This article is more than 5 years old. Information may no longer be current.
Ixabepilone: a new spin on an old idea
Columnist discusses this principal agent in a novel class of drugs approved for treatment of metastatic breast cancer.
Anthracyclines and taxanes have long been described as the most active classes of chemotherapy against breast cancer. With incorporation of these agents into early stage breast cancer treatment regimens, researchers have conducted extensive investigation in pursuit of novel cytotoxic agents that have antitumor activity in anthracycline- and taxane-resistant disease. Capecitabine had been the only FDA-approved agent for the treatment of anthracycline- and taxane-resistant metastatic breast cancer. In June 2007, that changed when the FDA approved ixabepilone for the treatment of metastatic breast cancer.
|
Ixabepilone (Ixempra, Bristol-Myers Squibb) is the principal agent in a new class of drugs called the epothilones. Epothilones work by stabilizing microtubules, arresting cell division at the G2M phase, and ultimately inducing cell death much like the taxanes. Despite having a similar mechanism of action to the taxanes, the epothilones are disparate in structure, allowing them to overcome resistance to taxanes. Epothilones bind to a unique site on beta-microtubules and are able to overcome traditional taxane-resistance mechanisms such as mutations (isoforms) in beta-microtubule and p-glycoprotein–mediated drug efflux pumps (eg, MDR-1).
Clinical trials with ixabepilone
Ixabepilone has been approved for use with capecitabine (Xeloda, Roche) for the treatment of metastatic or locally advanced breast cancer after failure of an anthracycline and a taxane. It is also approved for use as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane and capecitabine. FDA approval of ixabepilone was based on a series of phase-2 clinical trials and one phase-3, randomized, open-label study.
Results from phase-2 studies with ixabepilone demonstrated clinical activity against a variety of tumor types such as lung, ovarian, prostate, renal carcinoma, non-Hodgkin’s lymphoma and breast cancer. The results from the phase-2 studies with ixabepilone in breast cancer have demonstrated clinical benefit in those who have been previously treated and who have resistant disease despite standard therapies, as well as synergistic antitumor activity with capecitabine. Some researchers have investigated multiday treatment regimens (eg, daily × 3 to 5 days) with limited efficacy and exaggerated toxicity (eg, neurotoxicity, myelosuppression). Therefore, a single-dose regimen given every three weeks has become the standard dose for ixabepilone administered as a single agent or in combination with capecitabine.
In one phase-2, multicenter study, researchers evaluated the efficacy and safety of ixabepilone in patients with metastatic breast cancer resistant to standard therapy. Eligible patients had tumor progression while on an anthracycline, taxane and capecitabine. Ixabepilone was given at a dose of 40 mg/m2 intravenously as a single agent through three hours on day one of a 21-day cycle (n=126). The objective response rate was 12%, and 13% of patients had stable disease for more than six months. The progression-free survival was 3.1 months and median overall survival was 8.6 months. Peripheral neuropathy was the most common nonhematologic adverse effect reported and severe (grade 3 or 4) neutropenia was reported in 54% of patients. However, only four patients experienced neutropenic fever and three patients had an infection during neutropenia.
The promising results of the phase-2 trials gave way to a large, international, randomized phase-3 trial. In this trial, ixabepilone with capecitabine was compared with capecitabine alone. Eligible patients included those with locally advanced or metastatic breast cancer who had been previously treated with or were resistant to anthracyclines and taxanes. Ixabepilone was given at a dose of 40 mg/m2 intravenously during three hours on day one of a 21-day cycle. Capecitabine was administered at either 2,000 mg/m2 per day orally on days one to 14 of a 21-day cycle in combination with ixabepilone, or 2,500 mg/m2 per day for 14 days as monotherapy (n=752).
The addition of ixabepilone to capecitabine increased progression-free survival (HR=0.75; 95% CI, 0.64-0.88; stratified log-rank P=.0003) with a 25% reduction in the estimated risk for disease progression compared with monotherapy. Median progression-free survival was prolonged to 5.8 months (95% CI, 5.45-6.97) with the addition of ixabepilone from 4.2 months with capecitabine alone (95% CI, 3.81-4.50) — an increase of 40%.
