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First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors

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Abstract

This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m2 (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m2). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m2 (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.

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References

  1. Hamann MT, Otto CS, Scheuer PJ, Dunbar DC (1996) Kahalalides: bioactive peptides from a marine mollusk Elysia rufescens and its algal diet bryopsis sp. (1). J Org Chem 61:6594–6600

    Article  CAS  PubMed  Google Scholar 

  2. Sparidans RW, Stokvis E, Jimeno JM, Lopez-Lazaro L, Schellens JH, Beijnen JH (2001) Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F. Anticancer Drugs 12:575–582

    Article  CAS  PubMed  Google Scholar 

  3. Faircloth G, Cuevas C (2006) Kahalalide F and ES285: potent anticancer agents from marine molluscs. Prog Mol Subcell Biol 43:363–379

    Article  CAS  PubMed  Google Scholar 

  4. Provencio M, Sanchez A, Gasent J, Gomez P, Rosell R (2009) Cancer treatments: can we find treasures at the bottom of the sea? Clin Lung Cancer 10:295–300

    Article  CAS  PubMed  Google Scholar 

  5. Varadi T, Roszik J, Lisboa D, Vereb G, Molina-Guijarro JM, Galmarini CM, Szollosi J, Nagy P (2011) ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment. Eur J Pharmacol 667:91–99

    Article  CAS  PubMed  Google Scholar 

  6. Molina-Guijarro JM, Macias A, Garcia C, Munoz E, Garcia-Fernandez LF, David M, Nunez L, Martinez-Leal JF, Moneo V, Cuevas C, Lillo MP, Villalobos Jorge C, Valenzuela C, Galmarini CM (2011) Irvalec inserts into the plasma membrane causing rapid loss of integrity and necrotic cell death in tumor cells. PLoS ONE 6:e19042

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Herrero AB, Astudillo AM, Balboa MA, Cuevas C, Balsinde J, Moreno S (2008) Levels of SCS7/FA2H-mediated fatty acid 2-hydroxylation determine the sensitivity of cells to antitumor PM02734. Cancer Res 68:9779–9787

    Article  CAS  PubMed  Google Scholar 

  8. Molina-Guijarro JM, Moneo V, Martínez-Leal JF, Cuevas C, García-Fernández LF, Galmarini CM (2009) PM02734, a new marine-derived antitumoral compound, has rapid effects on membrane integrity and permeability in tumor cells. In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research. p. Abstract #888

  9. Coronado C, Galmarini CM, Alfaro V, Yovine A (2010) Elisidepsin. Drugs Future 35:287–296

    Article  CAS  Google Scholar 

  10. Ling YH, Aracil M, Jimeno J, Perez-Soler R, Zou Y (2009) Molecular pharmacodynamics of PM02734 (elisidepsin) as single agent and in combination with erlotinib; synergistic activity in human non-small cell lung cancer cell lines and xenograft models. Eur J Cancer 45:1855–1864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Elices M, Lepage DJ, Grant W, Alvarez E, Guillen MJ, Cuevas C, Aviles P, Faircloth G (2006) Activity of PM02734 against human breast and prostate tumors. Proc Am Assoc Cancer Res 47:Abst. 4712

  12. Serova M, de Gramont A, Bieche I, Riveiro ME, Galmarini CM, Aracil M, Jimeno J, Faivre S, Raymond E (2013) Predictive factors of sensitivity to elisidepsin, a novel Kahalalide F-derived marine compound. Mar Drugs 11:944–959

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Teixido C, Arguelaguet E, Pons B, Aracil M, Jimeno J, Somoza R, Mares R, Ramon YCS, Hernandez-Losa J (2012) ErbB3 expression predicts sensitivity to elisidepsin treatment: in vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines. Int J Oncol 41:317–324

    CAS  PubMed  Google Scholar 

  14. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147

    Article  CAS  PubMed  Google Scholar 

  15. National Cancer Institute (2006) Common terminology criteria for adverse events (CTCAE) v.3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf:1-72

  16. 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 92:205–216

    Article  CAS  PubMed  Google Scholar 

  17. Yin J, Aviles P, Lee W, Ly C, Guillen MJ, Munt S, Cuevas C, Faircloth G (2006) Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM02734, a novel antineoplastic agent, in dog plasma. Rapid Commun Mass Spectrom 20:2735–2740

    Article  CAS  PubMed  Google Scholar 

  18. Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2009) NONMEM user's guides (1989–2009). Icon Development Solutions

