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  • [Clin Cancer Res.] 18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.

    Memorial Sloan Kettering Cancer Center / Gary A. Ulaner*

  • 출처
    Clin Cancer Res.
  • 등재일
    2017 Jun 15
  • 저널이슈번호
    23(12):3053-3060. doi: 10.1158/1078-0432.CCR-16-2197. Epub 2016 Dec 23.
  • 내용

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    Abstract


    Purpose:

    Evaluate 18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.

     

    Experimental Design: 

    In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.

     

    Results:

    Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.

     

    Conclusions:

    FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. 

     

    Author information

    Wang Y1, Ayres KL2, Goldman DA3, Dickler MN4, Bardia A5, Mayer IA6, Winer E7, Fredrickson J8, Arteaga CL6, Baselga J4, Manning HC2, Mahmood U1, Ulaner GA9.

    1 Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.

    2 Department of Radiology and Radiological Science, Vanderbilt University Medical Center, Nashville, Tennessee.

    3 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.

    4 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

    5 Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts.

    6 Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

    7 Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.

    8 Genentech, Inc., South San Francisco, California.

    9 Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. ulanerg@mskcc.org. 

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