Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: November 7, 2005
Presenter: Sandra M. Swain, MD Presenter's Affiliation: National Cancer Institute Type of Session: Scientific
Microtubules are formed from a protein called tubulin.
Microtubules form the skeleton of cells, and have to be broken down for a cell to divide.
Certain chemotherapy drugs are actually microtubule-stabilizing agents, like paclitaxel, docetaxel, and the epothilones.
Epothilones are a class of microtubule-stabilizing agents that were originally discovered in an African myxobacteria species known as Sorangium cellulosum.
The first epothilone that was discovered is epothilone B.
Ixabepilone is a semi-synthetic analog of epothilone B.
Epothilones are strong promoters of microtubulin polymerization.
Epothilone B has tubulin polymerizing activity that is 2-10 times stronger than paclitaxel.
Many preclinical studies have demonstrated that ixabepilone shows activity in cell lines that are resistant to paclitaxel.
Materials and Methods
A phase I trial was performed that used a daily regimen of 6 mg/m2 of ixabepilone x 5 days q 3 weeks in metastatic and locally advanced breast cancer, and patients were treated until disease progression.
A 22% response rate was seen, and all patients had received prior taxane therapy.
A similar trial that looked at patients who were taxane-naïve found an almost 40% response rate (unpublished data as per Dr. Swain).
In the NCI-0229 phase II trial, only 16% of patients had grade 3 or 4 neutropenia with ixabepilone.
Steroids and anti-emetics are not required before giving this drug.
There was a 3% incidence of grade 3 peripheral neuropathy with ixabepilone (no cases of grade 4), and this compares favorably to paclitaxel, which can have up to a 20% grade 3 neuropathy rate.
A variety of neurotoxicity assessment tools were employed including a Semmes Weinstein filament test, a Grooved Peg Board Test, a Jebsen Test of Hand Function, a questionnaire, balance testing, nerve conduction studies, and physical examination.
A matched pair analysis showed that the Grooved Peg Board Test and the Jebsen Test of Hand Function were predictive for which patients were going to develop neuro-toxicity based on their baseline evaluation.
For example, patients who scored greater than 55 on the Jebsen Test of Hand Function before receiving ixabepilone were likely to develop neuropathy within 4 months of treatment.
There was a low incidence of neuropathy with ixabepilone using a schedule of daily drug x 5 days, q 3 week schedule.
The Grooved Peg Board Test and the Jebsen Test of Hand Function most often correlated and predicted ixabepilone-induced grade 2-3 neuropathy.
Post-translational modification with acetylation occurs to the tubulin proteins that form microtubules, and this causes them to become stabilized microtubules.
Models suggest that the more stabilization you have of microtubules with acetlyation, the more sensitive the cells are to microtubule-stabilizing agents like ixabepilone.
At the NCI, immunohistochemistry revealed that patients who had a response to ixabepilone had significant acetylation of microtubules after 2 cycles, whereas patients who did not have a response never developed a pattern of acetlyation.
There have been 2 randomized phase III trials of ixabepilone, one where patients were pretreated with an antracycline but not a taxane, and another where patients saw both anthracyclines and taxanes before ixabepilone.
In the taxane-naïve trial, a 44% response rate was seen.
In the taxane-pretreated trial, only a 12% response rate was seen.
Ixabepilone had good clinical activity in heavily pretreated breast cancer patients (RR=22%).
Ixabepilone caused grade 3/4 sensory peripheral neuropathy in 3% of patients.
Baseline neurological functional tests may predict grade >=2 peripheral neuropathy.
Acetylation of tubulin may predict for a response to ixabepilone.
Many studies are ongoing with other agents including carboplatin, capecitabine, and trastuzumab.
In vivo data shows a significant interaction between ketoconazole and ixabepilone, as ixabepilone is a potent CYP3A4 inhibitor.
Advantages to ixabepilone include: no need for steroid premeditation, minimal hypersensitivity, and minimal nausea and vomiting
Dr. Swain presented an interesting talk on a novel chemotherapeutic agent, ixabepilone.It is important to remember the power of cytotoxic chemotherapeutics, especially with all of the excitement surrounding the new biologic agents.In the case of ixabepilone, it appears that we have found an active agent that may have a slightly better side effect profile than the current taxanes.We only have limited data on this drug, but it is currently being tested in a variety of places.One of the dangers of making conclusions about a new compound using only response rate data is that response rates may not always be good predictors for survival outcomes.A radiologist’s conclusion that tumor burden has decreased in size is not always going to predict for an improvement in disease-free or overall survival.With longer follow-up and further trials, we will hopefully have the data we need to feel comfortable using this agent outside of a clinical trial.It will also likely be tested earlier in the disease process, such as in the adjuvant or preoperative setting.