Brand Name: Ixempra (approved by FDA in October 2007)

Generic Name: ixabepilone

Manufacturer: Bristol-Myers Squibb

Drug Class:¹ Antineoplastic agent; epothilone; mitotic inhibitor

Uses:²

            Labeled:

- Breast cancer, locally advanced or metastatic, as monotherapy in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine

- Breast cancer, locally advanced or metastatic, in combination with capecitabine in patients who are taxane- or anthracycline-resistant, or taxane-resistant with a contraindication to anthracyclines

            Unlabeled:

                        - Hormone refractory prostate cancer, metastatic

Mechanism of Action:^1,2 Ixabepilone is an antimicrotubule agent. By inhibiting microtubules through microtubule stabilization, it stops cell division in the mitotic phase and causes subsequent cell death.

Pharmacokinetics:

Metabolism:¹ Primarily metabolized in the liver via CYP3A4. At least 30 inactive metabolites have been identified, none greater than 6% of the administered dose.

Elimination:¹ Major route: feces (65% -- approximately 1.6% unchanged). Minor route: urine (21% -- approximately 5.6% unchanged).

Efficacy:^4,5,6

Citation: Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. Journal of Clinical Oncology. April 20 2005; 23(12): 2726-34.

Study design: Phase II, multicenter (2 sites in the U.S.), open-label.

Description of study: The primary objective was to determine the efficacy and safety of ixabepilone. Eligible patients had a diagnosis of metastatic or locally advanced breast cancer, an ECOG performance status of 1, 2, or 3, and measurable disease by RECIST criteria. 37 patients were enrolled; all received at least one cycle of treatment, and all were included in data analysis. All patients had received at least two prior neoadjuvant, adjuvant, or metastatic regimen that contained docetaxel or paclitaxel; patients with nonmetastatic, locally advanced breast cancer had received and not responded to prior anthracycline and taxane neoadjuvant chemotherapy. Patients received a 1 hour IV infusion on 5 consecutive days every 3 weeks. All patients received 6 mg/m²/day for the first cycle. An absolute neutrophil count > 1.0 x 10⁹/L and thrombocyte count > 75 x 10⁹/L were required on the first day of each treatment cycle, and patients with grade 2 or greater neuropathy at baseline were excluded from the study. Efficacy: Patients received a median of 4 cycles of therapy (range, 1-11 cycles). 29 of the 37 patients were removed from study for disease progression. Objective response was 22% (95% CI, 9.8% to 38.2%) and consisted of complete response in 3% and partial response in 19% of patients. Stable disease for at least 6 weeks was the best response for 35% of patients (13), and median time to progression for all patients was 80 days. For eight patients with confirmed partial responses, the median response duration was 118 days. Safety: The most common toxicities involved hemoglobin (73% of patients, only grades 1 and 2), neutropenia (68% of patients, all four grades), and fatigue (65%, all four grades). Twelve patients required dose reduction (median, cycle 5; range, cycles 2 to 10) due to neuropathy (6 patients), diarrhea (2 patients), fatigue (2 patients), and neutropenia (2 patients). One patient required a second dose reduction due to grade 3 myalgia. In patients with no baseline neuropathy, 58% developed grade 1 neuropathy, 25% developed grade 2, and 4% developed grade 3.

Limitations: Potential conflicts of interest due to affiliation with Bristol-Myers Squibb (manufacturer of Ixempra). No values of statistical strength (e.g. p-values) were reported, and some ranges were omitted. The authors don’t present the total percentages of occurrence by toxicity – only broken down by percentage per grade. Relatively small number of patients included could make the response rates (percentages) seem more impressive. Comparing it to placebo or another treatment may better demonstrate efficacy.

Conclusion: Response rates for ixabepilone appear to be relatively modest (29 of the 37 patients were removed from the study for disease progression), while the frequency and severity of toxicities is high, and statistical significance cannot be assessed. However, this population has few effective treatment options available, and even somewhat modest results can be significant in this setting. Ixabepilone appears to warrant further study, preferably using randomized controlled trials, and different dosing schedules may yield more favorable toxicity profiles and perhaps a better response.       

