Advertisement

Investigational New Drugs

, Volume 37, Issue 4, pp 674–683 | Cite as

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors

  • Elena Elez
  • Carlos Gomez-Roca
  • Arturo Soto Matos-Pita
  • Guillem Argiles
  • Thibaud Valentin
  • Cinthya Coronado
  • Jorge Iglesias
  • Teresa Macarulla
  • Sarah Betrian
  • Salvador Fudio
  • Katrin Zaragoza
  • Josep Tabernero
  • Jean-Pierre DelordEmail author
PHASE I STUDIES

Summary

Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

Keywords

Plocabulin PM060184 Microtubule inhibitor First-in-human Phase I Solid tumors 

Notes

Acknowledgements

The authors wish to thank the patients, their families, and the clinical research teams for their time and trust, and for enabling this clinical trial and associated research.

Funding

This work was supported by Pharma Mar, S.A.

Compliance with ethical standards

Conflicts of interest

A Soto Matos-Pita, C Coronado, J Iglesias, S Fudio, and K Zaragoza are employees of Pharma Mar, S.A.

Ethical approval

All procedures performed in studies 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.

References

  1. 1.
    Schwartz EL (2009) Antivascular actions of microtubule-binding drugs. Clin Cancer Res 15:2594–2601.  https://doi.org/10.1158/1078-0432.CCR-08-2710 CrossRefGoogle Scholar
  2. 2.
    Bates D, Eastman A (2017) Microtubule destabilising agents: far more than just antimitotic anticancer drugs. Br J Clin Pharmacol 83:255–268.  https://doi.org/10.1111/bcp.13126 CrossRefGoogle Scholar
  3. 3.
    Mukhtar E, Adhami VM, Mukhtar H (2014) Targeting microtubules by natural agents for cancer therapy. Mol Cancer Ther 13:275–284.  https://doi.org/10.1158/1535-7163.MCT-13-0791 CrossRefGoogle Scholar
  4. 4.
    Martin MJ, Coello L, Fernandez R, Reyes F, Rodriguez A, Murcia C, Garranzo M, Mateo C, Sanchez-Sancho F, Bueno S, de Eguilior C, Francesch A, Munt S, Cuevas C (2013) Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds. J Am Chem Soc 135:10164–10171.  https://doi.org/10.1021/ja404578u CrossRefGoogle Scholar
  5. 5.
    Prota AE, Bargsten K, Diaz JF, Marsh M, Cuevas C, Liniger M, Neuhaus C, Andreu JM, Altmann KH, Steinmetz MO (2014) A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc Natl Acad Sci U S A 111:13817–13821.  https://doi.org/10.1073/pnas.1408124111 CrossRefGoogle Scholar
  6. 6.
    Pera B, Barasoain I, Pantazopoulou A, Canales A, Matesanz R, Rodriguez-Salarichs J, Garcia-Fernandez LF, Moneo V, Jimenez-Barbero J, Galmarini CM, Cuevas C, Penalva MA, Diaz JF, Andreu JM (2013) New interfacial microtubule inhibitors of marine origin, PM050489/PM060184, with potent antitumor activity and a distinct mechanism. ACS Chem Biol 8:2084–2094.  https://doi.org/10.1021/cb400461j CrossRefGoogle Scholar
  7. 7.
    Martinez-Diez M, Guillen-Navarro MJ, Pera B, Bouchet BP, Martinez-Leal JF, Barasoain I, Cuevas C, Andreu JM, Garcia-Fernandez LF, Diaz JF, Aviles P, Galmarini CM (2014) PM060184, a new tubulin binding agent with potent antitumor activity including P-glycoprotein over-expressing tumors. Biochem Pharmacol 88:291–302.  https://doi.org/10.1016/j.bcp.2014.01.026 CrossRefGoogle Scholar
  8. 8.
    Galmarini CM, Martin M, Bouchet BP, Guillen-Navarro MJ, Martinez-Diez M, Martinez-Leal JF, Akhmanova A, Aviles P (2018) Plocabulin, a novel tubulin-binding agent, inhibits angiogenesis by modulation of microtubule dynamics in endothelial cells. BMC Cancer 18:164.  https://doi.org/10.1186/s12885-018-4086-2 CrossRefGoogle Scholar
  9. 9.
    American Society of Clinical Oncology, Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM (2006) American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24:2932–2947.  https://doi.org/10.1200/JCO.2006.06.9591 CrossRefGoogle Scholar
  10. 10.
    Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F (2006) Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 33:15–49.  https://doi.org/10.1053/j.seminoncol.2005.12.010 CrossRefGoogle Scholar
  11. 11.
