Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Rosenberg, Jonathan E.; Ryan, Charles J.; Weinberg, Vivian; Smith, David C.; Hussain, Maha; Beer, Tomasz M.; Ryan, Christopher W.; Mathew, Paul; Pagliaro, Lance C.; Harzstark, Andrea L.; Sharib, Jeremy M.; Small, Eric J.

doi:10.1200/jco.2008.19.8002

Cited by 34 publications

(16 citation statements)

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“…On the basis of results from a randomized phase 2 study suggesting that ixabepilone and mitoxantrone with prednisone have noncross-resistance and a phase 1 trial of the ixabepilone and mitoxantrone with prednisone combination demonstrating surprisingly high activity, the present phase 2 trial was undertaken. 5 The ixabepilone and mitoxantrone with prednisone regimen was found to have significant activity, with a PSA response proportion of 45%, and an equally promising objective response proportion of 22%. The overall survival in this group of patients was 12.5 months.…”

Section: Discussionmentioning

confidence: 98%

“…2 Mitoxantrone with prednisone is often used as second-line therapy but is associated with a PSA response rate of only 20%. 5 Ixabepilone also has a disappointing PSA response rate of 17% after docetaxel. The objective response rates associated with ixabepilone monotherapy and mitoxantrone with prednisone after docetaxel are also low at 4% and 10%, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Harzstark

Rosenberg

Weinberg

et al. 2010

Cancer

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BACKGROUND: Mitoxantrone plus prednisone and ixabepilone each have modest activity as monotherapy for second-line chemotherapy in patients with docetaxel-refractory castration-resistant prostate cancer. Clinical noncrossresistance was previously observed. Phase 1 testing determined the maximum tolerated dose and dose-limiting toxicities with the combination regimen; a phase 2 study was conducted to evaluate the activity of the combination. METHODS: Patients with metastatic progressive castration-resistant prostate cancer during or after 3 or more cycles of taxane-based chemotherapy enrolled in a phase 2 multicenter study of ixabepilone 35 mg/m 2 and mitoxantrone 12 mg/m 2 administered on Day 1 every 21 days with pegfilgrastim support, along with prednisone 5 mg twice daily. Patients were evaluated for disease response and toxicity. RESULTS: Results are reported for the 56 evaluable patients. Twenty-five (45%; 95% confidence interval [CI], 31%-59%) experienced confirmed !50% prostate-specific antigen (PSA) declines, 33 (59%; 95% CI, 45%-72%) experienced confirmed !30% PSA declines, and 8 of 36 patients (22%; 95% CI, 10%-39%) with measurable disease experienced objective responses. Median time to PSA or objective progression was 4.4 months (95% CI, 3.5-5.6), and median progression-free survival was also 4.4 months (95% CI, 3.0-6.0). Median overall survival was 12.5 months (95% CI, 10.2-15.9). Thirty-two percent of patients experienced grade 3 of 4 neutropenia, and 11% experienced grade 3 or higher neutropenic infections, including 1 treatment-related death. Grade 2 and 3 neuropathy occurred in 11% and 12.5% of patients, respectively. CONCLUSIONS: These results suggest that the combination of ixabepilone and mitoxantrone is both feasible and active in castration-resistant prostate cancer and requires dosing with pegfilgrastim. Cancer 2011;117:2419-25.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Harzstark

Rosenberg

Weinberg

et al. 2010

Cancer

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“…Phase II trials of the epothilone B analogue ixabepilone in patients with chemotherapy-naïve HRPC have shown PSA responses both in single agent therapy (3348%) and in combination with estramustine (69%) [Rosenberg et al 2007;Bhandari and Hussain, 2005;Hussain et al 2005]. These agents were therefore combined in a phase I study [Rosenberg et al 2009] which demonstrated significant anticancer activity and manageable tolerability, confirmed in a recently reported phase II trial at ASCO 2009 [Small et al 2009a].…”

Section: New Chemotherapeutic Agentsmentioning

confidence: 99%

Review: Castration-resistant prostate cancer: new science and therapeutic prospects