Toxicity profile
The adverse effects of ixabepilone mirror those of the taxanes in many ways and appear to be schedule-dependent with more neurotoxicity seen with shorter infusions (eg, one hour infusions). The most common toxicities reported in clinical trials with single-agent ixabepilone administered to heavily pretreated patients were neutropenia/leucopenia, peripheral neuropathy, fatigue/asthenia, myalgias/arthralgias and alopecia. The use of myeloid growth factor support upfront should be considered in individual patients who are at high risk for complications related to neutropenia. Many patients had pre-existing neuropathy ( In the combination phase-3 trial mentioned above, 18% of patients receiving combination therapy had to discontinue therapy secondary to drug toxicity, vs. 7% of those receiving monotherapy. One of the sharpest differences in adverse effects between the two groups was peripheral neuropathy, which appears in 67% (grade 3 or 4; 21%) of patients receiving combination therapy compared to 16% (grade 3 or 4; 0%) of patients receiving monotherapy. Neuropathy was managed with dose reductions in most cases. Compared with capecitabine alone, patients in the combination group were more likely to experience neutropenia (89% vs. 43%), febrile neutropenia (19 patients vs. 2 patients) and neutropenia-related deaths (5 patients vs. 0 patients). All neutropenia-related deaths in the combination arm occurred in patients with liver dysfunction at baseline (grade >2 liver function tests: aspartate transaminase or alanine transaminase >2.5 × upper limit of normal or bilirubin >1.5 × upper limit of normal). Patients who experienced a neutropenic event were managed with subsequent dose reductions, due to the recommendation that myeloid growth factors be avoided during capecitabine therapy (days 1 to 14). Traditional capecitabine-related toxicities (eg, hand–foot syndrome, diarrhea, and mucositis) were not more frequent with the combination. Like the traditional taxanes, ixabepilone is extensively metabolized by the CYP450 system and therefore may be susceptible to a variety of drug interactions. Inducers of the enzymes will lead to decreased exposure to ixabepilone (eg, less antitumor activity and toxicity) and inhibitors to increased exposures (eg, more toxicity), respectively. The manufacturer recommends an empiric dose reduction for patients on strong inhibitors of CYP3A4. However, sound clinical judgment should always be used to determine the best dosing strategy for individual patients. Patients with hepatic impairment may experience increased exposure to the drug and increased toxicity, possibly necessitating a reduction in the dose. Ixabepilone use with capecitabine is contraindicated in patients with AST/ALT >2.5 times the upper limit of normal or bilirubin >1 times the upper limit of normal due to increased risk for toxicity and neutropenia-related death. The formulation of ixabepilone contains about 40% alcohol. The product also contains Cremophor EL (polyethoxylated castor oil, BASF Corp.) and should not be used in patients with an allergy to this excipient. This additive is also found in the formulation of paclitaxel (in greater amounts) and may lead to severe hypersensitivity reactions with ixabepilone as well. All patients receiving ixabepilone must be premedicated with an H1 antagonist (eg, diphenhydramine or hydroxyzine) as well as an H2 antagonist (eg, ranitidine or famotidine) prior to administration. Subsequent cycles may require steroid premedication if a hypersensitivity reaction is experienced. Stability and solubility of ixabepilone are related to solution concentration and pH. Ixabepilone must be diluted in Lactated Ringer’s Injection, USP only due to the optimal pH of 6 to 7.5. The use of non–DEHP [d-(2-ethylhexyl) phthalate] bags and tubing is also required due to potential for leaching of plasticizer into the solution secondary to the presence of Cremophor EL. These bags and tubing systems are similar to that used with paclitaxel. Lactated Ringer’s Injection is available in a non–DEHP bag from one manufacturer (B. Braun Medical Inc.). Acceptable solubility is obtained with a narrow range for the final solution concentration of 0.2 mg/mL to 0.6 mg/mL. The final solution in this concentration is stable at room temperature and room light for about six hours. Since the dose is generally administered during a three-hour period, this allows for a three-hour window for preparation. These specific dispensing requirements necessitate some preparation and planning, but are not insurmountable obstacles. What the future holds This novel class of agents provides an additional option for patients as they progress through various therapies to treat their breast cancer. Ixabepilone seems to carry a similar adverse effect profile compared with traditional taxanes, with the ability to overcome taxane resistance. This provides an effective treatment option for patients with resistant, metastatic breast cancer while allowing for familiarity with regard to adverse effect management. Although other epothilones appear to have differing toxicity profiles from ixabepilone (eg, patupilone and diarrhea), the entire class of agents may be useful in this era of drug resistance. Nousheen Samad, PharmD, is an Oncology Pharmacy Practice Resident at the University of Texas M.D. Anderson Cancer Center. Laura Boehnke Michaud, PharmD, BCOP, FASHP, is Manager, Clinical Pharmacy Services at the University of Texas M.D. Anderson Cancer Center. For more information: