EFFECT OF PROLONGED TOPOTECAN INFUSION ON TOPOISOMERASE-1 LEVELS - A PHASE-I AND PHARMACODYNAMIC STUDY

Topoisomerase 1 (topo-1) inhibitors act on the target enzyme by formin g ''cleavable complex,'' a high molecular weight DNA protein adduct, T he formation of such cleavable complexes results in depletion of the M -r 100,000 ''free'' topo-1 band detectable by Western blot, The object ives of this study mere to determine the maximally tolerated dose of p rolonged topotecan infusion in previously untreated and minimally pret reated patients, A secondary objective was to measure the effect of pr olonged topotecan infusion on topo-1 levels in peripheral blood mononu clear cells (PBMCs) as a pharmacodynamic end point, In a prior Phase I study of 21-day topotecan infusion (H. Hochster et al., J., Clin. Onc ol,, 12: 553-559, 1994), the maximum tolerated dose for patients treat ed previously was 0.53 mg/m(2)/day for 21 days every 28 days, In this study, patients with no prior therapy were treated similarly at 0.7 mg /m(2)/day for 21 days, and doses were escalated in 0.1 mg/m(2)/day inc rements, Patients who had one prior chemotherapy regimen or radiation therapy to a portal of less than or equal to 20 cm(2) were entered at the 0.6 mg/m(2)/day level, Cohorts of four patients were entered until the maximum tolerated dose was determined, Peripheral blood was sampl ed meekly to obtain plasma topotecan drug levels and topo-1 levels in PBMCs by Western Blot, For previously untreated patients, the dose-lim iting toxicity was myelosuppression at the dose of 0.8 mg/m(2)/day, An emia mas seen as a cumulative effect, Unexpected nonhematological toxi city was not observed, topo-1 level analysis by Western blot in 11 cyc les with meekly measurements showed progressive decrement in the perce ntage of free topo-1 (compared to baseline value) during weeks 1, 2, a nd 3, The median percentage of decrease from baseline was 26% (P, not significant; Wilcoxon signed rank test) at week 1, 45% (P = 0.10) at m eek 2, and 77% (P = 0.016) at week 3, At week 4, off drug treatment, t he median percentage of decrease from baseline was only 14%. Additiona l analysis of free topo-1 level as a function of both area under the c urve (P = 0.005) and day of infusion (P = 0.003) demonstrated a signif icant relationship by regression analysis using a linear mixed effects model, In this Phase I study of topotecan prolonged infusion, hematol ogical toxicity remained dose limiting without evidence of previously described nonhematological toxicity, The recommended Phase II dose is 0.7 mg/m(2)/day for 21 days every 28 days for previously untreated pat ients and 0.6 mg/m(2)/day for those with limited prior therapy, Wester n blot analysis of noncomplexed topo-1 in PBMCs sampled weekly showed a progressive depletion of free topo-1 over the 21 days of infusion, w hich reached statistical significance by week 3, Within 1 week of stop ping infusion, topo-1 levels return to baseline, A strong correlation of topo-1 level with area under the curve and duration of infusion was demonstrated, These data suggest that prolonged administration of top o-1 inhibitory drugs results in sustained depletion of free topo-1 enz yme as measured by Western Blot analysis, which may be an important co nsideration in the clinical use of these agents, Direct randomized, co mparative trials will be necessary to determine whether such schedules will improve therapeutic index and efficacy.