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Purpose <p>Preclinical models of glucocorticoid receptor (GR)-positive breast cancer (BC) and ovarian cancer (OC) suggest GR activity inhibits chemotherapy-induced apoptosis, and GR antagonism using mifepristone (Mif) enhances cytotoxicity. We performed a phase I trial combining mifepristone, carboplatin (C), gemcitabine (G).</p> Methods <p>A standard “3 + 3” dose escalation scheme was used. Objectives were safety and to determine the maximum tolerated dose (MTD) of Mif + CG. CG was administered intravenously on days 1 and 8 of a 21-day cycle, and mifepristone was administered orally the day before and day of chemotherapy.</p> Results <p>Thirty-one patients enrolled with a median age of 54&#xa0;years; the median prior metastatic regimens were one. Twenty-five patients were evaluable for dose-limiting toxicities (DLT) including 16 BC and 9 OC. Dose was de-escalated to dose level (DL) -1 due to 2/4 neutropenia-related DLT's. DLT definition was updated to exclude hematologic DLTs starting at DL-1. The dose&#xa0; was further de-escalated due to neutropenia, and 2/3, 1/4 and 0/6 patients experienced a DLT at DL-1, DL-2, and DL-3, respectively. At DL-1, prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) was instituted. Dose levels -1 and -2 were expanded to add 3 and 6 patients, respectively, to evaluate tolerability&#xa0; in dose levels -1a and -2a. There were 3 major responses (1CR, 2PR) at DL1, and 1 CR at DL-1. No responses were observed at lower levels.</p> Conclusion <p>The MTD was carboplatin AUC 2  + gemcitabine 600&#xa0;mg/m<sup>2</sup> on&#xa0;D1 and 8 with Mif 300&#xa0;mg D-1 and D1 with pegylated G-CSF administered on day 9 of a 21-day cycle.</p>

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Carboplatin, gemcitabine, and mifepristone for advanced breast and recurrent/persistent epithelial ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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  • Erica M. Stringer-Reasor,
  • Poornima Saha,
  • Masha Kocherginsky,
  • Ricardo Lastra,
  • Gabrielle Baker,
  • Ernst Lenygel,
  • Theodore Karrison,
  • Lauren Olalde,
  • Elizabeth Mokrzycki,
  • Olwen M. Hahn,
  • Philip C. Hoffman,
  • Suzanne D. Conzen,
  • Gini F. Fleming,
  • Rita Nanda

摘要

Purpose

Preclinical models of glucocorticoid receptor (GR)-positive breast cancer (BC) and ovarian cancer (OC) suggest GR activity inhibits chemotherapy-induced apoptosis, and GR antagonism using mifepristone (Mif) enhances cytotoxicity. We performed a phase I trial combining mifepristone, carboplatin (C), gemcitabine (G).

Methods

A standard “3 + 3” dose escalation scheme was used. Objectives were safety and to determine the maximum tolerated dose (MTD) of Mif + CG. CG was administered intravenously on days 1 and 8 of a 21-day cycle, and mifepristone was administered orally the day before and day of chemotherapy.

Results

Thirty-one patients enrolled with a median age of 54 years; the median prior metastatic regimens were one. Twenty-five patients were evaluable for dose-limiting toxicities (DLT) including 16 BC and 9 OC. Dose was de-escalated to dose level (DL) -1 due to 2/4 neutropenia-related DLT's. DLT definition was updated to exclude hematologic DLTs starting at DL-1. The dose  was further de-escalated due to neutropenia, and 2/3, 1/4 and 0/6 patients experienced a DLT at DL-1, DL-2, and DL-3, respectively. At DL-1, prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) was instituted. Dose levels -1 and -2 were expanded to add 3 and 6 patients, respectively, to evaluate tolerability  in dose levels -1a and -2a. There were 3 major responses (1CR, 2PR) at DL1, and 1 CR at DL-1. No responses were observed at lower levels.

Conclusion

The MTD was carboplatin AUC 2  + gemcitabine 600 mg/m2 on D1 and 8 with Mif 300 mg D-1 and D1 with pegylated G-CSF administered on day 9 of a 21-day cycle.