The epothilones are a new class of non-taxane tubulin polymerisation agents obtained by natural fermentation of the myxobacterium Sorangium cellulosum. The cytotoxic activities of the epothilones, like those of the taxanes, have been linked to stabilisation of microtubules which results in mitotic arrest at the G2/M transition. Ixabepilone is a semisynthetic derivative of the natural product epothilone B (see Figures 1 and 2). It has demonstrated efficacy in taxane-sensitive and taxane-resistant tumours in vitro and in vivo.[2,3] The efficacy of ixabepilone in resistant tumours may be explained by the fact that ixabepilone has low susceptibility to key mechanisms of tumour resistance including changes in tubulin isotypes, tubulin mutations and overexpression of cell membrane transporters mediated by P-glycoprotein (P-gp) and multidrug resistance protein (MRP). These promising preclinical observations motivated the initiation of clinical studies.
Phase I studies of single-agent ixabepilone
The administration of ixabepilone once every three weeks as a one-hour infusion was studied in a first phase I trial. The MTD was established as 50 mg/m², but the neuropathy that emerged was a major cause of concern for its routine use. The infusion duration of ixabepilone was prolonged from one hour to three hours based on the relationship between the neuropathy of tubulin polymerising agents and their peaks of concentration, the results of a preclinical study in rats that showed the lower deleterious impact of longer infusion of ixabepilone. The prolongation of infusion has resulted in more myelosuppresion and mucositis, so the recommended dose was reduced to 40 mg/m² in clinical trials.
Additional schedules were studied but remained investigational: five consecutive days for five days every three weeks and a weekly administration which seems feasible but the benefit versus the three-week administration needs to be assessed.
Clinical pharmacokinetics and human metabolisms
Pharmacokinetic data are available from the first phase I study. The mean AUC values increase linearly according to dosage. Plasma half-life ranged between 11 and 19 hours. Mean total body clearance values represented 30–51% of the average hepatic blood flow. Mean volume of distribution values suggested an extensive extravascular distribution. The pharmacokinetics parameters appeared to remain similar across cycles 1 and 2.
Ixabepilone did not inhibit human CYP1A2, CYP2C9, CYP2C19 or CYP2D6 in vitro; in contrast, it was a weak inhibitor of human CYP3A4 in vitro. Nevertheless, taking into account its intermittent administration, that it is a weak inhibitor of CYP3A4 in vitro and that its plasma concentrations are generally less than the IC50 for CYP3A4 inhibition in vitro, the likelihood of clinically important pharmacokinetic drug interactions seems limited.
Table 1 summarises the toxicity profile of ixabepilone alone given at a dosage of 40 mg/m² with a three-hour infusion every three weeks in patients with breast cancer.
Peripheral neuropathy appears to be the major relevant toxicity of ixabepilone. The neuropathy is described as sensory manifestations (ie, dysaesthesias, paraesthesias, involving hands and feet) but neuropathic pain has also been reported. This neuropathy is cumulative and gradually recovered after the discontinuation of therapy.
The diluent used with ixabepilone is a poly‑oxyethylated oil (Cremophor®) which has the potential for inducing a hypersensitivity reaction. In clinical trials, severe hypersensitivity reactions occurred in fewer than 1% of patients with routine premedication, including H1 and H2 antihistamines.
Haematological events, consisting primarily of neutropenia and leucopenia, were manageable and did not contribute noticeably to dose reductions or discontinuations. Other commonly reported severe adverse events included fatigue, myalgias/arthralgia, nausea/vomiting and mucositis.
Trials with ixabepilone
In metastatic breast cancer three phase II studies assessed the activity of ixabepilone in several subsets of patients selected according to their tumour resistance or sensitivity to taxanes, anthracyclines and capecitabine.[8–10] In 65 patients with taxane-sensitive metastatic breast cancer ixabepilone showed an objective response rate (ORR) of 41.5% (95% CI, 29.4–54.4%). In 49 patients with a taxane-resistant metastatic breast cancer the ORR was 12% (95% CI, 4.7–26.5%) in the cohort treated at a dose of 40 mg/m2 over three hours. The third study assessed the activity in tumours resistant to anthracycline, taxane and capecitabine. In this resistant subset of patients, the ORR among all 126 treated patients was 18.3% (95% CI: 11.9–26.1%). This study appears to be the first to demonstrate an activity in this unmet situation of patients with an anthracycline-taxane-capecitabine resistant tumour. This study is to be submitted for registration to the regulatory authorities.
Combining ixabepilone and capecitabine is based on the complementary mechanisms of action and primarily non-overlapping toxicity profile of these two agents. This association is being studied in two ongoing randomised phase III trials comparing capecitabine alone versus ixabepilone and capecitabine in patients with metastatic breast cancer. In the first trial, all patients received prior treatment including both an anthracycline and a taxane but the tumour was not defined as resistant. Among 752 patients the association provided a significant higher ORR (35% vs 14%; p = 0.0001) and longer disease-free progression (5.8 vs 4.2 months; p = 0.0003). The second study focused on resistant tumours and the results will be available within three months. The design of these randomised phase III trials has been performed to submit an application for registration.
Currently, ixabepilone is assessed in neoadjuvant and adjuvant settings, in association with bevacizumab or trastuzumab in the metastatic setting.
Chemotherapy resistance represents a major obstacle and the development of an agent which avoids the principal mechanisms of resistance is a welcome advance. Ixabepilone demonstrated consistent preclinical activity in chemotherapy-resistant cell lines and xenograft models. Ixabepilone’s activity in clinical studies is consistent with its preclinical profile. Those results might allow a first registration in metastatic breast cancer and it seems probable that ixabepilone will demonstrate benefit in various tumour types and clinical settings.
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