Pharmacy & Therapeutics - September 2008 - (Page 526)

DRUG FORECAST radiology facility, as well as in 18% (95% CI, 11.9%–27.0%), as assessed by the investigator. An ORR was achieved in 12% (5/42) of patients with triple-negative tumors whose responses were assessable by the radiology facility.36 The response rate in patients with progressive disease as a best response to prior taxanes was 11%, according to the manufacturer. The median time to response was 6.1 weeks (range, 5–19 weeks). The median progression-free survival was 3.1 months (95% CI, 2.7–4.2 months); the median response duration was 5.7 months (95% CI, 4.4–7.3 months). The potential for combined therapy with ixabepilone and capecitabine was initially highlighted through preclinical studies, which demonstrated synergy between these compounds.43 Subsequently, a phase 1/2 study confirmed the activity and feasibility of this regimen and identified appropriate doses for a phase 3 study.44–46 It is encouraging that in this phase 1/2 trial, ixabepilone and capecitabine had non-overlapping toxicity profiles.45 In phase 2 studies, ixabepilone monotherapy demonstrated activity and good tolerability with a range of tumor types, including non–small-cell lung cancer, squamous cell cancer of the head and neck, and prostate cancer.47–59 Many of the patients in these studies had advanced pretreated tumors that were resistant to other antineoplastic agents. arm (4.2 months) (hazard ratio = 0.75; 95% CI, 0.64–0.88 months; P = 0.00003), with a 25% reduction in estimated risk of disease progression. A subset analysis also revealed that this advantage was maintained across a range of predefined patient types, including patients whose tumors were triple-negative (ER–, PR–, and HER-2–) and those whose tumors were HER-2 positive (HER-2+). The ORR was 35% in the ixabepilone/capecitabine arm and 14% in the capecitabine arm (P < 0.0001).44 In patients who exhibited progression of disease as a best response to prior taxane therapy, the ORR in the experimental arm was 33% (95% CI, 26%–42%); in the control arm, the ORR was 14% (95% CI, 8%–20%). The median duration of response was 6.4 months for ixabepilone/capecitabine (95% CI, 5.6–7.1 months) and 5.6 months for capecitabine (95% CI, 4.2–7.5 months). The time to response was similar for the two treatment arms: 11.7 and 12 weeks, respectively. In the ixabepilone/capecitabine arm, 41% of patients achieved stable disease; in the capecitabine monotherapy arm, 46% of patients achieved stable disease.44 Table 2 lists grade 3/4 adverse events for this phase 3 study. Hematological toxicity was common and consisted primarily of leukopenia and neutropenia, with a 4% incidence of febrile neutropenia. Growth factor support was not required but was administered to 20% of patients who received ixabepilone/capecitabine and to 3% of the capecitabine patients. Anemia and thrombocytopenia were most often grade 1/2 in both treatment groups. 44 Peripheral neuropathy was common, as it is with any of the tubulinactive drugs. The peripheral neuropathy associated with ixabepilone in this study occurred in 65% of patients in the combination arm and was primarily sensory and cumulative but generally reversible. Peripheral neuropathy was related mainly to the maximum plasma concentration (Cmax) and, to a lesser extent, to the area-under-the-curve (AUC) concentration. Patients received a median of four cycles before the onset of grade 3/4 neuropathy. After dose reductions, the patients were able to receive a median of three additional cycles of therapy. The median time to resolution (a return to baseline or to grade 1) of grade 3/4 neuropathy was six weeks.44 A second phase 3 trial of ixabepilone plus capecitabine in taxane-pretreated patients (trial NCT00082433) has com- Table 2 Incidence of Grade 3 and 4 Adverse Events in the Pivotal Phase 3 Trial of Ixabepilone/Capecitabine or Capecitabine Alone In Patients with Metastatic Breast Cancer Previously Treated with Or Resistant to Anthracycline and Resistant to Taxanes Ixabepilone plus Capecitabine (n = 369) Hematological toxicities Leukopenia Anemia Neutropenia Thrombocytopenia Febrile neutropenia Nonhematological toxicities Peripheral neuropathy Hand–foot syndrome Fatigue Myalgia Diarrhea Vomiting Nausea Mucositis Arthralgia % 57 10 68 8 4 23 18 9 8 6 4 3 3 3 Capecitabine (n = 368) % 6 4 11 4 <1 0 17 3 .3 9 2 2 2 0 Phase 3 Clinical Trials The value of ixabepilone combined with capecitabine was confirmed in a randomized phase 3 controlled trial, conducted in patients with anthracyclinepretreated/resistant and taxane-resistant metastatic breast cancer.44 In total, 752 patients were randomly assigned: 375 received ixabepilone (40 mg/m2 IV over three hours, ever y three weeks) plus capecitabine (1,000 mg/m2 orally twice daily every 14 days), and 377 received capecitabine (1,250 mg/m2 twice daily orally every 14 days). The primary endpoint was progression-free survival. Secondary endpoints included ORR, overall survival, duration of response, and time to response. Progression-free survival was found to be significantly longer for the experimental arm (5.8 months) than for the control Data derived from Thomas ES, Gomez HL, Li RK, et al. J Clin Oncol 2007;25:5210–5217.44 526 P&T® • September 2008 • Vol. 33 No. 9

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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