PURPOSE: Resistance to topoisomerase (TOP) 1 and 2 inhibitors is a potentially important reason for treatment failure, and may be related, in part, to a down-regulation of the specific TOP target. Investigators in our laboratories previously noted such a down-regulation of the target, along with a reciprocal up-regulation of the alternate TOP. Therefore, sequencing TOP inhibitors may provide a means for overcoming resistance to the TOP I and II inhibitors. Furthermore, point mutations in TOP I, which confer resistance to TOP I inhibitors, were associated with collateral sensitivity to @entity900 . EXPERIMENTAL DESIGN: A dose escalating Phase I trial of @entity1945 (at doses of 0.75 to 1.0 mg/m(2)/day) on days 1 to 3 with @entity2879 (70-80 mg/m(2)/day) and @entity900 (20-25 mg/m(2)/day) on days 8 to 10. The timing of the drug sequence was based on the prior Phase I pharmacokinetic and pharmacodynamic studies of @entity9800 and @entity2879 , and the level of the TOP targets in peripheral blood monocytes. RESULTS: Fifteen @entity1 (7 males and 8 females) received 40 courses of therapy across three dose levels. The median age was 56 (range, 39-77), and the median performance status was 1 (range, 0-2). The diagnoses included: @entity1149 (7), @entity135 (2), @entity5 of unknown primary (2), and 1 each of @entity43 , @entity263 , @entity356 , and @entity703 . Level 1 ( @entity1945 1.0 mg/m(2)/day; @entity2879 80 mg/m(2)/day; and @entity900 25 mg/m(2)/day) produced severe and @entity1398 in the first @entity1 treated, and the subsequent @entity1 were then entered onto a reduced dose level (cohort 2: @entity1945 0.75 mg/m(2)/day; @entity2879 70 mg/m(2)/day; and @entity900 20 mg/m(2)/day). Three of 6 @entity1 on cohort 2 experienced grade IV @entity1398 >5 days, and a decision was then made to add filgrastim at 5 micro g/kg rather than additionally reduce the dosages (cohort 3). Eight @entity1 were then treated on cohort 3, and 1 of the 8 @entity1 experienced a grade 4 @entity1398 . Thus, cohort level three was considered the recommended dose for Phase II studies. Twelve of the 15 @entity1 had disease assessable for response to therapy. Seven achieved stable disease for >/==" BORDER="0">2 months, whereas 5 showed continued progression of their disease. CONCLUSIONS: These data show that sequencing TOP 1 and 2 inhibitors is feasible, and @entity1945 0.75 mg/m(2)/day days 1-3; @entity2879 70 mg/m(2)/day days 8-10; and @entity900 20 mg/m(2)/day days 8-10 with filgrastim at 5 micro g/kg is an appropriate dose and schedule to test the concept of modulating TOP levels by sequencing the administration of the respective TOP inhibitors.

Sequencing @entity1945 and XXXX plus @entity900 to overcome topoisomerase I and II resistance: a pharmacodynamically based Phase I trial.

@entity1 :: ('9606', 'Species') :: ['patients', 'patient'] @entity135 :: ('MESH:D006258', 'Disease') :: ['head and neck cancer'] @entity43 :: ('MESH:D010051', 'Disease') :: ['ovarian cancer'] @entity263 :: ('MESH:D011471', 'Disease') :: ['prostate cancer'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer'] @entity900 :: ('MESH:D002945', 'Chemical') :: ['cisplatin'] @entity1149 :: ('MESH:D002289', 'Disease') :: ['non-small cell lung cancer'] @entity2879 :: ('MESH:D005047', 'Chemical') :: ['etoposide'] @entity1398 :: ('MESH:D009503', 'Disease') :: ['neutropenia', 'prolonged febrile neutropenia'] @entity9800 :: ('MESH:D002166', 'Chemical') :: ['camptothecin'] @entity356 :: ('MESH:D013274', 'Disease') :: ['gastric cancer'] @entity1945 :: ('MESH:D019772', 'Chemical') :: ['topotecan'] @entity703 :: ('MESH:D007680', 'Disease') :: ['renal cancer']
@entity2879 :: (MESH:D005047,Chemical) :: ['etoposide']
