Phase II Clinical Trial of @entity19878 in Metastatic XXXX .

@entity1 @entity137 @entity4024 @entity0 @entity5 @entity16 @entity19878 @entity2622 @entity900 @entity3907 @entity391 @entity1295 @entity367
LESSONS LEARNED: Accrual to cervical @entity5 studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of @entity1 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 @entity1 indicates that @entity19878 has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance. BACKGROUND: @entity19878 is a microtubule-stabilizing agent approved for metastatic @entity0 . Preclinical data have shown that @entity19878 is active in @entity3907 -sensitive and -resistant cells. Metastatic @entity2622 (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of @entity19878 in previously treated mCC. METHODS: @entity1 with histologically confirmed mCC and at least one prior @entity900 -containing regimen were treated with @entity19878 [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 @entity5 (RECIST). Secondary endpoints were response rate, rate of @entity5 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 @entity1 were enrolled; 34 had @entity5 with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four @entity1 (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for @entity3907 - @entity4024  ve, and 2.03 for @entity3907 -pretreated @entity1 (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in @entity3907 -naive @entity1 (0.0035 per day) and @entity3907 pretreated @entity1 (0.0053 per day). Median OS was 5.84 months. G1/2 @entity137 included @entity391 (43%), @entity16 (21%), and @entity1295 (60%). Bowel fistulas were observed in 7% of @entity1 . @entity367 and acetylated tubulin were assessed in @entity5 samples from 11 @entity1 during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all @entity5 , a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. CONCLUSION: @entity19878 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.
