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
Clinical Trial Report
First Online:
Received:
Accepted:

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/m2. 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.

Keywords

PR-104 Sorafenib Hepatocellular carcinoma AKR1C3 
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Notes

Acknowledgments

We thank the medical, nursing, and research staff at each of the centers for their efforts on this study. Chia-Chi Lin thanks Li-Mei Yeh, R. N., National Clinical Trial & Research Center, National Taiwan University Hospital, for her dedicated patient care. Ghassan K. Abou-Alfa thanks Eileen M. O’Reilly, MD, and Jennifer Ma, Memorial Sloan-Kettering Cancer Center. We also thank Brenda Gibson for her assistance with study management.

Conflict of interest

Stephan L. Chen, Chia-Chi Lin, E. Gabriela Chiorean, Randall F. Holocombe, Kashyap Patel, and Chao-Jung Tsao: None. Ghassan Abou-Alfa: Consultant/Advisory role: Proacta, and funding: Bayer. Mary Mulchay: Renumeration: Bayer. William Carter: Consultant/Advisory role: Proacta. William R. Wilson: Consultant/Advisory role, stock ownership, and funding: Proacta. Teresa J. Melink and John C. Gutheil: Renumeration and stock ownership.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ghassan K. Abou-Alfa
    • 1
  • Stephan L. Chan
    • 2
  • Chia-Chi Lin
    • 3
  • E. Gabriela Chiorean
    • 4
  • Randall F. Holcombe
    • 5
  • Mary F. Mulcahy
    • 6
  • William D. Carter
    • 7
  • Kashyap Patel
    • 8
  • William R. Wilson
    • 8
  • Teresa J. Melink
    • 9
  • John C. Gutheil
    • 9
  • Chao-Jung Tsao
    • 10
  1. 1.Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.State Key Laboratory in Oncology in South China, Department of Clinical Oncology, Prince of Wales HospitalThe Chinese University of Hong KongSha TinHong Kong
  3. 3.National Taiwan University HospitalTaipeiTaiwan
  4. 4.Indiana University Melvin and Bren Simon Cancer CenterIndianapolisUSA
  5. 5.Mt Sinai School of Medicine Tisch Cancer InstituteNew YorkUSA
  6. 6.Northwestern UniversityChicagoUSA
  7. 7.Sharp HospitalSan DiegoUSA
  8. 8.University of AucklandAucklandNew Zealand
  9. 9.Proacta, Inc.San DiegoUSA
  10. 10.Chi Mei Medical Center, Department of OncologyNational Taiwan University HospitalTainanTaiwan

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