title: Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma.
abstract: CONCLUSIONS
  Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance.
  
  
  BACKGROUND
  Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC.
  
  
  METHODS
  Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot.
  
  
  RESULTS
  In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated.
  
  
  CONCLUSIONS
  Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; mburotto@alemana.cl.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Burotto
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Maureen
authors.initials: M
authors.lastname: Edgerly
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Marianne
authors.initials: M
authors.lastname: Poruchynsky
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Margarita
authors.initials: M
authors.lastname: Velarde
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Herb
authors.initials: H
authors.lastname: Kotz
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Susan
authors.initials: S
authors.lastname: Bates
authors.affiliation: Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Sanjeeve
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA;
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D034261:Epothilones / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; C430592:ixabepilone