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Phase III Randomized Controlled Trial Comparing the Survival of Patients With Unresectable Hepatocellular Carcinoma Treated With Nolatrexed or Doxorubicin

Robert G. Gish, Camillo Porta, Lucian Lazar, Paul Ruff, Ronald Feld, Adina Croitoru, Lynn Feun, Krzysztof Jeziorski, John Leighton, Jennifer Knox, José Gallo, Gerard T. Kennealey

From the California Pacific Medical Center, San Francisco, CA; University of Miami, FL; Albert Einstein Medical Center, Philadelphia, PA; GPC Biotech Inc, Princeton, NJ; MGI Pharma, Bloomington, MN; IRCCS San Matteo University Hospital, Pavia, Italy; Oncology Institute Ion Chiricuta, Cluj-Napoca; Fundeni Clinical Institute, Bucharest, Romania; The University of Witwatersrand, Johannesburg, South Africa; Princess Margaret Hospital, Toronto, Canada; the Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; and Eximias Pharmaceutical Corp, Berwyn, PA

Address reprint requests to Robert G. Gish, MD, California Pacific Medical Center, 2340 Clay St 423, San Francisco, CA 94115; e-mail: gishr{at}sutterhealth.org

Purpose The study objective was to compare the overall survival (OS) of patients with unresectable or metastatic hepatocellular carcinoma (HCC) treated with nolatrexed (NOL) or doxorubicin (DOX).

Patients and Methods Patients from North America, Europe, and South Africa (N = 445) with HCC were randomly assigned to receive NOL or DOX. Eligible patients had Karnofsky performance status (KPS) 60%, Cancer of the Liver Italian Program (CLIP) score 3, and adequate organ function. Primary end point was OS. Secondary end points included progression-free survival (PFS), objective response rates, and safety. The treatment groups were well-balanced with regards to age, sex, ethnic origin, and underlying liver disease. Randomization was stratified according to KPS and CLIP score.

Results At the time of the final analysis, 377 patients had died. Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068). The hazard ratio was 0.753 in favor of DOX. Objective response rate (complete response [CR] plus partial response [PR]) was 1.4% for NOL and 4.0% for DOX. Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091). Median time to treatment failure was 8.4 weeks for NOL and 9.1 weeks for DOX (P = .0969). Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were more common in the NOL arm. Alopecia was more common in the DOX arm. More patients were withdrawn from study for toxicity in the NOL arm than in the DOX arm.

Conclusion NOL showed minimal activity in this phase III trial. Further exploration at this dose and schedule in HCC is not warranted.

Presented in part in abstract format at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, San Francisco, CA, 2006; International Liver Congress, Shanghai, 2006; and at the 41st Annual Meeting of the European Association for the Study of the Liver, Vienna, Austria, 2006.

Supported by the Eximias Pharmaceutical Corporation.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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