Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma

  • Antonio Silvani
  • Irene De SimoneEmail author
  • Vittorio Fregoni
  • Elena Biagioli
  • Enrico Marchioni
  • Manuela Caroli
  • Andrea Salmaggi
  • Andrea Pace
  • Valter Torri
  • Paola Gaviani
  • Erica Quaquarini
  • Giorgia Simonetti
  • Eliana Rulli
  • Maurizio D’Incalci
  • the Italian Association of Neuro-Oncology
Clinical Study


Background and purpose

Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment.


In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m2 i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints.


Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients.


Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time.

Trial registration: This study is registered with, number NCT01989884.


Glioblastoma Ortataxel Recurrence Taxane 



Authors commemorate the colleague Irene Floriani of the Mario Negri Institute, who passed away on 12 January 2016 and who dedicated her life to the research. She has been deeply involved in the statistical design and coordination of this clinical trial. Authors remember the colleague Dr Gian Antonio Da Prada of ICS Maugeri of Pavia, who passed away on 15th December 2015. He spent his life in the research and treatment of cancer with fully dedication and contributed in the drawing up and enrollment for this trial. Presentation: This work has not been yet presented. List of participating institutions and coauthors: Members of the Italian association of neuro-oncology (AINO): Antonio Silvani (Fondazione Istituto Neurologico Carlo Besta - IRCCS - Milano), Andrea Salmaggi (Ospedale A. Manzoni—Lecco), Manuela Caroli (Fondazione Ca’ Granda Ospedale Maggiore Policlinico—IRCCS—Milano), Enrico Marchioni (Fondazione Istituto Neurologico Nazionale Casimiro Mondino—IRCCS—Pavia), Andrea Pace (Istituto Nazionale Tumori Regina Elena—Roma), Paola Gaviani (Fondazione Istituto Neurologico Carlo Besta—IRCCS—Milano). Fondazione Istituto Neurologico Carlo BestaIRCCSMilano: UOC Neurologia 2—Neuroncologia clinica: A. Silvani, P. Gaviani, G. Simonetti. IRFMN (Istituto Ricerche Farmacologiche Mario Negri): Laboratorio di Metodologia per la Ricerca Clinica: I. De Simone, E. Biagioli, E. Rulli, V. Torri, Davide Poli, Evelina Mariotti, Grazia Caramia, Angela Pesenti Gritti, Ilaria Pacchetti. Laboratorio Farmacologia antitumorale: M. D’Incalci, Massimo Zucchetti. Fondazione Salvatore MaugeriIRCCSPavia: S.C. Oncologia: V. Fregoni, E. Quaquarini, Annalisa Lanza. Servizio di diagnostica per immagini: Gianpaolo Basso. Fondazione Istituto Neurologico Nazionale Casimiro MondinoIRCCSPavia: U.O. Neuroncologia: E. Marchioni, Paola Bini, Giulia Berzero, Luca Diamanti. Fondazione Ca’Granda Ospedale Maggiore PoliclinicoIRCCSMilano: U.O.C. Neurochirurgia: M.Caroli, Andrea Di Cristofori, Andrea Manzoni, Giordano Lanfranchi. Ospedale A. ManzoniLecco: S.C. Oncologia: A. Salmaggi, Antonio Ardizzoia. Istituto Nazionale Tumori Regina ElenaRoma: UOSD Neuroncologia: A. Pace, Veronica Villani.


This study was supported by Spectrum Pharmaceuticals Inc that supplied the study drug to the participating centres, without any costs or expenses.

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest with regard to the research, authorship, and/or publication of this article.

Supplementary material

11060_2019_3116_MOESM1_ESM.doc (532 kb)
Supplementary material 1 (DOC 531 KB)