Bellmunt¹,

2010

Ther Adv Med Oncol

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There is a growing number of new therapies targeting different pathways that will revolutionize patient management strategies in castration-resistant prostate cancer (CRPC) patients. Today there are more clinical trial options for CRPC treatment than ever before, and there are many promising agents in late-stage clinical testing. The hypothesis that CRPC frequently remains driven by a ligand-activated androgen receptor (AR) and that CRPC tissues exhibit substantial residual androgen levels despite gonadotropin-releasing hormone therapy, has led to the evaluation of new oral compounds such as abiraterone and MDV 3100. Their results, coupled with promising recent findings in immunotherapy (eg sipuleucel-T) and with agents targeting angiogenesis (while awaiting the final results of the CALGB trial 90401) will most probably impact the management of patients with CRPC in the near future.Other new promising agents need further development. With our increased understanding of the biology of this disease, further trial design should incorporate improved patient selection so that patient populations are those who may be most likely to benefit from treatment.

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“…Because of the different mechanisms of action and the lack of crossresistance between these regimens, Harzstark and colleagues investigated the regimens' additive or synergistic activity when administered together in men with metastatic CRPC who had progressed after three or more cycles of docetaxel [56,57]. In a phase I trial, patients received escalating doses of i.v.…”

Section: Docetaxel-resistant Crpcmentioning

confidence: 99%

“…In a phase I trial, patients received escalating doses of i.v. ixabepilone (20 -35 mg/m 2 ) plus mitoxantrone (8 -12 mg/m 2 ) on day 1 of a 21-day cycle plus continuous prednisone (5 mg twice daily) to define a maximum-tolerated dose for the combination [57]. Of the six patients treated with ixabepilone at a dose of 30 mg/m 2 plus mitoxantrone at a dose of 12 mg/m 2 , two experienced DLTs (grade 3 diarrhea and grade 4 neutropenia), and of the five patients treated with ixabepilone at a dose of 35 mg/m 2 plus mitoxantrone at a dose of 12 mg/ m 2 , another two experienced DLTs (both grade 4 neutropenia).…”

Section: Docetaxel-resistant Crpcmentioning

confidence: 99%

The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

Dorff

Gross

2011

The Oncologist

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The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy and durability with currently available therapeutics. The epothilones represent a novel class of anticancer therapy that stabilizes microtubules, causing cell death and tumor regression in preclinical models. The structure of the tubulin-binding site for epothilones is distinct from that of the taxanes. Moreover, preclinical studies suggest nonoverlapping mechanisms of resistance between epothilones and taxanes. In early-phase studies in patients with CRPC, treatment with ixabepilone, a semisynthetic analog of epothilone B, induced objective responses and prostatespecific antigen declines in men previously progressing on docetaxel-based regimens. Clinical activity has been observed in nonrandomized trials for patients with CRPC using ixabepilone in the first-and second-line settings as a single agent and in combination with estramustine. Patupilone and sagopilone were also shown to have promising efficacy in phase II clinical trials of patients with CRPC. All three epothilones appear to be well tolerated, with modest rates of neutropenia and peripheral neuropathy. The lack of crossresistance between epothilones and taxanes may allow sequencing of these agents. Evaluating epothilones in phase III comparative trials would provide much-needed insight into their potential place in the management of patients with CRPC. The Oncologist 2011;16:1349 -1358

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Phase I Study of Ixabepilone, Mitoxantrone, and Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Therapy: A Study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Abstract: These results suggest that the combination of ixabepilone and mitoxantrone is feasible and active in CRPC and requires dosing with pegfilgrastim.

Cited by 34 publications

References 12 publications

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Ixabepilone, mitoxantrone, and prednisone for metastatic castration‐resistant prostate cancer after docetaxel‐based therapy

Review: Castration-resistant prostate cancer: new science and therapeutic prospects

The Epothilones: New Therapeutic Agents for Castration-Resistant Prostate Cancer

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