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Ixabepilone, mitoxantrone potentially effective combination for docetaxel-refractory, castration-resistant prostate cancer, new data reveal

Tuesday, April 21 2009 | Comments

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What's This? Ixabepilone, mitoxantrone, and prednisone can be safely given in combination at doses that have demonstrated single-agent action in metastatic castration-resistant prostate cancer (CRPC), but these dose levels require pegfilgrastim to prevent prolonged neutropenia, according to recently published study results.

Currently, there is no standard therapy for the treatment of patients with CRPC whose disease progressed following docetaxel therapy, the authors explained. Ixabepilone and mitoxantrone have both shown some single-agent activity in the CRPC setting, but it is not known if combining the agents will be safe, despite mostly nonoverlapping toxicities, they added.

To determine the safety of the combination plus prednisone and to find the optimal dosing regimen, the researchers conducted a Phase I dose-escalating study in 36 patients with metastatic CRPC and disease progression during or after treatment. Ixabepilone and mitoxantrone were administered every 21 days, along with prednisone, in escalating doses.

Toxicity, specifically dose-limiting toxicity, and disease response were measured.

Grade III diarrhea, prolonged grade IV neutropenia, and grade V neutropenic infection were the dose-limiting toxicities. Grade III/IV neutropenia was seen in 59% of patients, which led the researchers to administer pegfilgrastim on day 2 of subsequent cycles when the highest dose levels of mitoxantrone and ixabepilone were being delivered.

Although the maximum tolerated dose in combination with pegfilgrastim was not exceeded, mitoxantrone 12 mg/m2 of body surface area and ixabepilone 35 mg/m2 every 21 days, pegfilgrastim 6 mg subcutaneously on day 2, and continuous prednisone 5 mg twice per day was found to be the optimal dose recommended for Phase II study.

Two objective responses were seen, and 31% of patients experienced prostate-specific antigen declines of at least 50%.

"[T]he combination of ixabepilone and mitoxantrone with pegfilgrastim is safe and feasible in metastatic CRPC patients who have developed progressive disease despite docetaxel-based therapy," the authors concluded. "Furthermore, this regimen has demonstrated sufficient activity to warrant Phase II testing."

The study was published online ahead of print April 6 in the Journal of Clinical Oncology by Rosenberg J, et al.

This information concerns a use that has not been approved by the Food and Drug Administration.

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