  1. 1.
    Brandes AA, Finocchiaro G, Zagonel V, Reni M, Fabi A, Caserta C, Tosoni A, Eoli M, Lombardi G, Clavarezza M, Paccapelo A, Bartolini S, Cirillo L, Agati R, Franceschi E (2017) Early tumour shrinkage as a survival predictor in patients with recurrent glioblastoma treated with bevacizumab in the AVAREG randomized phase II study. Oncotarget 8(33):55575–55581. CrossRefGoogle Scholar
  2. 2.
    Central Brain Tumor Registry of the United States. Accessed 10 Jan 2017
  3. 3.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10):987–996. CrossRefGoogle Scholar
  4. 4.
    Boiardi A, Silvani A, Eoli M, Lamperti E, Salmaggi A, Gaviani P, Fiumani A, Botturi A, Falcone C, Solari A, Filippini G, Di Meco F, Broggi G (2008) Treatment of recurrent glioblastoma: can local delivery of mitoxantrone improve survival? J Neurooncol 88(1):105–113. CrossRefGoogle Scholar
  5. 5.
    Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25(22):3357–3361. CrossRefGoogle Scholar
  6. 6.
    Carrabba ADIC, Lanfranchi G, Menghetti G, Rampini C, Caroli P M (2013) Continuous tamoxifen and dose-dense temozolomide in recurrent glioblastoma. Anticancer Res 33(8):3383–3389Google Scholar
  7. 7.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740. CrossRefGoogle Scholar
  8. 8.
    Silvani A, Lamperti E, Gaviani P, Eoli M, Fiumani A, Salmaggi A, Falcone C, Filippini G, Botturi A, Boiardi A (2008) Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients. J Neurooncol 87(2):143–151. CrossRefGoogle Scholar
  9. 9.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345(8956):1008–1012CrossRefGoogle Scholar
  10. 10.
    Frenay M, Giroux B, Khoury S, Derlon JM, Namer M (1991) Phase II study of fotemustine in recurrent supratentorial malignant gliomas. Eur J Cancer 27(7):852–856CrossRefGoogle Scholar
  11. 11.
    Addeo R, Caraglia M, De Santi MS, Montella L, Abbruzzese A, Parlato C, Vincenzi B, Carraturo M, Faiola V, Genovese M, Cennamo G, Del Prete S (2011) A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. J Neurooncol 102(3):417–424. CrossRefGoogle Scholar
  12. 12.
    Scoccianti S, Detti B, Sardaro A, Iannalfi A, Meattini I, Leonulli BG, Borghesi S, Martinelli F, Bordi L, Ammannati F, Biti G (2008) Second-line chemotherapy with fotemustine in temozolomide-pretreated patients with relapsing glioblastoma: a single institution experience. Anticancer Drugs 19(6):613–620. CrossRefGoogle Scholar
  13. 13.
    Fellner S, Bauer B, Miller DS, Schaffrik M, Fankhanel M, Spruss T, Bernhardt G, Graeff C, Farber L, Gschaidmeier H, Buschauer A, Fricker G (2002) Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo. J Clin Invest 110(9):1309–1318. CrossRefGoogle Scholar
  14. 14.
    Kemper EM, Verheij M, Boogerd W, Beijnen JH, van Tellingen O (2004) Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. Eur J Cancer 40(8):1269–1274. CrossRefGoogle Scholar
  15. 15.
    Semiond D, Sidhu SS, Bissery MC, Vrignaud P (2013) Can taxanes provide benefit in patients with CNS tumors and in pediatric patients with tumors? An update on the preclinical development of cabazitaxel. Cancer Chemother Pharmacol 72(3):515–528. CrossRefGoogle Scholar
  16. 16.
    Polizzi D, Pratesi G, Tortoreto M, Supino R, Riva A, Bombardelli E, Zunino F (1999) A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Res 59(5):1036–1040Google Scholar
  17. 17.
    Pratesi G (2001) BAY 59-8862. Drugs Fut 25(6):533–544CrossRefGoogle Scholar
  18. 18.
    Nicoletti MI, Colombo T, Rossi C, Monardo C, Stura S, Zucchetti M, Riva A, Morazzoni P, Donati MB, Bombardelli E, D’Incalci M, Giavazzi R (2000) IDN5109, a taxane with oral bioavailability and potent antitumor activity. Cancer Res 60(4):842–846Google Scholar
  19. 19.
    Ramnath N, Hamm J, Schwartz G, Holden S, Eckhardt SG, Vredenburg MR, Bernacki RJ, Lathia C, Kanter P, Creaven PJ (2004) A phase I and pharmacokinetic study of BAY59: a novel taxane. Oncology 67(2):123–129. CrossRefGoogle Scholar
  20. 20.
    Laccabue D, Tortoreto M, Veneroni S, Perego P, Scanziani E, Zucchetti M, Zaffaroni M, D’Incalci M, Bombardelli E, Zunino F, Pratesi G (2001) A novel taxane active against an orthotopically growing human glioma xenograft. Cancer 92(12):3085–3092CrossRefGoogle Scholar
  21. 21.
    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972. CrossRefGoogle Scholar
  22. 22.
    Shuster JJ (1991) Median follow-up in clinical trials. J Clin Oncol 9(1):191–192. CrossRefGoogle Scholar
  23. 23.
    Wan YF, Guo XQ, Wang ZH, Ying K, Yao MH (2004) Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin 25(3):378–384Google Scholar
  24. 24.
    Peng S, Dhruv H, Armstrong B, Salhia B, Legendre C, Kiefer J, Parks J, Virk S, Sloan AE, Ostrom QT, Barnholtz-Sloan JS, Tran NL, Berens ME (2017) Integrated genomic analysis of survival outliers in glioblastoma. Neuro Oncol 19(6):833–844. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Antonio Silvani
    • 1
  • Irene De Simone
    • 2
    Email author
  • Vittorio Fregoni
    • 3
  • Elena Biagioli
    • 2
  • Enrico Marchioni
    • 4
  • Manuela Caroli
    • 5
  • Andrea Salmaggi
    • 6
  • Andrea Pace
    • 7
  • Valter Torri
    • 2
  • Paola Gaviani
    • 1
  • Erica Quaquarini
    • 3
  • Giorgia Simonetti
    • 1
  • Eliana Rulli
    • 2
  • Maurizio D’Incalci
    • 2
  • the Italian Association of Neuro-Oncology
  1. 1.Fondazione Istituto Neurologico Carlo BestaIRCCSMilanItaly
  2. 2.Istituto di Ricerche Farmacologiche Mario NegriIRCCSMilanItaly
  3. 3.Fondazione Salvatore MaugeriIRCCSPaviaItaly
  4. 4.Fondazione Istituto Neurologico Nazionale Casimiro MondinoIRCCSPaviaItaly
  5. 5.Fondazione Ca’Granda Ospedale Maggiore PoliclinicoIRCCSMilanItaly
  6. 6.Ospedale A. ManzoniLeccoItaly
  7. 7.Istituto Nazionale Tumori Regina ElenaRomaItaly

Personalised recommendations