Investigational New Drugs

, Volume 30, Issue 5, pp 1942–1949

Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies

  • Lia Gore
  • E. Rivera
  • M. Basche
  • S. L. Moulder-Thompson
  • J. Li
  • S. Eppers
  • S. Grolnic
  • C. O’Bryant
  • D. Cleere
  • Y. A. Elsayed
  • S. G. Eckhardt


Background To determine the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies. Design In this Phase I, open-label, dose-finding study, patients refractory to standard therapy received trabectedin (3-h intravenous infusion, 0.4–1.3 mg/m2, day 1) and capecitabine (2,000 or 1,600 mg/m2/day orally, days 2–15) every 3 weeks. Standard “3 + 3” dose escalation was used to define the MTD. Antitumor response was assessed every two cycles; adverse events (AEs) were recorded throughout. Results Forty patients received 149 cycles of treatment (median 2; range 1–11) at nine dose levels. Gastrointestinal dose-limiting toxicities in two patients at two dose levels with capecitabine at 2,000 mg/m2/day prompted dose reduction to 1,600 mg/m2/day and initiation of new trabectedin dose escalation at 0.6 mg/m2. The MTD was capecitabine 1,600 mg/m2/day + trabectedin 1.1 mg/m2. Common grade 3–4 drug-related AEs were neutropenia (20%), nausea (18%), diarrhea (15%) and palmar-plantar erythrodysesthesia (15%). One patient with cholangiocarcinoma achieved a sustained partial response, and 18 patients maintained stable disease (six for ≥6 months). Conclusions The combination of trabectedin and capecitabine is generally well tolerated, without pharmacokinetic interactions, and shows some activity in patients with advanced cancers.