Citation: Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. Journal of Clinical Oncology. Aug 10 2007; 25(23): 3399-406.

Study design: Phase II, international, multicenter (11 centers in 4 countries), open-label.

Description of study: The primary objective was to evaluate the efficacy of ixabepilone in patients with taxane-resistant metastatic breast cancer. 40 mg/m² ixabepilone was administered as a 3-hour infusion. Median patient age was 54 (86% younger than 65 years); 78% had an ECOG performance status of 1; fairly evenly split between pre- and post-menopausal status and positive and negative hormone receptor status; 76% were positive for HER-2 receptor; 84% had 2 or more involved disease sites; 84% of disease sites (all lesions) were visceral. Efficacy: Objective tumor response rate for all patients receiving the 40 mg/m² over 3 hours dose every 3 weeks was 12% (95% CI, 4.7% to 26.5%), with all responders achieving a partial response. The median time to progression for the treatment group was 2.2 months (95% CI, 1.4 to 3.2 months). Median survival for the treatment group was 7.9 months (95% CI, 6.1 to 14.5 months). Safety: 98% of patients in the treatment group reported at least one treatment-related adverse event, and 43% reported at least one grade 3 or 4 toxicity. The most frequent grade 3 treatment-related adverse events for this group were fatigue (27%), sensory neuropathy (12%), myalgia (10%), nausea (6%), and vomiting (6%). 22% of the treatment group had serious (i.e. fatal or life threatening) adverse events. Treatment-related neuropathy was grade 1 or 2 in 51% of the treatment group patients and grade 3 in 12% -- none experienced grade 4 neuropathy. Neutropenia was the most common grade 3 or 4 abnormality in the treatment group (33% grade 3, 20% grade 4).

Limitations: Heavy association between Bristol-Myers Squibb (manufacturer of Ixempra) and many of the study authors. Responses (e.g. partial response, complete response, etc.) were not confirmed by an independent review committee. The lack of a control treatment may not fully demonstrate ixabepilone’s efficacy (or lack thereof).

Conclusion: Ixabepilone appears to produce a modest response in this population, with a high occurrence of treatment-related adverse events and toxicities. However, for patients at this stage of disease, even relatively small improvements in disease status and survival may be worth the adverse effects that may be somewhat expected with this type of treatment.  More study is needed, preferably randomized controlled trials.

Citation: Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficay and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology. Aug 10 2007; 25(23): 3407-14.

Study design: Phase II, multicenter (36 centers in 10 countries), open-label, single-arm design.

Description of study: Primary objective was to assess the objective response rate of ixabepilone 40 mg/m² monotherapy administered as a 3-hour IV infusion on day 1 of a 21-day cycle. Eligible patients were women with metastatic breast cancer or locally advanced breast cancer resistant to anthracyclines, taxanes, and capecitabine. 128 patients were enrolled, 126 were treated, and 113 were designated as assessable for response by the independent radiology facility. Efficacy: Independent radiology facility objective response rate among response-assessable patients was 11.5% (95% CI, 6.3% to 18.9%), with 12% showing a partial response and 50% showing stable disease. Investigator-assessed objective response rate among these patients was 18.6% (95% CI, 11.9% to 27.0%). Median duration of response was 5.7 months (95% CI, 6.3 to 18.9 months), while 13.3% of patients had stable disease for greater than 6 months (95% CI, 7.6 to 20.9 months). Patients received a median of 4.0 cycles of therapy (range, one to 16 cycles). Safety: 94% of treated patients (118 out of 126) had at least one treatment-related event; 55% of these toxicities were grade 1 or 2 in intensity. The highest percentage of toxicities experienced were as follows: 90% of patients developed leukopenia, 84% developed anemia, 79% developed neutropenia, 60% developed peripheral sensory neuropathy, and 50% developed fatigue/asthenia. The hematologic events are described as manageable and did not contribute noticeably to dose reductions or discontinuations. 11% of patients discontinued treatment due to treatment-related adverse events.

