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A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma

S Thomas1, R Aggarwal1, T Jahan1

  • 1Department of Medicine/Hematology and Oncology, University of California, San Francisco, San Francisco, USA.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|February 24, 2016
PubMed
Abstract

Insights

This study shows that combining panobinostat with epirubicin is a well-tolerated treatment for advanced sarcoma. The combination therapy demonstrated clinical benefit, potentially reversing resistance to anthracyclines.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Sarcoma treatment options are limited.
  • Histone deacetylase inhibitors enhance topoisomerase II inhibitor efficacy by improving chromatin access and reducing DNA repair.
  • Combined panobinostat and epirubicin therapy was investigated for refractory sarcoma.

Purpose of the Study:

  • To evaluate the safety and efficacy of combined panobinostat and epirubicin in patients with advanced solid tumors, particularly sarcoma.
  • To determine the maximum tolerated dose (MTD) of panobinostat in combination with epirubicin.
  • To explore potential predictive biomarkers for treatment response.

Main Methods:

  • A phase I dose-escalation trial enrolled patients with advanced solid tumors.
  • Panobinostat was administered on days 1, 3, and 5, followed by epirubicin on day 5 in 21-day cycles.
  • Dose expansion was performed at the MTD in 20 sarcoma patients, with peripheral blood mononucleocyte histone acetylation evaluated.

Main Results:

  • The MTD of panobinostat was determined to be 50 mg due to dose-limiting toxicities at 60 mg (thrombocytopenia, febrile neutropenia, fatigue).
  • Among 37 assessable patients, four responses were observed, all in patients previously treated with topoisomerase II inhibitors.
  • In 20 sarcoma patients, 12 achieved clinical benefit (1 partial response, 11 stable disease), with a median overall survival of 8.3 months. Eight of these patients had previously progressed on topoisomerase II therapy.

Conclusions:

  • The combination of panobinostat and epirubicin is well-tolerated and may overcome anthracycline resistance.
  • Increased histone acetylation and decreased neutrophil count correlated with clinical benefit and may serve as predictive biomarkers for treatment response.
Keywords:
epirubicinhistone deacetylasepanobinostatsarcomatopoisomerase

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