A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer

Rita Nanda*, Erica M. Stringer-Reasor, Poornima Saha, Masha Kocherginsky, Jean Gibson, Bernadette Libao, Philip C. Hoffman, Elias Obeid, Douglas E. Merkel, Galina Khramtsova, Maxwell Skor, Thomas Krausz, Ronald N. Cohen, Mark J. Ratain, Gini F. Fleming, Suzanne D. Conzen

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Purpose: Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods: A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results: Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions: GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.

Original languageEnglish (US)
Article number947
JournalSpringerPlus
Volume5
Issue number1
DOIs
StatePublished - Dec 1 2016

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Mifepristone
Glucocorticoid Receptors
Nanoparticles
Breast Neoplasms
Neutropenia
Pharmacokinetics
Albumin-Bound Paclitaxel
Drug Therapy
Clinical Trials, Phase I
Hydrocortisone
130-nm albumin-bound paclitaxel
Neoplasms
Intercellular Signaling Peptides and Proteins
Cell Death
Placebos
Staining and Labeling
Recurrence

ASJC Scopus subject areas

  • General

Cite this

Nanda, Rita ; Stringer-Reasor, Erica M. ; Saha, Poornima ; Kocherginsky, Masha ; Gibson, Jean ; Libao, Bernadette ; Hoffman, Philip C. ; Obeid, Elias ; Merkel, Douglas E. ; Khramtsova, Galina ; Skor, Maxwell ; Krausz, Thomas ; Cohen, Ronald N. ; Ratain, Mark J. ; Fleming, Gini F. ; Conzen, Suzanne D. / A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer. In: SpringerPlus. 2016 ; Vol. 5, No. 1.
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title = "A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer",
abstract = "Purpose: Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods: A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results: Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions: GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.",
author = "Rita Nanda and Stringer-Reasor, {Erica M.} and Poornima Saha and Masha Kocherginsky and Jean Gibson and Bernadette Libao and Hoffman, {Philip C.} and Elias Obeid and Merkel, {Douglas E.} and Galina Khramtsova and Maxwell Skor and Thomas Krausz and Cohen, {Ronald N.} and Ratain, {Mark J.} and Fleming, {Gini F.} and Conzen, {Suzanne D.}",
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Nanda, R, Stringer-Reasor, EM, Saha, P, Kocherginsky, M, Gibson, J, Libao, B, Hoffman, PC, Obeid, E, Merkel, DE, Khramtsova, G, Skor, M, Krausz, T, Cohen, RN, Ratain, MJ, Fleming, GF & Conzen, SD 2016, 'A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer', SpringerPlus, vol. 5, no. 1, 947. https://doi.org/10.1186/s40064-016-2457-1

A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer. / Nanda, Rita; Stringer-Reasor, Erica M.; Saha, Poornima; Kocherginsky, Masha; Gibson, Jean; Libao, Bernadette; Hoffman, Philip C.; Obeid, Elias; Merkel, Douglas E.; Khramtsova, Galina; Skor, Maxwell; Krausz, Thomas; Cohen, Ronald N.; Ratain, Mark J.; Fleming, Gini F.; Conzen, Suzanne D.

In: SpringerPlus, Vol. 5, No. 1, 947, 01.12.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer

AU - Nanda, Rita

AU - Stringer-Reasor, Erica M.

AU - Saha, Poornima

AU - Kocherginsky, Masha

AU - Gibson, Jean

AU - Libao, Bernadette

AU - Hoffman, Philip C.

AU - Obeid, Elias

AU - Merkel, Douglas E.

AU - Khramtsova, Galina

AU - Skor, Maxwell

AU - Krausz, Thomas

AU - Cohen, Ronald N.

AU - Ratain, Mark J.

AU - Fleming, Gini F.

AU - Conzen, Suzanne D.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Purpose: Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods: A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results: Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions: GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.

AB - Purpose: Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods: A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results: Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions: GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.

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U2 - 10.1186/s40064-016-2457-1

DO - 10.1186/s40064-016-2457-1

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