Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer

Dana Rathkopf, Michael A. Carducci, Michael J. Morris, Susan F. Slovin, Mario A. Eisenberger, Roberto Pili, Samuel R. Denmeade, Moshe Kelsen, Tracy Curley, Melinda Halter, Connie Collins, Martin Fleisher, Glenn Heller, Sharyn D. Baker, Howard I. Scher

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Abstract

Purpose: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. Patients and Methods: Noncastrate patients with ≤ 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m2), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m2), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; ≤ 0.05, ≤ 0.5, or ≤ 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results: A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles. Conclusion: The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.

Original languageEnglish (US)
Pages (from-to)2959-2965
Number of pages7
JournalJournal of Clinical Oncology
Volume26
Issue number18
DOIs
StatePublished - 2008
Externally publishedYes

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docetaxel
Androgens
Prostatic Neoplasms
Testosterone
Leuprolide
Cytochrome P-450 CYP3A
Febrile Neutropenia
Castration
Incidence
Prostate-Specific Antigen
Prostatectomy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Rathkopf, D., Carducci, M. A., Morris, M. J., Slovin, S. F., Eisenberger, M. A., Pili, R., ... Scher, H. I. (2008). Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. Journal of Clinical Oncology, 26(18), 2959-2965. https://doi.org/10.1200/JCO.2007.15.1928

Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. / Rathkopf, Dana; Carducci, Michael A.; Morris, Michael J.; Slovin, Susan F.; Eisenberger, Mario A.; Pili, Roberto; Denmeade, Samuel R.; Kelsen, Moshe; Curley, Tracy; Halter, Melinda; Collins, Connie; Fleisher, Martin; Heller, Glenn; Baker, Sharyn D.; Scher, Howard I.

In: Journal of Clinical Oncology, Vol. 26, No. 18, 2008, p. 2959-2965.

Research output: Contribution to journalArticle

Rathkopf, D, Carducci, MA, Morris, MJ, Slovin, SF, Eisenberger, MA, Pili, R, Denmeade, SR, Kelsen, M, Curley, T, Halter, M, Collins, C, Fleisher, M, Heller, G, Baker, SD & Scher, HI 2008, 'Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer', Journal of Clinical Oncology, vol. 26, no. 18, pp. 2959-2965. https://doi.org/10.1200/JCO.2007.15.1928
Rathkopf, Dana ; Carducci, Michael A. ; Morris, Michael J. ; Slovin, Susan F. ; Eisenberger, Mario A. ; Pili, Roberto ; Denmeade, Samuel R. ; Kelsen, Moshe ; Curley, Tracy ; Halter, Melinda ; Collins, Connie ; Fleisher, Martin ; Heller, Glenn ; Baker, Sharyn D. ; Scher, Howard I. / Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 18. pp. 2959-2965.
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abstract = "Purpose: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. Patients and Methods: Noncastrate patients with ≤ 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m2), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m2), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; ≤ 0.05, ≤ 0.5, or ≤ 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results: A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13{\%} v 0{\%}). The 16{\%} incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50{\%} reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles. Conclusion: The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.",
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T1 - Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer

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AU - Carducci, Michael A.

AU - Morris, Michael J.

AU - Slovin, Susan F.

AU - Eisenberger, Mario A.

AU - Pili, Roberto

AU - Denmeade, Samuel R.

AU - Kelsen, Moshe

AU - Curley, Tracy

AU - Halter, Melinda

AU - Collins, Connie

AU - Fleisher, Martin

AU - Heller, Glenn

AU - Baker, Sharyn D.

AU - Scher, Howard I.

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N2 - Purpose: We evaluated rapid androgen cycling in combination with docetaxel for men with progressive noncastrate prostate cancers. Patients and Methods: Noncastrate patients with ≤ 6 months of hormone therapy were eligible. Cohort 1 (62 patients) received six 28-day cycles of docetaxel (75 mg/m2), leuprolide, and 7 days of topical testosterone. Cohort 2 (38 patients) received nine 21-day cycles of docetaxel (70 mg/m2), leuprolide, and 3 days of testosterone. The primary end point was the proportion of patients at 18 months who achieved noncastrate testosterone levels (> 150 ng/dL) and an undetectable prostate-specific antigen (PSA; ≤ 0.05, ≤ 0.5, or ≤ 2.0 ng/mL with prior prostatectomy, radiation therapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results: A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% v 0%). The 16% incidence of febrile neutropenia was higher than that observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the noncastrate group. There was no alteration in CYP3A4 activity (P = .87) or docetaxel clearance (P = .88) between cycles. Conclusion: The undetectable PSA end point allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles after a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with noncastrate versus castrate testosterone levels.

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