Investigational New Drugs

, Volume 32, Issue 3, pp 555–560

PF-03446962, a fully-human monoclonal antibody against transforming growth-factor β (TGFβ) receptor ALK1, in pre-treated patients with urothelial cancer: an open label, single-group, phase 2 trial

  • A. Necchi
  • P. Giannatempo
  • L. Mariani
  • E. Farè
  • D. Raggi
  • M. Pennati
  • N. Zaffaroni
  • F. Crippa
  • A. Marchianò
  • N. Nicolai
  • M. Maffezzini
  • E. Togliardi
  • M. G. Daidone
  • A. M. Gianni
  • R. Salvioni
  • F. De Braud
PHASE II STUDIES

Summary

Despite a compelling preclinical rationale for the use of anti-angiogenic drugs in urothelial cancer (UC), short-living responses have been observed in clinical trials. PF-03446962 is a novel monoclonal antibody against Activin Receptor-Like Kinase-1 (ALK1), a type I subclass of the TGFβ receptor, with dose-dependent anti-angiogenic activity. An open label, single-group, phase 2 trial of PF-03446962 was conducted in salvage setting. Patients failing at least one chemotherapy regimen were eligible. Design provided PF-03446962 10 mg/Kg intravenously fortnightly until disease progression (PD) or unacceptable toxicity. Two-month progression-free survival (PFS) was the primary endpoint. The trial was registered with ClinicalTrials.gov, number NCT01620970. Fourteen patients were enrolled from October 2012 to July 2013. Median age was 64 years (interquartile range [IQR]: 58.2–69.5), 9 patients had a Bellmunt score of 1–2, median number of prior drugs was 3. One stable disease and 13 PD were recorded and the study met the futility stopping rule of interim analysis. Median PFS was 1.8 months (95 %CI, 1.4–2.0). After a median follow up of 7.4 months (IQR 4.5–10.9), 8 patients are alive. Median overall survival (OS) was 8 months (95 %CI, 2.9-not estimable). Most common toxicities were thrombocytopenia (G1-2 in 5 cases, persistent G3 in one, with 3 dose delays and 1 dose interruption), fatigue and abdominal pain (G1-2 in 4 cases each). Impairment of quality of life (ESAS score) was observed as well as an increase from baseline to +2 month median levels of vascular endothelial growth factor (VEGF) and interleukin-8. PF-03446962 had no activity as single drug in refractory UC and we do not recommend further investigation outside of the combination with agents targeting the VEGF receptor axis.

Keywords

Transitional cell carcinoma Advanced urothelial cancer Salvage therapy Angiogenesis PF-03446962 

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • A. Necchi
    • 1
  • P. Giannatempo
    • 1
  • L. Mariani
    • 2
  • E. Farè
    • 1
  • D. Raggi
    • 1
  • M. Pennati
    • 3
  • N. Zaffaroni
    • 3
  • F. Crippa
    • 4
  • A. Marchianò
    • 5
  • N. Nicolai
    • 7
  • M. Maffezzini
    • 7
  • E. Togliardi
    • 6
  • M. G. Daidone
    • 3
  • A. M. Gianni
    • 1
  • R. Salvioni
    • 7
  • F. De Braud
    • 1
  1. 1.Department of Medical OncologyFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  2. 2.Clinical Epidemiology and Trials Organization UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  3. 3.Department of Experimental Oncology and Molecular Medicine (DOSMM)Fondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  4. 4.Nuclear Medicine and PET UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  5. 5.Department of RadiologyFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  6. 6.Pharmacy UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  7. 7.Department of Surgery-Urology UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly

Personalised recommendations