Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts
F. Y. LeeAmy CamusoStephen CastenadaChristine FleflehI. IngioDavid KanKelly McGlincheyKrista MenardWilliam C. Rose
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12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]Keywords:
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Aim: We conducted a systematic review to estimate efficacy and safety of ixabepilone plus capecitabine compared with capecitabine alone for patients of anthracycline- and/or taxane-resistant metastatic breast cancer. Materials & methods: PubMed, Cochrane Library, EMBASE, ClinicalTrials.gov and other databases were searched. Randomized controlled trials containing ixabepilone plus capecitabine for anthracycline- and/or taxane-resistant metastatic breast cancer were eligible. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Overall response rates and toxicity were analyzed as dichotomous variables. Overall survival and time to progression data were analyzed as inverse variables. Meta-analyses were carried out by Review Manager 5.0 Software. Results: This report included two large clinical trials (1973 patients) for patients with metastatic breast cancer resistant to taxanes and resistant to or pretreated with anthracyclines. Ixabepilone plus capecitabine has prolonged the median time to progression, increased overall survival and significantly increased response rates compared with capecitabine alone. Adverse events observed with the combination arm were generally manageable and well tolerated with neutropenia and febrile neutropenia, and peripheral neuropathy, myalgia, diarrhea, stomatitis and hand–foot syndrome were easily controlled. Conclusion: Ixabepilone plus capecitabine demonstrated clinical activity with an acceptable safety profile, which seems to be a valid option for patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer.
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The clinical benefits provided by using combined taxanes and anthracyclines in first-line chemotherapy for metastatic breast carcinoma (MBC) remain uncertain. This meta-analysis compares the benefits of using a combination of anthracyclines along with taxanes versus using single-agent-based chemotherapeutic regimens in the treatment of MBC. Relevant clinical trials as well as abstracts from articles presented at major cancer conferences were searched in various databases including PubMed, Embase, and Cochrane Library. The relevant studies had a primary endpoint of overall survival (OS) and secondary endpoints that included progression-free survival (PFS), time-to-treatment failure (TTF), time to progression (TTP), objective response rate (ORR), disease control rate (DCR), and safety. The hazard ratios of OS, PFS, TTF, and TTP, the odds ratios of ORR and DCR, and the risk ratios (RRs) for grades 1–2 and 3–4 toxicities were extracted from the retrieved studies and analyzed using various statistical methods. Meta-analytic estimates were derived from a random-effect model. Fifteen trials were included in the final meta-analysis, and the results suggest that chemotherapy with combined anthracyclines and taxanes does not significantly improve the OS of MBC patients when compared with the OS achieved using separate taxane or anthracycline-based regimens. Compared with taxane-based regimens, combined taxane along with anthracycline regimens failed to significantly improve TTP, ORR, or DCR, but did significantly improve TTP and ORR when compared with anthracycline-based regimens. Furthermore, both individual taxane-based and anthracycline-based regimens produced fewer toxic reactions compared to combined taxane along with anthracycline regimens. Taxane-based regimens had lower RRs for side effects of neutropenia, infection/febrile neutropenia, nausea, and vomiting, whereas patients receiving anthracycline-based regimens had lower RRs for neutropenia, infection/febrile neutropenia, anorexia, stomatitis/mucosal inflammation, diarrhea, and sensory neuropathy. In contrast, patients receiving taxane-based regimens were at higher RRs for hand–foot syndrome and diarrhea, whereas patients receiving anthracycline-based regimens had higher RRs for nausea and vomiting. A taxane-based treatment regimen may be a better option than a combined taxane/anthracycline regimen for managing patients with advanced breast cancer, as it produces equivalent clinical outcomes and has less toxicity compared to other similar regimens.
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Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were ran- domized to ixabepilone (40 mg/m 2 intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m 2 orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m 2 on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a
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1083 Background: Data on chemotherapy for elderly patients (pts) with metastatic breast cancer (MBC) are limited. We performed a retrospective analysis of elderly pts (≥65 years of age) enrolled into the pivotal phase III studies of ixabepilone plus capecitabine versus capecitabine alone in order to determine the efficacy and safety of these agents compared with the overall population. Methods: 1,973 pts with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase III studies to receive either ixabepilone (40 mg/m2 IV over 3h q3w) plus capecitabine (1,000 mg/m2 PO BID x 14d q3w) or capecitabine alone (1,250 mg/m2 PO BID x 14d q3w). Due to the similarity of the study populations, individual patient data from both studies were pooled. 251 randomized pts were ≥65 years of age. Results: Efficacy endpoints in the elderly population were consistent with pts <65 years of age. The combination of ixabepilone plus capecitabine was favored over capecitabine monotherapy (Table). Grade 3 or 4 hematologic adverse events (AEs) occurring in >5% of pts receiving ixabepilone plus capecitabine were similar in pts <65 and ≥65 years of age: neutropenia 21% vs 26% and febrile neutropenia 5% vs 10%. Non-hematologic AEs occurring in >5% of pts receiving ixabepilone plus capecitabine were also similar in these age groups and included: fatigue 10% vs 12%, asthenia 6% vs 14%, peripheral sensory neuropathy 14% vs 17%, and hand-foot syndrome 20% vs 19%. Conclusions: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly pts with anthracycline and taxane pretreated MBC. Furthermore, the safety profile of ixabepilone plus capecitabine is similar in pts <65 and ≥65 years of age. <65 years of age ≥65 years of age Ixa + cape cape Ixa + cape cape n 751 740 104 116 ORR,* n (%) 317 (42) 194 (26) 38 (37) 22 (19) Median PFS, mo 5.6 4.2 5.5 3.9 HR (95% CI) 0.81 (0.73–0.90) 0.77 (0.59–1.02) n 868 853 116 135 Median OS, mo 14.7 13.9 13.9 12.2 HR (95% CI) 0.90 (0.81–1.01) 1.07 (0.81–1.40) * ORR and PFS were computed on all randomized pts with measurable disease strata.
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Background: The optimal duration of ixabepilone and capecitabine chemotherapy combination is currently not known and will most likely be patient-specific based on efficacy, toxicity, quality of life, and patient preference. Case Report: We report an extremely long duration of chemotherapy with ixabepilone and capecitabine (42 cycles) in a patient with triple-negative metastatic breast cancer previously treated with anthracyclines and taxanes. Partial remission was achieved, and acceptable toxicity was observed. Conclusions: This report adds to the pool of knowledge regarding the use of this important new metastatic breast cancer regimen, especially with respect to the optimal duration of its use.
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