• 11/14/2006
  • Prague, Czech Republic
  • Chris Berrie
  • Doctor’s Guide (www.docguide.com)

The tubulin-polymerising agent ixabepilone (BMS 247550; NSC 710428) is active and tolerable in taxane-naive patients with metastatic/ recurrent squamous cell cancer of the head and neck (SCCHN), according to results of a randomised, phase 2 study.

The findings were presented here on November 10th at the American Association for Cancer Research 18th Symposium on Molecular Targets and Cancer Therapeutics – National Cancer Institute – 18th European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC).

The epothilones are derived from fermentation of myxobacteria and they have been shown to have broad-spectrum antitumour activity. Thus, as principal investigator Barbara Burtness, MD, attending physician, medical oncology, division of medical sciences, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said of this semi-synthetic epothilone derivative, “Ixabepilone is a novel tubulin-polymerising agent, which has the same target as the taxanes, but there is preclinical evidence that ixabepilone is active even if there are tubulin mutations or if MDR is over-expressed, the basis for taxane resistance.”

Eligibility for study entry required measurable SCCHN, with distant metastases and locoregional recurrence/ persistence. Up to 2 prior treatment regimens for recurrent/ metastatic disease were allowed (including taxanes), accompanied by: Eastern Cooperative Oncology Group (ECOG) performance status, 0/1; absolute neutrophil count, >1,500/mm2; adequate renal/ hepatic function. “It is also important to note that the majority of the taxane-naive patients in this study had previously been exposed to chemotherapy and/or radiation therapy,” added Dr. Burtness.

Patients were stratified according to previous taxane exposure, then were randomised to 1 of 4 groups. In arm A, ixabepilone was administered at 6 mg/m2/day for 5 days, every 21 days; in this group, 17 patients were taxane naive and 15 were taxane exposed. In arm B, ixabepilone was administered at 20 mg/m2/day on days 1, 8 and 15, every 28 days; in this group, 34 patients were taxane naive and 18 were taxane exposed.

The larger arm B taxane-naive group arose from the 2-stage study design starting with 14 evaluable patients per cohort, with continuation to 32 patients for any cohort showing at least 1 response.

Patient baseline disease characteristics across these cohorts were essentially the same, according to the researchers.

There were no complete responses. Partial responses were seen in 6.7% of the arm A taxane-exposed group and 14.7% of the arm B taxane-naive group. Rates of stable disease in arm A (naive/exposed) and arm B (naive/exposed) were as follows: 41.2%, 33.3%, 32.4%, 33.3%. Rates of progressive disease were as follows, respectively: 7 (41.2%), 6 (40.0%), 9 (26.5%), 8 (44.4%).

Rates of nonevaluable patients in each group were as follows: 17.7%, 20.0%, 26.5%, 22.2%.

Similarly, progression-free survival (PFS) and median overall survival (OS) across these cohorts were: PFS, 1.5, 1.8, 1.9, 1.6 months; OS, 5.6, 6.5, 7.8, 6.8 months.

Rates of grade 3/4 toxicities greater than 10% in arm A were as follows: taxane-naive patients, 11.8%, anaemia; 23.5% fatigue; taxane-exposed patients, none. In arm B, rates were as follows (naive/exposed): neutropenia, 17.7%/11.1%; fatigue, 23.5%/33.3%; motor neuropathy, 26.5%/16.7%; sensory neuropathy, 5.9%/11.1%; nausea/vomiting, 20.6%/0.0%.

Baseline tissue samples were stained for survivin, to determine any correlation between survivin expression and response/ survival. However, Dr. Burtness indicated that the numbers in this study were too small (arm A, 6 patients; arm B, 9 patients) for any further immediate conclusions, although it could be said that survivin expression is common with SSCHN.

Thus, ixabepilone has modest activity in SCCHN, Dr. Burtness concluded.

“The response rate for the taxane-naive, weekly-schedule patients was actually 15%, which for previously treated patients with head and neck cancer is reasonable,” she said.

She also indicated that the researchers used Response Evaluation Criteria in Solid Tumours (RECIST) criteria for response evaluation, which tends to underestimate SCCHN.

However, she noted, “[Ixabepilone] had substantial toxicity for this group of patients, especially with pretty high rates of sensory and motor neuropathy and some fatigue,” which points to the need for future studies to concentrate on more specific patient groups for whom ixabepilone might be worthwhile or on its potential as a combination therapy.

This study was supported by Bristol Myer Squibb.

Presentation title: Randomised Phase 2 Study of BMS-247550 (NSC 710428) Given Daily x5 or Weekly in Patients With Metastatic or Recurrent Squamous Cell Cancer of the Head and Neck (SCCHN): E2301. Abstract 632