PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma

Ghassan K. Abou-Alfa*, Stephan L. Chan, Chia Chi Lin, E. Gabriela Chiorean, Randall F. Holcombe, Mary F. Mulcahy, William D. Carter, Kashyap Patel, William R. Wilson, Teresa J. Melink, John C. Gutheil, Chao Jung Tsao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Purpose: PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC. Methods: Patients with advanced-stage HCC, Child-Pugh A cirrhosis, and adequate organ function, were assigned to dose escalating cohorts of monthly PR-104 in combination with twice daily sorafenib. The plasma pharmacokinetics (PK) of PR-104 and its metabolites were evaluated. Results: Fourteen (11 men, 3 women) HCC patients: median age 60 years, ECOG 0-1, received PR-104 at two dose levels plus sorafenib. Six patients were treated at starting cohort of 770 mg/m 2. In view of one DLT of febrile neutropenia and prolonged thrombocytopenia, a lower PR-104 dose cohort (550 mg/m2) was added and accrued 8 patients. One patient had a partial response and three had stable disease of ≥8 weeks in the 770 mg/m2 cohort. Three patients at the 550 mg/m2 had stable disease. There were no differences in PK of PR-104 or its metabolites with or without sorafenib, but the PR-104A AUC was twofold higher (P < 0.003) than in previous phase I studies at equivalent dose. Conclusions: PR-104 plus sorafenib was poorly tolerated in patients with advanced HCC, possibly because of compromised clearance of PR-104A in this patient population. Thrombocytopenia mainly and neutropenia were the most clinically significant toxicities and led to discontinuation of the study. PR-104 plus sorafenib is unlikely to be suitable for development in this setting.

Original languageEnglish (US)
Pages (from-to)539-545
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • AKR1C3
  • Hepatocellular carcinoma
  • PR-104
  • Sorafenib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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