    Kerckhove N, Collin A, Conde S, Chaleteix C, Pezet D, Balayssac D (2017) Long-term effects, pathophysiological mechanisms, and risk factors of chemotherapy-induced peripheral neuropathies: a comprehensive literature review. Front Pharmacol 8:86.  https://doi.org/10.3389/fphar.2017.00086 CrossRefGoogle Scholar
  12. 12.
    Beijers AJ, Mols F, Vreugdenhil G (2014) A systematic review on chronic oxaliplatin-induced peripheral neuropathy and the relation with oxaliplatin administration. Support Care Cancer 22:1999–2007.  https://doi.org/10.1007/s00520-014-2242-z CrossRefGoogle Scholar
  13. 13.
    Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C, investigators E (2011) Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377:914–923.  https://doi.org/10.1016/S0140-6736(11)60070-6 CrossRefGoogle Scholar
  14. 14.
    Hirvonen HE, Salmi TT, Heinonen E, Antila KJ, Valimaki IA (1989) Vincristine treatment of acute lymphoblastic leukemia induces transient autonomic cardioneuropathy. Cancer 64:801–805CrossRefGoogle Scholar
  15. 15.
    Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C (2008) Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649.  https://doi.org/10.1200/JCO.2007.11.6699 CrossRefGoogle Scholar
  16. 16.
    Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP (2000) Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 18:1212–1219.  https://doi.org/10.1200/JCO.2000.18.6.1212 CrossRefGoogle Scholar
  17. 17.
    Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer I (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351.  https://doi.org/10.1056/NEJMoa032709 CrossRefGoogle Scholar
  18. 18.
    Kalofonos HP, Aravantinos G, Kosmidis P, Papakostas P, Economopoulos T, Dimopoulos M, Skarlos D, Bamias A, Pectasides D, Chalkidou S, Karina M, Koutras A, Samantas E, Bacoyiannis C, Samelis GF, Basdanis G, Kalfarentzos F, Fountzilas G (2005) Irinotecan or oxaliplatin combined with leucovorin and 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II study. Ann Oncol 16:869–877.  https://doi.org/10.1093/annonc/mdi193 CrossRefGoogle Scholar
  19. 19.
    Cassidy J, Tabernero J, Twelves C, Brunet R, Butts C, Conroy T, Debraud F, Figer A, Grossmann J, Sawada N, Schoffski P, Sobrero A, Van Cutsem E, Diaz-Rubio E (2004) XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084–2091.  https://doi.org/10.1200/JCO.2004.11.069 CrossRefGoogle Scholar
  20. 20.
    Maindrault-Goebel F, Louvet C, Andre T, Carola E, Lotz JP, Molitor JL, Garcia ML, Gilles-Amar V, Izrael V, Krulik M, de Gramont A (1999) Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 35:1338–1342CrossRefGoogle Scholar
  21. 21.
    Argyriou AA, Velasco R, Briani C, Cavaletti G, Bruna J, Alberti P, Cacciavillani M, Lonardi S, Santos C, Cortinovis D, Cazzaniga M, Kalofonos HP (2012) Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients. Ann Oncol 23:3116–3122.  https://doi.org/10.1093/annonc/mds208 CrossRefGoogle Scholar
  22. 22.
    Argyriou AA, Polychronopoulos P, Iconomou G, Koutras A, Makatsoris T, Gerolymos MK, Gourzis P, Assimakopoulos K, Kalofonos HP, Chroni E (2007) Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer. Acta Oncol 46:1131–1137.  https://doi.org/10.1080/02841860701355055 CrossRefGoogle Scholar
  23. 23.
    Peters AM, Glass DM (2010) Use of body surface area for assessing extracellular fluid volume and glomerular filtration rate in obesity. Am J Nephrol 31:209–213.  https://doi.org/10.1159/000271272 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Elena Elez
    • 1
  • Carlos Gomez-Roca
    • 2
  • Arturo Soto Matos-Pita
    • 3
  • Guillem Argiles
    • 1
  • Thibaud Valentin
    • 2
  • Cinthya Coronado
    • 3
  • Jorge Iglesias
    • 3
  • Teresa Macarulla
    • 1
  • Sarah Betrian
    • 2
  • Salvador Fudio
    • 3
  • Katrin Zaragoza
    • 3
  • Josep Tabernero
    • 1
  • Jean-Pierre Delord
    • 2
    Email author
  1. 1.Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO)Universitat Autònoma de BarcelonaBarcelonaSpain
  2. 2.Clinical Research Unit, Institut Claudius RegaudIUCT- OncopoleToulouseFrance
  3. 3.Pharma Mar, S.A., Clinical R&D, Colmenar ViejoMadridSpain

Personalised recommendations