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a new class of drug (epothilones--antitubulins) for those running out of options
Epothilones are a new class of anticancer drugs that have shown activity in taxane-resistant disease. Ixabepilone, an epothilone derivative in the later stages of clinical development, has demonstrated antitumor activity in heavily pretreated breast cancer patients, including disease resistant to anthracycline and taxane therapy. The most common adverse events associated with ixabepilone are sensory neuropathy and neutropenia. Neurotoxicity appears to be less severe in patients treated with ixabepilone than in patients treated with weekly paclitaxel.
In a recent phase II clinical trial (NCI-0229), patients with measurable metastatic or locally advanced incurable breast cancer previously treated with taxane therapy had combined CR and PR rates to ixabepilone of 22%, with stable disease observed in 38%. Other data from phase II trials demonstrated that ixabepilone was active in patients with metastatic breast cancer previously treated with anthracyclines in the adjuvant or neoadjuvant setting and in patients who were refractory to taxane therapy.
Randomized phase III trials are currently underway to evaluate the ixabepilone in combination with capecitabine for patients with advanced breast cancer. Phase II trials of ixabepilone in advanced colorectal cancer and progressive metastatic prostate cancer have recently been reported. Other epothilones currently in phase I/II clinical development include patupilone (EPO906) and KOS-862. These agents are structurally similar to ixabepilone but appear to have different activity and toxicity profiles.
Ixabepilone is also being evaluated in combination with trastuzumab in patients with HER2-positive breast cancer. One phase II trial (study chair: Stacy L. Moulder, MD) combines carboplatin with trastuzumab in addition to ixabepilone and will include patients with stage IV breast cancer, recurrent breast cancer, and male gender.[19] Patients will receive trastuzumab on Days 1, 8, 15, and 22, with ixabepilone and carboplatin given on Days 1, 8, and 15. Treatment is repeated every 28 days for up to 6 courses if toxicity is deemed acceptable. The projected accrual is 10-60 patients over 6 months and the primary objective is to determine response rate.
In addition, ixabepilone plus trastuzumab is being evaluated in an ongoing phase II study (principal investigator: Craig Bunnell, MD, Dana Farber) including women with stage IV or recurrent breast cancer.[20] Patients receive trastuzumab over 30-90 minutes and ixabepilone over 3 hours on Day 1. Cycles are repeated every 21 days in the absence of disease progression or unacceptable toxicity. Patients are being stratified according to prior trastuzumab therapy, and a total of 60 patients (30 per stratified group) is planned for accrual, including a cohort of patients who have received no prior treatment for metastatic breast cancer (except hormone therapy) and another cohort that has received prior chemotherapy + trastuzumab. The primary objective of this trial is to determine response rate.
Ixabepilone is also being evaluated in combination with liposomal doxorubicin in patients with metastatic breast cancer.[21] Included in this phase I/II trial (principal investigator: Ellen Chuang, MD, Weill Cornell) are patients with previously treated metastatic breast, ovarian epithelial, primary peritoneal cavity, or fallopian tube cancer. The investigators plan to enroll 20-50 patients. All study entrants will receive liposomal pegylated doxorubicin and ixabepilone at the maximum tolerated dose determined in the phase I portion of the trial and will be followed for up to 2 years after treatment to determine safety and efficacy.
These trials promise to elucidate the benefits of ixabepilone in patients with metastatic breast cancer. Thus far, this first in class novel cytotoxic agent can be administered without steroid premedication and may be safer to given than taxanes. Furthermore, ixabepilone has shown efficacy in phase I and phase II studies of heavily pretreated patients with metastatic breast cancer, including taxane pretreated patients, and appears to be active in combination with capecitabine.
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