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

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Summary

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.

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References

  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 35:13303–13309

    Article  PubMed  CAS  Google Scholar 

  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 120:2490–2491

    Article  CAS  Google Scholar 

  3. Zewail-Foote M, Hurley LH (1999) Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 42:2493–2497

    Article  PubMed  CAS  Google Scholar 

  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 97:6780–6784

    Article  PubMed  CAS  Google Scholar 

  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 7:961–966

    Article  PubMed  CAS  Google Scholar 

  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 92:583–588

    Article  CAS  Google Scholar 

  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 8:886–903

    CAS  Google Scholar 

  8. Vincenzi B, Napolitano A, Frezza A et al (2010) Wide spectrum characterization of trabectedin: biology, clinical activity and future perspectives. Pharmacogenomics 11:865–878

    Article  PubMed  CAS  Google Scholar 

  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 7:2908–2911

    CAS  Google Scholar 

  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 8:3893–3903

    CAS  Google Scholar 

  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 9:981–987

    Article  PubMed  CAS  Google Scholar 

  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 4:1977–1983

    CAS  Google Scholar 

  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 19:1256–1265

    PubMed  CAS  Google Scholar 

  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 8:75–85

    CAS  Google Scholar 

  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 7:231–242

    CAS  Google Scholar 

  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 19:1248–1255

    PubMed  CAS  Google Scholar 

  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 21:113–119

    Article  CAS  Google Scholar 

  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 94:1610–1614

    Article  CAS  Google Scholar 

  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 22:890–899

    Article  PubMed  CAS  Google Scholar 

  20. Laverdiere C, Kolb EA, Supko JG et al (2003) Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma. Cancer 98:832–840

    Article  PubMed  CAS  Google Scholar 

  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 23:576–584

    Article  PubMed  Google Scholar 

  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 22:1480–1490

    Article  PubMed  CAS  Google Scholar 

  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 23:5484–5492

    Article  PubMed  CAS  Google Scholar 

  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 23:1867–1874

    Article  PubMed  CAS  Google Scholar 

  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 4517

    Article  Google Scholar 

  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 10060

    Google Scholar 

  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 97:1618–1624

    Article  CAS  Google Scholar 

  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 27:4188–4196

    Article  PubMed  CAS  Google Scholar 

  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 20:1794–1802

    Article  PubMed  Google Scholar 

  30. Monk BJ, Herzog TJ, Kaye SB et al (2010) Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 28:3107–3114

    Article  PubMed  CAS  Google Scholar 

  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 22:48–58

    Article  Google Scholar 

  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 22:39–48

    Article  PubMed  CAS  Google Scholar 

  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 7:3251–3257

    CAS  Google Scholar 

  34. Meco D, Colombo T, Ubezio P et al (2003) Effective combination of ET-743 and doxorubicin in sarcoma: preclinical studies. Canc Chemother Pharmacol 52:131–138

    Article  CAS  Google Scholar 

  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 63:181–188

    Article  CAS  Google Scholar 

  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 3074

    Article  Google Scholar 

  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 14:6656–6662

    Article  CAS  Google Scholar 

  38. Xeloda® (capecitabine) tablets [prescribing information] (2006) Nutley, NJ: Roche Pharmaceuticals

  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 18:3558–3585

    PubMed  CAS  Google Scholar 

  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 373

    Google Scholar 

  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 39:1842–1851

    Article  CAS  Google Scholar 

  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 13:381–393

    Article  Google Scholar 

  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 625

    Google Scholar 

  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 5086

    Google Scholar 

  45. Casali PG, Sanfilippo R, D’Incalci M (2010) Trabectidin therapy for sarcomas. Curr Opin Oncol 22:342–346

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the support of the research data staff at the participating institutions for their diligent support of the conduct of this study. We are indebted to the patients and their families for participation in this study.

We also would like to thank Edisa Gozun, PharmD, formerly of Scientific Connexions, and Tracey Duncan, PA-C, for their medical research, writing and editing services.

Funding

This study was supported by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA; PharmaMar S.A.U., Madrid, Spain.

Disclosures and Conflict of Interest

S.G. Eckhardt has received a minor commercial research grant from Roche. J. Li and Y.A. Elsayed are employed by Johnson & Johnson PRD, USA. All other authors have no financial relationships to disclose.

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Authors and Affiliations

  1. University of Colorado Cancer Center, 13123 East 16th Ave, Box B115 TCH, Aurora, CO, 80045, USA

    Lia Gore, M. Basche, S. Eppers, S. Grolnic, C. O’Bryant & S. G. Eckhardt

  2. M. D. Anderson Cancer Center, Houston, TX, USA

    E. Rivera & S. L. Moulder-Thompson

  3. Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA

    J. Li & Y. A. Elsayed

  4. The Methodist Hospital, Houston, TX, USA

    D. Cleere

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  1. Lia Gore
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Correspondence to Lia Gore.

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Gore, L., Rivera, E., Basche, M. et al. Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies. Invest New Drugs 30, 1942–1949 (2012). https://doi.org/10.1007/s10637-011-9747-9

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  • DOI: https://doi.org/10.1007/s10637-011-9747-9

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