Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in @entity3052 , and to evaluate the effects of in vivo exposure to @entity1945 on topoisomerase II levels in leukemic blast cells as measured by image cytometry. @entity1 who were eligible for this phase I study had relapsed or refractory @entity3052 (< or = 2 prior regimens) or @entity9638 (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m2 day), followed by @entity2879 at two dose levels (100 and 150 mg/m2) i.v. bolus days 6, 7 and 8. Topoisomerase IIalpha levels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting @entity137 was seen in two of six @entity1 at the first dose level (topotecan 1.5 mg/m2/day, @entity2879 100 mg/m2/day; > or = grade 3 @entity33 in both cases). This cohort was expanded to 10 @entity1 ; no further non-hematologic dose-limiting @entity137 was observed, but given the extent of @entity137 seen, further dose escalation was judged not to be feasible. Topo IIalpha levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone @entity236 by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a @entity1 with @entity9638 was observed in the 10 @entity1 evaluable for response. The sequential administration of topotecan 1.5 mg/m2/day continuous infusion for 5 days followed by @entity2879 100 mg/m2/day x 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIalpha expression in vivo in @entity1778 cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in @entity3052 .

Phase I trial of sequential topotecan followed by XXXX in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study.

@entity1 :: ('9606', 'Species') :: ['Patients', 'patients', 'patient'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity33 :: ('MESH:D052016', 'Disease') :: ['mucositis'] @entity9638 :: ('MESH:D001752', 'Disease') :: ['CML blast crisis'] @entity2879 :: ('MESH:D005047', 'Chemical') :: ['etoposide'] @entity3052 :: ('MESH:D015470', 'Disease') :: ['acute myeloid leukemia', 'acute leukemia'] @entity1778 :: ('MESH:D007938', 'Disease') :: ['leukemia'] @entity236 :: ('MESH:D001855', 'Disease') :: ['marrow blasts'] @entity1945 :: ('MESH:D019772', 'Chemical') :: ['topotecan']
@entity2879 :: (MESH:D005047,Chemical) :: ['etoposide']
