Phase 1/2 study of everolimus in advanced hepatocellular carcinoma

Authors

  • Andrew X. Zhu MD,

    Corresponding author
    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
    • Massachusetts General Hospital Cancer Center, 55 Fruit Street, LH/POB 232, Boston, MA 02114
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    • Fax: (617) 724-3166

  • Thomas A. Abrams MD,

    1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Rebecca Miksad MD,

    1. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Lawrence S. Blaszkowsky MD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Jeffrey A. Meyerhardt MD,

    1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Hui Zheng PhD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Alona Muzikansky MA,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
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  • Jeffrey W. Clark MD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Eunice L. Kwak MD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Deborah Schrag MD,

    1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Kathryn R. Jors BA,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
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  • Charles S. Fuchs MD,

    1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • A. John Iafrate MD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • Darrell R. Borger PhD,

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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  • David P. Ryan MD

    1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts
    2. Harvard Medical School, Boston, Massachusetts
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Abstract

BACKGROUND:

The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single-arm, phase 1/2 study of everolimus in patients with advanced HCC.

METHODS:

Patients with histologically confirmed measurable advanced HCC, 0-2 prior regimens, and adequate hematologic, hepatic, and renal functions received everolimus at 5 mg/day or 10 mg/day orally (6 weeks/cycle). The primary end points were determination of a safe dosage of everolimus (phase 1) and progression-free survival (PFS) at 24 weeks (phase 2).

RESULTS:

Twenty-eight patients were enrolled and evaluable for efficacy and toxicity. No dose-limiting toxicities were observed at the 5 mg/day (n = 3) or 10 mg/day (n = 6) dosage level in phase 1. Twenty-five patients received everolimus at 10 mg/day. Grade 3-4 adverse events included lymphopenia (n = 3), aspartate transaminase (n = 3), hyponatremia (n = 2), and 1 patient each with anemia, alanine transaminase, hyperglycemia, proteinuria, rash, and hypoxia. One patient (4%) had partial response (95% confidence interval [CI], 0.9%-19.6%). The median PFS and overall survival were 3.8 months (95% CI, 2.1-4.6) and 8.4 months (95% CI, 3.9-21.1), respectively. The estimated PFS rate at 24 weeks was 28.6% (95% CI, 7.9%-49.3%).

CONCLUSION:

Everolimus was well tolerated in patients with advanced HCC, and 10 mg/day was defined as the phase 2 dosage. Although the study did not proceed to the second stage of phase 2, preliminary antitumor activity was observed with everolimus in patients with advanced HCC, most of whom had prior systemic treatment. Cancer 2011. © 2011 American Cancer Society.

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