Investigational New Drugs

, Volume 29, Issue 6, pp 1406–1413 | Cite as

Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas

  • Ramón Salazar
  • Ruth Plummer
  • Ana Oaknin
  • Angela Robinson
  • Beatriz Pardo
  • Arturo Soto-Matos
  • Alejandro Yovine
  • Sergio Szyldergemajn
  • Alan Hilary Calvert
PHASE I STUDIES

Summary

This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m2 and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m2 and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m2 and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m2 and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.

Keywords

Plitidepsin Carboplatin Advanced solid tumors Marine compounds 

Notes

Acknowledgments

The authors would like to acknowledge the work done by Martin Cullell-Young (medical writer, Pharma Mar S.A.) and Sonia Extremera (biostatistician, Pharma Mar S.A.) in the preparation of this manuscript.

References

  1. 1.
    Depenbrock H, Peter R, Faircloth GT, Manzanares I, Jimeno J, Hanauske AR (1998) In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer 78:739–744PubMedCrossRefGoogle Scholar
  2. 2.
    Gonzalez-Santiago L, Suarez Y, Zarich N, Muñoz-Alonso MJ, Cuadrado A, Martinez T, Goya L, Iradi A, Saez-Tormo G, Maier JV, Moorthy A, Cato AC, Rojas JM, Munoz A (2006) Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation. Cell Death Differ 13:1968–1981PubMedCrossRefGoogle Scholar
  3. 3.
    Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, Gonzalez L, Nakayama K, Nakayama KI, Fernandez-Sousa JM, Munoz A, Sanchez-Puelles JM (2002) Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene 21:7533–7544PubMedCrossRefGoogle Scholar
  4. 4.
    Cuadrado A, Gonzalez L, Suarez Y, Martinez T, Munoz A (2004) JNK activation is critical for Aplidin-induced apoptosis. Oncogene 23:4673–4680PubMedCrossRefGoogle Scholar
  5. 5.
    Muñoz M, Alvarez E, Martinez T, Gonzalez-Santiago L, Sasak H, Lepage D, Aviles P, Muñoz A (2007) JNK Activation as an In Vivo Marker of Aplidin® Activity. Proceedings AACR Annual Meeting:Abstract 5580Google Scholar
  6. 6.
    Biscardi M, Caporale R, Balestri F, Gavazzi S, Jimeno J, Grossi A (2005) VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia. Ann Oncol 16:1667–1674PubMedCrossRefGoogle Scholar
  7. 7.
    Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, Faircloth GT, Broggini M, D’Incalci M, Ribatti D, Giavazzi R (2004) Antiangiogenic activity of aplidine, a new agent of marine origin. Br J Cancer 90:2418–2424PubMedGoogle Scholar
  8. 8.
    Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, Sironi M, Jimeno J, Faircloth GT, Giavazzi R, D’Incalci M (2003) Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia 17:52–59PubMedCrossRefGoogle Scholar
  9. 9.
    Straight AM, Oakley K, Moores R, Bauer AJ, Patel A, Tuttle RM, Jimeno J, Francis GL (2006) Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother Pharmacol 57:7–14PubMedCrossRefGoogle Scholar
  10. 10.
    Stewart DJ (2007) Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol 63:12–31PubMedCrossRefGoogle Scholar
  11. 11.
    Cuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide V, Martinez T, Fernandez-Sousa JM, Sanchez-Puelles JM, Munoz A (2003) Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. J Biol Chem 278:241–250PubMedCrossRefGoogle Scholar
  12. 12.
    Anthoney A, Paz-Ares L, Twelves C, Cortes-Funes H, Kaye S, Pronk L, Celli N, Lopez-Lazaro L, Guzman C, Jimeno J (2000) Phase I and pharmacokinetic (PK) study of Aplidin (APL) using a 24-hour, weekly schedule. Proc Am Soc Clin Oncol 19:Abstract 734Google Scholar
  13. 13.
    Ciruelos EM, Twelves C, Dominguez MJ, Mckay H, Anthony A, Castellanos D, Bezares S, Ruiz A, Lopez-Lazaro L, Jimeno J, Celli C, Cortes-Funes H, Paz-Ares L (2002) Phase I clinical and pharmacokinetic study of the marine compound Aplidin (APL) administered as a 3 h infusion every 2 weeks. Proc Am Soc Clin Oncol 21:Abstract 422Google Scholar
  14. 14.
    Bowman A, Izquierdo MA, Jodrell D, Martinez M, Cicchella B, Jimeno J, Guzman C, Germa-Lluch J, Celli N, Smyth J (2001) Phase I clinical and pharmacokinetic (PK) study of the marine compound Aplidin (APL), administered as a 1 h weekly infusion. Proc Am Soc Clin Oncol 20:Abstract 476Google Scholar
  15. 15.
    Faivre S, Chieze S, Delbaldo C, Ady-Vago N, Guzman C, Lopez-Lazaro L, Lozahic S, Jimeno J, Pico F, Armand JP, Martin JA, Raymond E (2005) Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies. J Clin Oncol 23:7780–7782CrossRefGoogle Scholar
  16. 16.
    Maroun JA, Belanger K, Seymour L, Matthews S, Roach J, Dionne J, Soulieres D, Stewart D, Goel R, Charpentier D, Goss G, Tomiak E, Yau J, Jimeno J, Chiritescu G (2006) Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115. Ann Oncol 17:1371–1378PubMedCrossRefGoogle Scholar