Advanced malignancy Capecitabine Pharmacokinetics Phase I Trabectedin 


  1. 1.
    Pommier Y, Kohlhagen G, Bailly C et al (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 35:13303–13309PubMedCrossRefGoogle Scholar
  2. 2.
    Moore BM, Seaman FC, Wheelhouse RT, Hurley LH (1998) Mechanism for the catalytic activation of ecteinascidin 743 and its subsequent alkylation of guanine N2. J Am Chem Soc 120:2490–2491CrossRefGoogle Scholar
  3. 3.
    Zewail-Foote M, Hurley LH (1999) Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 42:2493–2497PubMedCrossRefGoogle Scholar
  4. 4.
    Minuzzo M, Marchini S, Broggini M et al (2000) Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743. Proc Natl Acad Sci U S A 97:6780–6784PubMedCrossRefGoogle Scholar
  5. 5.
    Takebayashi Y, Pourquier P, Zimonjic DB et al (2001) Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 7:961–966PubMedCrossRefGoogle Scholar
  6. 6.
    Damia G, Silvestri S, Carrassa L et al (2001) Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Canc 92:583–588CrossRefGoogle Scholar
  7. 7.
    Barthomeuf C, Bourguet-Kondracki ML, Kornprobst JM (2008) Marine metabolites overcoming or circumventing multidrug resistance mediated by ATP-dependent transporters: a new hope for patient with tumors resistant to conventional chemotherapy. Anti Canc Agents Med Chem 8:886–903Google Scholar
  8. 8.
    Vincenzi B, Napolitano A, Frezza A et al (2010) Wide spectrum characterization of trabectedin: biology, clinical activity and future perspectives. Pharmacogenomics 11:865–878PubMedCrossRefGoogle Scholar
  9. 9.
    Li WW, Takahashi N, Jhanwar S et al (2001) Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent. Clin Canc Res 7:2908–2911Google Scholar
  10. 10.
    Scotlandi K, Perdichizzi S, Manara MC et al (2002) Effectiveness of ecteinascidin-743 against drug-sensitive and -resistant bone tumor cells. Clin Canc Res 8:3893–3903Google Scholar
  11. 11.
    Izbicka E, Lawrence R, Raymond E et al (1998) In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 9:981–987PubMedCrossRefGoogle Scholar
  12. 12.
    Valoti G, Nicoletti MI, Pellegrino A et al (1998) Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts. Clin Canc Res 4:1977–1983Google Scholar
  13. 13.
    Taamma A, Misset JL, Riofrio M et al (2001) Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 19:1256–1265PubMedGoogle Scholar
  14. 14.
    Villalona-Calero MA, Eckhardt SG, Weiss G et al (2002) A phase I and pharmacokinetic study of ecteinascidin-743 on a daily × 5 schedule in patients with solid malignancies. Clin Canc Res 8:75–85Google Scholar
  15. 15.
    Ryan DP, Supko JG, Eder JP et al (2001) Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Canc Res 7:231–242Google Scholar
  16. 16.
    Delaloge S, Yovine A, Taamma A et al (2001) Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 19:1248–1255PubMedGoogle Scholar
  17. 17.
    Fayette J, Boyle H, Chabaud S et al (2010) Efficacy of trabectedin for advanced sarcomas in clinical trials versus compassionate use programs: analysis of 92 patients treated in a single institution. Anti Canc Drugs 21:113–119CrossRefGoogle Scholar
  18. 18.
    Zelek L, Yovine A, Brain E et al (2006) A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer. Br J Canc 94:1610–1614CrossRefGoogle Scholar
  19. 19.
    Yovine A, Riofrio M, Blay JY et al (2004) Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J Clin Oncol 22:890–899PubMedCrossRefGoogle Scholar
  20. 20.
    Laverdiere C, Kolb EA, Supko JG et al (2003) Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 98:832–840PubMedCrossRefGoogle Scholar
  21. 21.
    Le Cesne A, Blay JY, Judson I et al (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 23:576–584PubMedCrossRefGoogle Scholar
  22. 22.
    Garcia-Carbonero R, Supko JG, Manola J et al (2004) Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 22:1480–1490PubMedCrossRefGoogle Scholar
  23. 23.
    Garcia-Carbonero R, Supko JG, Maki RG et al (2005) Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol 23:5484–5492PubMedCrossRefGoogle Scholar
  24. 24.
    Sessa C, De Braud F, Perotti A et al (2005) Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J Clin Oncol 23:1867–1874PubMedCrossRefGoogle Scholar
  25. 25.
    Michaelson MD, Gilligan T, Oh W et al (2005) Phase II study of 3 h, weekly infusion of trabectedin (ET-743) in men with metastatic, androgen-independent prostate carcinoma (AIPC) [abstract]. J Clin Oncol 23:16s, Abstract 4517CrossRefGoogle Scholar
  26. 26.
    Morgan JA, Le Cesne A, Chawla S et al (2007) Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracyclines (A) and ifosfamide (I) [abstract]. J Clin Oncol 25:18s, Abstract 10060Google Scholar
  27. 27.
    Krasner CN, McMeekin DS, Chan S et al (2007) A phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens. Br J Canc 97:1618–1624CrossRefGoogle Scholar
  28. 28.
    Demetri GD, Chawla SP, von Mehren M et al (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 27:4188–4196PubMedCrossRefGoogle Scholar
  29. 29.
    Del Campo JM, Roszak A, Bidzinski M et al (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 20:1794–1802PubMedCrossRefGoogle Scholar
  30. 30.
    Monk BJ, Herzog TJ, Kaye SB et al (2010) Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 28:3107–3114PubMedCrossRefGoogle Scholar
  31. 31.
    Kaye SB, Colombo N, Monk BJ et al (2011) Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval. Ann Oncol 22:48–58CrossRefGoogle Scholar
  32. 32.
    Poveda A, Vergote I, Tjulandin S et al (2011) Trabectedin plus pegylated liposomal doxorubicin in relpased ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 22:39–48PubMedCrossRefGoogle Scholar
  33. 33.
    Takahashi N, Li WW, Banerjee D et al (2001) Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Canc Res 7:3251–3257Google Scholar
  34. 34.
    Meco D, Colombo T, Ubezio P et al (2003) Effective combination of ET-743 and doxorubicin in sarcoma: preclinical studies. Canc Chemother Pharmacol 52:131–138CrossRefGoogle Scholar
  35. 35.
    Messersmith WA, Jimeno A, Ettinger D et al (2008) Phase I trial of weekly trabectedin (ED-743) and gemcitabine in patients with advanced solid tumors. Canc Chemother Pharmacol 63:181–188CrossRefGoogle Scholar
  36. 36.
    Cohen RB, Schilder RJ, Cheng J et al (2005) Final results of a combination study between trabectedin and pegylated liposomal doxorubicin (PLD) in patients with advanced malignancies [abstract]. J Clin Oncol 23:16s, Abstract 3074CrossRefGoogle Scholar
  37. 37.
    Blay J-Y, von Mehren M, Samuels BL et al (2008) Phase I combination of trabectedin and doxorubicin in patients with soft tissue sarcoma. Clin Canc Res 14:6656–6662CrossRefGoogle Scholar
  38. 38.
    Xeloda® (capecitabine) tablets [prescribing information] (2006) Nutley, NJ: Roche PharmaceuticalsGoogle Scholar
  39. 39.
    Ozer H, Armitage JO, Bennett CL et al (2000) 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 18:3558–3585PubMedGoogle Scholar
  40. 40.
    Forouzesh B, Hidalgo M, Denis L et al (2001) Phase I and pharmacokinetic study of ET-743, a minor groove DNA binder, administrated weekly to patients with advanced cancer [abstract]. Proc Am Soc Clin Oncol 20:94a, Abstract 373Google Scholar
  41. 41.
    Twelves C, Hoekman K, Bowman A et al (2003) Phase I and pharmacokinetic study of Yondelis™ (ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours. Eur J Canc 39:1842–1851CrossRefGoogle Scholar
  42. 42.
    van Kesteren C, Twelves C, Bowman A et al (2002) Clinical pharmacology of the novel marine-derived anticancer agent ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study. Anti Canc Drugs 13:381–393CrossRefGoogle Scholar
  43. 43.
    Gurtler JS, Goldstein L, Delprete S et al (2005) Trabectedin in third line breast cancer: a multicenter, randomized, phase II study comparing two administration regimens [abstract]. J Clin Oncol 23:16s, Abstract 625Google Scholar
  44. 44.
    McMeekin DS, Manikas G, Crispens M et al (2004) A phase II study of trabectedin (ET-743) as a second line therapy in patients with persistent or recurrent endometrial carcinoma [abstract]. J Clin Oncol 22:14s, Abstract 5086Google Scholar
  45. 45.
    Casali PG, Sanfilippo R, D’Incalci M (2010) Trabectidin therapy for sarcomas. Curr Opin Oncol 22:342–346PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lia Gore
    • 1
  • E. Rivera
    • 2
  • M. Basche
    • 1
  • S. L. Moulder-Thompson
    • 2
  • J. Li
    • 3
  • S. Eppers
    • 1
  • S. Grolnic
    • 1
  • C. O’Bryant
    • 1
  • D. Cleere
    • 4
  • Y. A. Elsayed
    • 3
  • S. G. Eckhardt
    • 1
  1. 1.University of Colorado Cancer CenterAuroraUSA
  2. 2.M. D. Anderson Cancer CenterHoustonUSA
  3. 3.Johnson & Johnson Pharmaceutical Research & Development, L.L.C.RaritanUSA
  4. 4.The Methodist HospitalHoustonUSA

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