A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study

Rahul Aggarwal, Alan H Bryce, Charles J. Ryan, Andrea Harzstark, Christina Derleth, Won Kim, Terence Friedlander, Amy M. Lin, Tammy Rodvelt-Bagchi, Mallika Dhawan, Li Zhang, Mina Lee, Eric Siebeneck, Jeffrey Hough, Eric J. Small

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. Objective To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. Methods and materials Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25 mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4 mg/m2), given with prednisone 5 mg twice daily. Results A total of 25 patients were enrolled, with median age of 67 (range: 51–78) and prostate-specific antigen of 66.8 ng/ml (range: 3–791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20 mg/m2 plus mitoxantrone 12 mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). Conclusions The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.

Original languageEnglish (US)
Pages (from-to)149.e7-149.e13
JournalUrologic Oncology: Seminars and Original Investigations
Volume35
Issue number4
DOIs
StatePublished - Apr 1 2017

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Mitoxantrone
Castration
Prednisone
Prostatic Neoplasms
Clinical Trials
Drug Therapy
Febrile Neutropenia
Maximum Tolerated Dose
Prostate-Specific Antigen
Neutropenia
Disease-Free Survival
cabazitaxel
Sepsis
Survival
Therapeutics
Neoplasms

Keywords

  • Cabazitaxel
  • Castration-resistant
  • Chemotherapy
  • Clinical trial
  • Metastatic
  • Mitoxantrone
  • Phase 1
  • Prednisone
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer : A department of defense prostate cancer clinical trials consortium study. / Aggarwal, Rahul; Bryce, Alan H; Ryan, Charles J.; Harzstark, Andrea; Derleth, Christina; Kim, Won; Friedlander, Terence; Lin, Amy M.; Rodvelt-Bagchi, Tammy; Dhawan, Mallika; Zhang, Li; Lee, Mina; Siebeneck, Eric; Hough, Jeffrey; Small, Eric J.

In: Urologic Oncology: Seminars and Original Investigations, Vol. 35, No. 4, 01.04.2017, p. 149.e7-149.e13.

Research output: Contribution to journalArticle

Aggarwal, Rahul ; Bryce, Alan H ; Ryan, Charles J. ; Harzstark, Andrea ; Derleth, Christina ; Kim, Won ; Friedlander, Terence ; Lin, Amy M. ; Rodvelt-Bagchi, Tammy ; Dhawan, Mallika ; Zhang, Li ; Lee, Mina ; Siebeneck, Eric ; Hough, Jeffrey ; Small, Eric J. / A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer : A department of defense prostate cancer clinical trials consortium study. In: Urologic Oncology: Seminars and Original Investigations. 2017 ; Vol. 35, No. 4. pp. 149.e7-149.e13.
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abstract = "Background Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-na{\"i}ve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. Objective To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. Methods and materials Patients with chemotherapy-na{\"i}ve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25 mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4 mg/m2), given with prednisone 5 mg twice daily. Results A total of 25 patients were enrolled, with median age of 67 (range: 51–78) and prostate-specific antigen of 66.8 ng/ml (range: 3–791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20 mg/m2 plus mitoxantrone 12 mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32{\%}), febrile neutropenia (n = 5; 20{\%}), and thrombocytopenia (n = 4; 16{\%}). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50{\%} from baseline was observed in 15 patients (60{\%}). Objective responses were observed in 10/14 (71{\%}) evaluable patients. The median radiographic progression-free survival was 14.5 months (95{\%} CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95{\%} CI: 14.3-NR). Conclusions The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.",
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T1 - A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer

T2 - A department of defense prostate cancer clinical trials consortium study

AU - Aggarwal, Rahul

AU - Bryce, Alan H

AU - Ryan, Charles J.

AU - Harzstark, Andrea

AU - Derleth, Christina

AU - Kim, Won

AU - Friedlander, Terence

AU - Lin, Amy M.

AU - Rodvelt-Bagchi, Tammy

AU - Dhawan, Mallika

AU - Zhang, Li

AU - Lee, Mina

AU - Siebeneck, Eric

AU - Hough, Jeffrey

AU - Small, Eric J.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Background Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. Objective To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. Methods and materials Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25 mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4 mg/m2), given with prednisone 5 mg twice daily. Results A total of 25 patients were enrolled, with median age of 67 (range: 51–78) and prostate-specific antigen of 66.8 ng/ml (range: 3–791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20 mg/m2 plus mitoxantrone 12 mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). Conclusions The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.

AB - Background Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. Objective To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. Methods and materials Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25 mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4 mg/m2), given with prednisone 5 mg twice daily. Results A total of 25 patients were enrolled, with median age of 67 (range: 51–78) and prostate-specific antigen of 66.8 ng/ml (range: 3–791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20 mg/m2 plus mitoxantrone 12 mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). Conclusions The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.

KW - Cabazitaxel

KW - Castration-resistant

KW - Chemotherapy

KW - Clinical trial

KW - Metastatic

KW - Mitoxantrone

KW - Phase 1

KW - Prednisone

KW - Prostate cancer

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