Limitations: Lack of a control treatment, and possible conflict of interest among some authors.

Conclusion: This study is valuable because it included a larger number of patients, and focused on those who were resistant to anthracyclines, taxanes, and capecitabine (100% had received and failed prior therapy with all three agents). Ixabepilone appears to be effective in a small percentage of this population. Although the incidence of adverse events is quite high, most appear to be manageable. Given the lack of alternative treatments for patients at this advanced stage of disease, the modest response rate and high incidence of adverse events may be an acceptable risk of this treatment.

Contraindications:^1,3

• [Black Box Warning] Concomitant use of capecitabine in patients with AST or ALT greater than 2.5 times the upper limit of normal or bilirubin greater than 1 times the upper limit of normal (increased risk of toxicity and neutropenia-related death)
• History of severe hypersensitivity reaction (Common Toxicity Criteria grade 3 or 4) to agents containing Cremophor EL or its derivatives (polyoxyethylated castor oil)
• Neutrophil count less than 1500 cells/mm³ 
• Platelet count less than 100,000 cells/mm³

Precautions:^1,3

• Hepatic impairment, elevated AST, ALT, or bilirubin (increased ixabepilone exposure and increased frequency of toxicity)
• Alcohol-containing product (Ixempra contains 39.8% dehydrated alcohol)
• History of cardiac disease (risk of cardiac adverse events)
• Concomitant capecitabine (increased risk of cardiac adverse events including myocardial ischemia and ventricular dysfunction)
• Concomitant use with CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanvir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, fosamprenavir, indinavir, nelfinavir, delavirdine, or voriconazole) and grapefruite juice (increased ixabepilone exposure)
• Concomitant use with CYP3A4 inducers (e.g. St. John’s Wort) (reduced ixabepilone exposure)
• Diabetes mellitus (increased risk of severe neuropathy)
• Hypersensitivity reactions including anaphylaxis may occur
• Dose-dependent myelosuppression (severe neutropenia and thrombocytopenia) may occur
• Moderate to severe peripheral neuropathy (new or worsening symptoms) may occur, especially during the first 3 cycles of treatment

Adverse Effects:²

• Common:
• Dermatologic: Alopecia (monotherapy, 48%; in combination with capecitabine, 31% ), Hand-foot syndrome due to cytotoxic therapy (monotherapy, 8%; in combination with capecitabine, 64% ), Nail changes (monotherapy, 9%; in combination with capecitabine, 24% )
• Gastrointestinal: Abdominal pain (monotherapy, 13%; in combination with capecitabine, 24% ), Constipation (monotherapy, 16%; in combination with capecitabine, 22% ), Diarrhea (monotherapy, 22%; in combination with capecitabine, 44% ), Inflammatory disease of mucous membrane, Loss of appetite (monotherapy, 19%; in combination with capecitabine, 34% ), Nausea (monotherapy, 42%; in combination with capecitabine, 53% ), Stomatitis, Vomiting (monotherapy, 29%; in combination with capecitabine, 39% )
• Musculoskeletal: Arthralgia, Musculoskeletal pain (monotherapy, 20%; in combination with capecitabine, 23% ), Myalgia
• Neurologic: Asthenia, Peripheral neuropathy, Any grade (monotherapy, 63%; in combination with capecitabine, 67% )
• Other: Fatigue

• Serious:
• Cardiovascular: Left ventricular dysfunction, Myocardial ischemia, Supraventricular arrhythmia (0.5% )
• Hematologic: Febrile neutropenia, Any grade (monotherapy, 3%; in combination with capecitabine, 5% ), Febrile neutropenia, Grade 3, 4, and 5 (monotherapy, 3%; in combination with capecitabine, 4% ), Leukopenia, Grade 3 and 4 (monotherapy, 49%; in combination with capecitabine, 57% ), Myelosuppression, Neutropenia, Grade 3 and 4 (monotherapy, 54%; in combination with capecitabine, 68% ), Neutropenia, Resulting in death (monotherapy, 0.4%; in combination with capecitabine, patients with liver impairment, 29%; in combination with capecitabine, patients without or mild liver impairment, 1.9% ), Neutropenia associated with infectious disease (monotherapy, 5%; in combination with capecitabine, 6% )
• Immunologic: Hypersensitivity reaction (Severe)
• Neurologic: Peripheral neuropathy, Grade 3 and 4 (monotherapy, 14%; in combination with capecitabine, 23% )