  19. Salazar R, Jones RJ, Oaknin A, Crawford D, Cuadra C, Hopkins C, Gil M, Coronado C, Soto-Matos A, Cullell-Young M, Iglesias Dios JL, Evans TR (2012) A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors. Cancer Chemother Pharmacol 70:673–681

    Article  CAS  PubMed  Google Scholar 

  20. Bergstrand M, Karlsson MO (2009) Handling data below the limit of quantification in mixed effect models. AAPS J 11:371–380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Beal SL (2001) Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn 28:481–504

    Article  CAS  PubMed  Google Scholar 

  22. Evans TR, Oaknin A, Jones RJ, Vandermeeren A, Coronado C, Soto-Matos A, Germa JR, Crawford D, Frontelo P, Salazar R (2009) Phase I dose-escalating study of PM02734 in a 24-h infusion schedule every 21 days in advanced solid tumors. ASCO American Society of Clinical Oncology, 45th Annual Meeting, May 29- Jun 2, 2009. Orlando, FL. J Clin Oncol 27(15 Supl):110, Abstrac no. 2511

  23. Coronado C, Kahatt C, Szyldergemajn S, Iglesias JL, Florez A, Yovine A (2010) Transient isolated transaminase increases do not correlate with permanent clinical liver damage: phase I experience with elisidepsin. Ann Oncol 21:180–18, abstract No. 553

    Google Scholar 

  24. Rademaker-Lakhai JM, Horenblas S, Meinhardt W, Stokvis E, de Reijke TM, Jimeno JM, Lopez-Lazaro L, Lopez Martin JA, Beijnen JH, Schellens JH (2005) Phase I clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer. Clin Cancer Res 11:1854–1862

    Article  CAS  PubMed  Google Scholar 

  25. Pardo B, Paz-Ares L, Tabernero J, Ciruelos E, Garcia M, Salazar R, Lopez A, Blanco M, Nieto A, Jimeno J, Izquierdo MA, Trigo JM (2008) Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-h infusion to patients with advanced solid tumors. Clin Cancer Res 14:1116–1123

    Article  CAS  PubMed  Google Scholar 

  26. Martin-Algarra S, Espinosa E, Rubio J, Lopez Lopez JJ, Manzano JL, Carrion LA, Plazaola A, Tanovic A, Paz-Ares L (2009) Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma. Eur J Cancer 45:732–735

    Article  CAS  PubMed  Google Scholar 

  27. Goldwasser F, Faivre S, Alexandre J, Coronado C, Fernandez-Garcia EM, Kahatt CM, Paramio PG, Dios JL, Miguel-Lillo B, Raymond E (2014) Phase I study of elisidepsin (Irvalec(R)) in combination with carboplatin or gemcitabine in patients with advanced malignancies. Investig New Drugs 32:500–509

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by PharmaMar, S.A., and presented in part at the 44th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30-June 3, 2008. Chicago, Illinois. Phase I study of PM02734: Association of dose-limiting hepatotoxicity with plasma concentrations. JY Bruce; D. Geary.; B. de las Heras; A. Soto; P. Garcia-Paramio; A. Yovine; R.L. Schilsky; SD Undevia and MJ Ratain. Abstract No. 2513.

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Disclosure of potential conflicts of interest

Cinthya Coronado, Vicente Alfaro, Jorge L. Iglesias and Bernardo Miguel-Lillo are employees of PharmaMar.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Medicine, University of Chicago, MC2115, 5841 South Maryland Avenue, Chicago, IL, 60637, USA

    Mark J. Ratain, David Geary, Samir D. Undevia & Richard L. Schilsky

  2. PharmaMar, Clinical R&D, Colmenar Viejo, Madrid, Spain

    Cinthya Coronado, Vicente Alfaro, Jorge L. Iglesias & Bernardo Miguel-Lillo

Authors
  1. Mark J. Ratain
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  2. David Geary
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  3. Samir D. Undevia
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  4. Cinthya Coronado
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  5. Vicente Alfaro
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  6. Jorge L. Iglesias
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  7. Richard L. Schilsky
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  8. Bernardo Miguel-Lillo
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Correspondence to Mark J. Ratain.

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Ratain, M.J., Geary, D., Undevia, S.D. et al. First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors. Invest New Drugs 33, 901–910 (2015). https://doi.org/10.1007/s10637-015-0247-1

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  • DOI: https://doi.org/10.1007/s10637-015-0247-1

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