Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy

Authors

  • Daniel C. Cho MD,

    Corresponding author
    1. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
    • 330 Brookline Avenue, Boston, MA 02215; Fax: (617) 632-9260

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    • Fax: (617) 632-9260

  • Thomas E. Hutson DO,

    1. Division of Oncology, Baylor University Medical Center, Dallas, Texas
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Wolfram Samlowski MD,

    1. Comprehensive Cancer Centers of Nevada, Southern Hills, Nevada
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Peter Sportelli BS,

    1. Keryx Pharmaceuticals, Inc., New York, New York
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Brad Somer MD,

    1. The West Clinic, Memphis, Tennessee
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Paul Richards MD,

    1. Blue Ridge Cancer Care, Salem, Virginia
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Jeffrey A. Sosman MD,

    1. Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Igor Puzanov MD,

    1. Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • M. Dror Michaelson MD, PhD,

    1. Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Keith T. Flaherty MD,

    1. Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts
    2. Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
    3. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Robert A. Figlin MD,

    1. Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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  • Nicholas J. Vogelzang MD

    1. Cedars-Sinai Medical Center, Los Angeles, California
    2. Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
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Abstract

BACKGROUND:

The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)-kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independent phase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)-targeted therapy.

METHODS:

In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor.

RESULTS:

In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%-20%), and 11 patients (46%) had stable disease as their best response. The median progression-free survival was 14.2 weeks (95% confidence interval, 7.7-21.6 weeks). In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%-22.2%) and 16 patients (32%) had stable disease as their best response. The median progression-free survival was 14 weeks (95% confidence interval, 12.9, 20.7 weeks). Overall, perifosine was well tolerated, and there were very few grade 3 and 4 events. The most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue.

CONCLUSIONS:

Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGF-targeted therapy, its activity was not superior to currently available second-line agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies. Cancer 2012. © 2012 American Cancer Society.

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