Drug Interactions:¹

• CYP3A4 Inhibitors (increased ixabepilone plasma concentrations)
• Examples: Amprenavir, Atazanavir, Clarithromycin, Delaviridine, Erythromycin, Fluconazole, Fosamprenavir, Indinavir, Itraconazole, Ketoconazole, Nefazodone, Nelfinavir, Ritonavir, Saquinavir, Telithromycin, Verapamil, Voriconazole, Grapefruit juice
• CYP 3A4 Inducers (decreased ixabepilone plasma concentrations)
• Examples: Carbamazepine, Dexamethasone, Phenobarbital, Phenytoin, Rifabutin, Rifampin, St. John’s Wort

Dosing/Administration:²

• As monotherapy, for locally advanced or metastatic breast cancer, in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine:
• 40 mg/m² IV over 3 hours every 3 weeks
• In combination with capecitabine, for locally advanced or metastatic breast cancer, in patients who are taxane- or anthracycline-resistant, or taxane-resistant with a contraindication to anthracyclines:
• 40 mg/m² IV over 3 hours every 3 weeks
• Note:
• Use MAX body surface area (BSA) of 2.2 m² in patients whose BSA is greater than 2.2 m²
• Premedicate 1 hour before each infusion with an H₁ antagonist and an H₂ antagonist
• Additionally, premedicate with a corticosteroid in patients with a previous hypersensitivity reaction
• Geriatric use:³ Clinical studies of Ixempra did not include sufficient numbers of subjects aged sixty-five and over to determine whether they respond differently from younger subjects.
• Pediatric use:^1,2,3 Safety and efficacy not established
• Renal impairment:³ Ixabepilone is minimally excreted via the kidney. No controlled pharmacokinetic studies were conducted with Ixempra in patients with renal impairment. In a population pharmacokinetic analysis of Ixempra as monotherapy, there was no meaningful effect of mild and moderate renal insufficiency (CrCL >30 mL/min) on the pharmacokinetics of ixabepilone.
• Hepatic impairment:²
• Bilirubin greater than 1 x ULN or AST/ALT greater than 2.5 x ULN, when used in combination with capecitabine: Do not administer
• Bilirubin of 1 x ULN or less, or AST/ALT of 2.5 x ULN or less, when used in combination with capecitabine: no dosage adjustment necessary.
• Bilirubin greater than 1.5 x ULN and up to 3 x ULN and AST/ALT of up to 10 x ULN, when used as monotherapy: Use starting dose of 20 mg/m2; may escalate dose up to 30 mg/m2 maximum in subsequent cycles, if tolerated.
• Bilirubin 1 x ULN or less and AST/ALT levels of 2.5 x ULN or less, when used as monotherapy: No dosage adjustment necessary.
• Bilirubin of 1 x ULN or less and AST/ALT levels of 10 x ULN or less, when used as monotherapy: Reduce the dose to 32 mg/m(2).
• Other dosage adjustments:²
• Concomitant use of strong CYP3A4 inhibitors and grapefruit juice: Avoid if possible. If use is necessary, consider reducing the dose to 20 mg/m². After discontinuation of a strong CYP3A4 inhibitor, a 1-week washout period is necessary before increasing the dose to the indicated dose.
• Febrile neutropenia: Delay treatment to allow recovery (including until neutrophil count is 1500/cubic millimeter (mm³) or more), then reduce dose by 20% when given either as monotherapy or in combination with capecitabine. If toxicity recurs, delay treatment until recovery again, and then decrease the dose by an additional 20%. If concurrent diarrhea or stomatitis occurs in combination therapy, stop capecitabine until the neutrophil count is greater than 1000/mm³, then restart at the same dose.
• Neutrophil count less than 500/cubic millimeter (mm³) for 7 or more days: Delay treatment until neutrophil count is 1500/mm³ or more, then decrease dose by 20% when given either as monotherapy or in combination with capecitabine. If toxicity recurs, delay treatment until recovery again, and then decrease the dose by an additional 20%. If concurrent diarrhea or stomatitis occurs in combination therapy, stop capecitabine until the neutrophil count is greater than 1000/mm³, then restart at the same dose.
• Platelet count less than 25,000/cubic millimeter (mm³) or platelet count less than 50,000/mm³ with bleeding: Delay treatment until platelet count is 100,000/mm³ or more, then decrease dose by 20% when given either as monotherapy or in combination with capecitabine. If toxicity recurs, delay treatment until recovery again, then decrease dose by an additional 20%. If concurrent diarrhea or stomatitis occurs in combination therapy, stop capecitabine until the platelet count is greater than 50,000/mm³, then restart at the same dose.
• Neuropathy (grade 2 lasting 7 or more days or grade 3 lasting less than 7 days): Delay treatment to allow recovery to grade 1 or less, then decrease dose by 20% when given either as monotherapy or in combination with capecitabine. If toxicity recurs in combination therapy, delay treatment until recovery again, then decrease the dose by an additional 20%.
• Neuropathy (grade 3 lasting 7 or more days or disabling): Discontinue ixabepilone.
• Arthralgia, myalgia, or fatigue (transient grade 3): Delay treatment to allow recovery to grade 1 or less, then restart at the same dose.
• Hand-foot syndrome (grade 3): Delay treatment to allow recovery to grade 1 or less, then restart at the same dose.
• Grade 3 toxicity besides neuropathy, hand-foot syndrome, or transient arthralgia, myalgia, or fatigue: Delay treatment to allow recovery to grade 1 or less, then decrease the dose by 20% when given either as monotherapy or in combination with capecitabine. If toxicity recurs, delay treatment until recovery again, then decrease the dose by an additional 20%.
• Grade 4 toxicity: Discontinue ixabepilone.
• Administration notes:³
• Ixempra Kit contains two vials, a vial containing ixabepilone powder and a vial containing diluent for constitution. Only the supplied diluents must be used for constituting Ixempra for injection.
• Storage: Ixempra Kit must be stored in a refrigerator at 2 to 8 degrees C (36 to 46 degrees F) in the original package to protect from light. Prior to constitution, the kit should be removed from the refrigerator and allowed to stand at room temperature for approximately 30 minutes.
• After constituting with the diluents, the concentration of ixabepilone is 2 mg/mL.

