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

Yingbing Wang, Karen L. Ayres, Debra A. Goldman, Maura N. Dickler, Aditya Bardia, Ingrid A. Mayer, Eric Winer, Jill Fredrickson, Carlos L. Arteaga, José Baselga, Henry C. Manning, Umar Mahmood, Gary A. Ulaner

Research output: Contribution to journalArticle

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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 ontherapy. 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.

Original languageEnglish (US)
Pages (from-to)3053-3060
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number12
DOIs
StatePublished - Jun 15 2017

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Estrogen Receptors
Biomarkers
Pharmaceutical Preparations
Down-Regulation
Tamoxifen
Therapeutics
Clinical Trials, Phase I
3-(4-(2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid
Positron-Emission Tomography
Research Design
Clinical Trials
Breast Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Wang, Yingbing; Ayres, Karen L.; Goldman, Debra A.; Dickler, Maura N.; Bardia, Aditya; Mayer, Ingrid A.; Winer, Eric; Fredrickson, Jill; Arteaga, Carlos L.; Baselga, José; Manning, Henry C.; Mahmood, Umar; Ulaner, Gary A.

In: Clinical Cancer Research, Vol. 23, No. 12, 15.06.2017, p. 3053-3060.

Research output: Contribution to journalArticle

Wang, Yingbing ; Ayres, Karen L. ; Goldman, Debra A. ; Dickler, Maura N. ; Bardia, Aditya ; Mayer, Ingrid A. ; Winer, Eric ; Fredrickson, Jill ; Arteaga, Carlos L. ; Baselga, José ; Manning, Henry C. ; Mahmood, Umar ; Ulaner, Gary A. / 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. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 12. pp. 3053-3060.
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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 ontherapy. 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.",
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T1 - 18F-fluoroestradiol PET/CT measurement of estrogen receptor suppression during a phase I trial of the novel estrogen receptor-targeted therapeutic GDC-0810

T2 - Using an imaging biomarker to guide drug dosage in subsequent trials

AU - Wang, Yingbing

AU - Ayres, Karen L.

AU - Goldman, Debra A.

AU - Dickler, Maura N.

AU - Bardia, Aditya

AU - Mayer, Ingrid A.

AU - Winer, Eric

AU - Fredrickson, Jill

AU - Arteaga, Carlos L.

AU - Baselga, José

AU - Manning, Henry C.

AU - Mahmood, Umar

AU - Ulaner, Gary A.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - 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 ontherapy. 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.

AB - 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 ontherapy. 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.

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