alfaro V, Lebedinsky C, Rowinsky EK (2010) Phase I and pharmacokinetic study of sequential paclitaxel and trabectedin every 2 weeks in patients with advanced solid tumors. Clin Cancer Res 16:2656–2665CrossRefGoogle Scholar
  21. 21.
    Fossella F, Pereira JR, von Pawel J, Pluzanska A, Gorbounova V, Kaukel E, Mattson KV, Ramlau R, Szczesna A, Fidias P, Millward M, Belani CP (2003) Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 21:3016–3024CrossRefGoogle Scholar
  22. 22.
    Spriggs DR, Brady MF, Vaccarello L, Clarke-Pearson DL, Burger RA, Mannel R, Boggess JF, Lee RB, Hanly M (2007) Phase III randomized trial of intravenous cisplatin plus a 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25:4466–4471CrossRefGoogle Scholar
  23. 23.
    Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21:3194–3200CrossRefGoogle Scholar
  24. 24.
    Novello S, Bruzzi P, Barone C, Buosi R, Masotti A, Michetti G, Fioretti M, Barbera S, Spatafora M, Garetto L, Mazzanti P, Dongiovanni V, Selvaggi G, Crino L, Scagliotti GV (2007) Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone. Ann Oncol 18:903–908CrossRefGoogle Scholar
  25. 25.
    Mouratidou D, Gennatas C, Michalaki V, Papadimitriou A, Andreadis CH, Sykiotis C, Tsavaris N (2007) A phase III randomized study comparing paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with advanced ovarian cancer. Anticancer Res 27:681–685PubMedGoogle Scholar
  26. 26.
    American Cancer Society-Statistics-Cancer Facts and Figures 2004, Soft Tissue Sarcoma. Available at https://doi.org/www.cancer.org
  27. 27.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefGoogle Scholar
  28. 28.
    Rosing H, Hillebrand MJ, Jimeno JM, Gomez A, Floriano P, Faircloth G, Henrar RE, Vermorken JB, Cvitkovic E, Bult A, Beijnen JH (1998) Quantitative determination of Ecteinascidin 743 in human plasma by miniaturized high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J Mass Spectrom 33:1134–1140CrossRefGoogle Scholar
  29. 29.
    Stokvis E, Rosing H, Lopez-Lazaro L, Beijnen JH (2004) Simple and sensitive liquid chromatographic quantitative analysis of the novel marine anticancer drug Yondelis (ET-743, trabectedin) in human plasma using column switching and tandem mass spectrometric detection. J Mass Spectrom 39:431–436CrossRefGoogle Scholar
  30. 30.
    Brouwers EE, Tibben MM, Rosing H, Hillebrand MJ, Joerger M, Schellens JH, Beijnen JH (2006) Sensitive inductively coupled plasma mass spectrometry assay for the determination of platinum originating from cisplatin, carboplatin, and oxaliplatin in human plasma ultrafiltrate. J Mass Spectrom 41:1186–1194CrossRefGoogle Scholar
  31. 31.
    Urien S, Brain E, Bugat R, Pivot X, Lochon I, Van ML, Vauzelle F, Lokiec F (2005) Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32 adult patients. Cancer Chemother Pharmacol 55:55–60CrossRefGoogle Scholar
  32. 32.
    Perez-Ruixo JJ, Zannikos P, Hirankarn S, Stuyckens K, Ludwig EA, Soto-Matos A, Lopez-Lazaro L, Owen JS (2007) Population pharmacokinetic meta-analysis of trabectedin (ET-743, yondelis((R))) in cancer patients. Clin Pharmacokinet 46:867–884CrossRefGoogle Scholar
  33. 33.
    Holford N: The Visual Predictive Check - Superiority to Standard Diagnostic (Rorschach) Plots. . In: https://doi.org/www.page-meeting.org/?abstract=972; (2005). p. 14, Abstract 738
  34. 34.
    Le Cesne A, Yovine A, Blay JY, Delaloge S, Maki RG, Misset JL, Frontelo P, Nieto A, Jiao JJ, Demetri GD (2012) A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials. Invest New Drugs 30:1193–1202CrossRefGoogle Scholar
  35. 35.
    Urien S, Lokiec F (2004) Population pharmacokinetics of total and unbound plasma cisplatin in adult patients. Br J Clin Pharmacol 57:756–763CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Cristiana Sessa
    • 1
    • 2
    Email author
  • Gianluca Del Conte
    • 2
  • Alexandre Christinat
    • 1
  • Sara Cresta
    • 3
  • Antonella Perotti
    • 2
  • Elisa Gallerani
    • 1
  • Pilar Lardelli
    • 4
  • Carmen Kahatt
    • 4
  • Vicente Alfaro
    • 4
  • Jorge L. Iglesias
    • 4
  • Carlos Fernández-Teruel
    • 4
  • Luca Gianni
    • 2
  1. 1.Istituto Oncologico della Svizzera (IOSI)Ospedale San GiovanniBellinzonaSwitzerland
  2. 2.Unit of New Drugs and Innovative Therapies, Department of Medical OncologySan Raffaele Hospital, IRCCSMilanItaly
  3. 3.Istituto Nazionale dei TumoriMilanoItaly
  4. 4.PharmaMar, Clinical R&DMadridSpain

Personalised recommendations