Use in special circumstances:

• Pregnancy: Category D^1,2,3
• Nursing mothers: Infant risk cannot be ruled out²

Conclusion:

            Ixempra (ixabepilone) appears to provide some hope for patients with advanced stages of breast cancer that is resistant to other treatments (taxanes, anthracyclines, and capecitabine). Like many other chemotherapy regimens, ixabepilone has a high incidence of adverse effects. Its benefits are generally somewhat short-term, and it appears to be effective in a somewhat small percentage of the population. However, these modest benefits may be sufficient for patients who are not yet ready to begin palliative-only therapies and who wish to continue their fight against breast cancer.

Prepared by Joelle K. Potts, Doctor of Pharmacy Candidate

References:

1. Ixabepilone. DrugDex, Micromedex.
2. Ixabepilone. DrugPoint Summary, Micromedex
3. Ixempra Kit (ixabepilone) for Injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; October 2007. Available at: http://packageinserts.bms.com/pi/pi_ixempra.pdf. Last accessed: March 26, 2008
4. Citation: Low JA, Wedam SB, Lee JJ, Berman AW, Brufsky A, Yang SX, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. Journal of Clinical Oncology. April 20 2005; 23(12): 2726-34.
5. Thomas E, Tabernero J, Fornier M, Conte P, Fumoleau P, Lluch A, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. Journal of Clinical Oncology. Aug 10 2007; 25(23): 3399-406.
6. Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology. Aug 10 2007; 25(23): 3407-14.