  17. 17.
    Chabner B, Longo DL (2006) Cancer chemotherapy and biotherapy: principles and practice, 4th edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  18. 18.
    Izquierdo MA, Bowman A, Garcia M, Jodrell D, Martinez M, Pardo B, Gomez J, Lopez-Martin JA, Jimeno J, Germa JR, Smyth JF (2008) Phase I clinical and pharmacokinetic study of plitidepsin as a 1-hour weekly intravenous infusion in patients with advanced solid tumors. Clin Cancer Res 14:3105–3112PubMedCrossRefGoogle Scholar
  19. 19.
    Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756PubMedGoogle Scholar
  20. 20.
    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 92:205–216PubMedCrossRefGoogle Scholar
  21. 21.
    Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, Schiffer CA, Smith TJ, Somlo G, Wade JC, Wade JL 3rd, Winn RJ, Wozniak AJ, Somerfield MR (2000) 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18:3558–3585PubMedGoogle Scholar
  22. 22.
    Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, Djulbegovic B, Goode MJ, Jakubowski AA, Lee SJ, Miller CB, Rarick MU, Regan DH, Browman GP, Gordon MS (2002) Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood 100:2303–2320PubMedCrossRefGoogle Scholar
  23. 23.
    Oh WK, Hagmann E, Manola J, George DJ, Gilligan TD, Jacobson JO, Smith MR, Kaufman DS, Kantoff PW (2005) A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer. Clin Cancer Res 11:284–289PubMedGoogle Scholar
  24. 24.
    Yonemori K, Katsumata N, Yamamoto N, Kasamatsu T, Yamada T, Tsunematsu R, Fujiwara Y (2005) A phase I study and pharmacologic evaluation of irinotecan and carboplatin for patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy. Cancer 104:1204–1212PubMedCrossRefGoogle Scholar
  25. 25.
    Fukuda M, Soda H, Soejima Y, Kinoshita A, Takatani H, Kasai T, Nagashima S, Kawabata S, Doi S, Kohno S, Oka M (2006) A phase I trial of carboplatin and etoposide for elderly (>or=75 year-old) patients with small-cell lung cancer. Cancer Chemother Pharmacol 58:601–606PubMedCrossRefGoogle Scholar
  26. 26.
    Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol 25:4603–4609PubMedCrossRefGoogle Scholar
  27. 27.
    Kaira K, Tsuchiya S, Sunaga N, Yanagitani N, Watanabe S, Imai H, Hisada T, Ishizuka T, Saito R, Mori M (2007) A phase I dose escalation study of weekly docetaxel and carboplatin in elderly patients with nonsmall cell lung cancer. Am J Clin Oncol 30:51–56PubMedCrossRefGoogle Scholar
  28. 28.
    Stinchcombe TE, Socinski MA, Walko CM, O’Neil BH, Collichio FA, Ivanova A, Mu H, Hawkins MJ, Goldberg RM, Lindley C, Claire Dees E (2007) Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. Cancer Chemother Pharmacol 60:759–766PubMedCrossRefGoogle Scholar
  29. 29.
    Ramirez PT, Landen CN Jr, Coleman RL, Milam MR, Levenback C, Johnston TA, Gershenson DM (2008) Phase I trial of the proteasome inhibitor bortezomib in combination with carboplatin in patients with platinum- and taxane-resistant ovarian cancer. Gynecol Oncol 108:68–71PubMedCrossRefGoogle Scholar
  30. 30.
    Schöffski P, Guillem V, Garcia M, Rivera F, Tabernero J, Cullell M, Lopez-Martin JA, Pollard P, Dumez H, Garcia del Muro X, Paz-Ares L (2009) Phase II randomized study of plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma. Mar Drugs 7:57–70PubMedCrossRefGoogle Scholar
  31. 31.
    Eisen T, Thatcher N, Leyvraz S, Miller WH Jr, Couture F, Lorigan P, Luthi F, Small D, Tanovic A, O’Brien M (2009) Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer. Lung Cancer 64:60–65PubMedCrossRefGoogle Scholar
  32. 32.
    Peschel C, Hartmann JT, Schmittel A, Bokemeyer C, Schneller F, Keilholz U, Buchheidt D, Millan S, Izquierdo MA, Hofheinz RD (2008) Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer. Lung Cancer 60:374–380PubMedCrossRefGoogle Scholar
  33. 33.
    Baylis C, Handa RK, Sorkin M (1990) Glucocorticoids and control of glomerular filtration rate. Semin Nephrol 10:320–329PubMedGoogle Scholar
  34. 34.
    Rabik CA, Dolan ME (2007) Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33:9–23PubMedCrossRefGoogle Scholar
  35. 35.
    Von Hoff DD, Turner J (1991) Response rates, duration of response, and dose response effects in phase I studies of antineoplastics. Invest New Drugs 9:115–122Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ramón Salazar
    • 1
  • Ruth Plummer
    • 2
  • Ana Oaknin
    • 1
  • Angela Robinson
    • 2
  • Beatriz Pardo
    • 1
  • Arturo Soto-Matos
    • 3
  • Alejandro Yovine
    • 3
  • Sergio Szyldergemajn
    • 3
  • Alan Hilary Calvert
    • 2
  1. 1.Instituto Catalán de OncologíaBarcelonaSpain
  2. 2.Northern Centre for Cancer TreatmentNewcastle General HospitalNewcastle upon TyneUK
  3. 3.Pharma Mar S.A., Sociedad UnipersonalMadridSpain

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