Original article
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

https://doi.org/10.1016/j.urolonc.2016.11.005Get rights and content

Highlights

  • A phase 1 study of cabazitaxel, mitoxantrone, and prednisone in mCRPC was performed.

  • The approved single-agent doses were safely combined.

  • Durable tumor responses were observed in most patients, including those with high-risk disease features.

  • Further clinical investigation of a taxane plus mitoxantrone is warranted in aggressive variant mCRPC.

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.

Introduction

Metastatic castration-resistant prostate cancer (mCRPC) is the fifth leading cause of cancer death among men worldwide, with an estimated 307,000 deaths in 2012 [1]. Taxane-based chemotherapy remains a cornerstone of treatment for advanced prostate cancer. In contrast to the substantial survival benefit observed with taxane-based chemotherapy in the metastatic hormone-sensitive setting [2], treatment with single-agent docetaxel in mCRPC has demonstrated only a modest survival benefit compared to older chemotherapeutic regimens such as mitoxantrone [3]. Additionally, multiple attempts to combine docetaxel with investigational agents have failed to improve survival compared to docetaxel monotherapy [4], [5], [6], [7], [8], [9], [10], [11]. Thus, new combination treatment approaches, including potentially combining agents with proven single-agent activity, are needed to improve outcomes with front-line chemotherapy in mCRPC.

Cabazitaxel is a semisynthetic taxane derivative that has significant antitumor activity in mCRPC at both the 25 and 20 mg/m2 dose levels, with the former approved for use in mCRPC that has progressed on prior docetaxel [12]. Front-line and second-line phase 3 studies comparing cabazitaxel 25 mg/m2, 20 mg/m2 cabazitaxel, and docetaxel 75 mg/m2, all delivered on an every 3-week interval, have recently been reported to demonstrate similar survival outcomes [13], [14]. Mitoxantrone is an anthracenedione approved for use in mCRPC on the basis of pain palliation, which has also demonstrated significant antitumor activity including prostate-specific antigen (PSA) and objective tumor responses in prior clinical studies [15], [16]. Given the largely nonoverlapping mechanisms of action and toxicity profile of these 2 agents, aside from potential additive myelosuppression that may be managed with prophylactic use of growth factors, and demonstrating single-agent activity with both agents, additional antitumor activity may be achieved with combination therapy with an acceptable safety profile.

Consequently, a multicenter phase 1 trial was conducted through the Prostate Cancer Clinical Trials Consortium to determine the maximally tolerated dose (MTD) and recommended phase 2 dose of cabazitaxel, mitoxantrone, and prednisone in patients with chemotherapy-naïve mCRPC.

Section snippets

Study population

Eligible patients had histologically confirmed prostate adenocarcinoma with evidence of progressive, metastatic, castration-resistant disease by PCWG2 criteria and a minimum serum PSA level of 2 ng/ml [17]. An Eastern Cooperative Oncology Group performance status of 0 to 2 was required, as was adequate hematologic, renal, and hepatic function. Patients were required to have a castrate level of testosterone (<50 ng/dl). Cardiac ejection fraction was required to be greater than institutional lower

Baseline characteristics and patient disposition

A total of 25 patients were enrolled between June 2012 and February 2016. Baseline characteristics of the patients are shown in Table 1. Characteristics were largely representative of a first-line chemotherapy population in mCRPC, with approximately 25% of patients with visceral metastases and 33% of patients with requirement for opioid analgesics for cancer-associated pain. Most patients (72%) had received abiraterone before enrollment. In contrast, owing to the timelines in which the study

Discussion

In the current phase 1 study, the approved single-agent dose of mitoxantrone (12 mg/m2) administered in combination with cabazitaxel 20 mg/m2, both delivered on day 1 of an every 21-day cycle, was established as the maximally tolerated and recommended phase 2 dose, in conjunction with daily prednisone and primary prophylactic growth factor support. The treatment combination produced objective and PSA responses in 71% and 60% of patients, respectively, and responses were durable in most patients.

Acknowledgments

This work was supported by Sanofi-Aventis. The funding source was not involved with study design, data analysis and interpretation, or preparation of the manuscript.

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