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Evaluation Of Topotecan For Ovarian Cancer

Evaluation Of Topotecan For Ovarian Cancer

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Evaluation Of Topotecan For Ovarian Cancer

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  1. Evaluation Of Topotecan For Ovarian Cancer • First-relapse therapy • Front-line in combination • 2-drug regimens • 3-drug regimens

  2. First-Relapse TherapySummary Of Topotecan Efficacy • Only published phase III in relapsedovarian cancer • Only drug proven comparable to paclitaxel • Set the standard for Independent Radiologic Review in relapsed trials • Platinum-sensitive RR ~ 30% to 33% • Response should be evaluated after 4 to 6 cyclesof therapy • Significant % of patients with stabilization of disease • may be clinically beneficial

  3. Topotecan For First-Relapse TherapyResults Outcome Topotecan Paclitaxel P Value Response rate (%) 20.5 14.0 .196 Median response 25.9 21.6 .476duration (wk) Median time to 18.9 14.7 .072progression (wk) Median time to 7.6 6.0 .147response (wk) Median survival (wk) 63.0 53.0 .872 ten Bokkel Huinink et al. J Clin Oncol. 1997;15:2183.

  4. Topotecan For First-Relapse TherapyGOG 146-C Study Design • Platinum-sensitive patients (N = 46) • median PFI = 9.6 mo • Topotecan 1.5 mg/m2 over 30 min QD x 5, q21d • 1 or 2 prior regimens • Patients received a median of 6 cycles PFI = progression-free interval. McGuire et al. J Clin Oncol. 2000;18:1062.

  5. Complete response 2 (4.3%) Partial response 13 (28.3%) Stable disease 22 (47.8%) Progressive disease 9 (19.6%) Topotecan For First-Relapse TherapyGOG 146-C Results (N = 46) Outcome ORR = 33% McGuire et al. J Clin Oncol. 2000;18:1062.

  6. Second-Line TherapyEffect of Platinum-Free Interval Response Rate (%) Interval From Previous Treatment (Mos) Markman et al. J Clin Oncol 1991;9:389.

  7. Second-Line TherapyDefinitions P R I M A R Y T R E A T M E N T 0 3 6 12 18 24 Months Refractory Resistant Sensitive Very Sensitive

  8. Second-Line Therapy“Artificial” Extension of PFI • 30 patients with platinum “resistant” disease  12 refractory 18 resistant • Treated with paclitaxel or docetaxel monotherapy then carboplatin post-taxane progression No CR 7 PR 6 Stable • Response rate of 23%; would predict < 12% based upon Blackledge & Markman data • Can this same concept convert platinum sensitive to very platinum sensitive disease Kavanagh et al. J Clin Oncol 13;1584, 1995.

  9. Topotecan Safety SummaryOvarian And SCLC Populations (N = 879) MedianNeutrophilNadirs (109/L)

  10. Topotecan Safety SummaryOvarian And SCLC Populations (N = 879) MedianPlateletNadirs (109/L)

  11. Topotecan-Related Myelosuppression: Impact Of Prior Regimens Armstrong and O’Reilly. Oncologist. 1998;3:4.

  12. * Extensive prior therapy defined as 6 cycles of platinum.O’Reilly et al. Gynecol Oncol. 1997;67:329. . Topotecan Dosing RecommendationsFor Patients With Renal Impairment Prior Therapy Creatinine CL (mL/min) Minimal Extensive*  60 1.5 mg/m2/d 1.25 mg/m2/d 40 - 59 1.25 mg/m2/d 1.0 mg/m2/d 20 - 39 0.75 mg/m2/d 0.5 mg/m2/d < 20 Not established Not established

  13. Lower-Dose Topotecan Study Design • Patient population • measurable and assessable disease • 65% refractory, 35% resistant • median performance status = 0 • median number of prior chemotherapies = 3 • Topotecan 1 mg/m2/d x5d q3wk • Chi square analysis • vs Bookman et al. J Clin Oncol. 1998;16:3345. Rodriguez et al. SGO Proc. 2000:A122.

  14. Lower-Dose Topotecan Results • 23 Assessable patients • 6/23 (26%) responded to lower-dose topotecan • 4/6 (67%) of responders had measurable disease • 11/23 (47.8%) experienced grade IV neutropenia • Bookman reported 82% grade IV neutropenia (P=.0016) • grade III neutropenia also statistically significant • 2/23 (8.6%) experienced grade IV leukopenia • Bookman reported 30.1% grade IV leukopenia (P=.03) Rodriguez et al. SGO Proc. 2000:A122.

  15. Ongoing Clinical StudiesWith TopotecanDaily x 3 Regimens • Phase II dose is 2.0 mg/m2 x 3 • West coast collaboration (Brown, Karlan, Peters) • 9 patients enrolled (sensitive and resistant patients) • Washington University (Mutch, Herzog) • 6 patients enrolled (sensitive patients only) • GOG 146-K • open to accrual (sensitive patients only)

  16. Ongoing Clinical StudiesWith TopotecanWeekly Regimens • Hoskins et al reported 1.75 mg/m2/wk ineffective vs QD x 5 regimen • Phase I/II data suggest efficacy of 4 to5 mg/m2/wk in ovarian and endometrial cancers • fatigue was dose limiting • Phase II studies to confirm efficacy ongoing • starting at 4 mg/m2

  17. Ongoing Clinical StudiesWith TopotecanCIV Topotecan In Ovarian Cancer • 0.4 mg/m2/day CIV x 21d q28d • 24 patients with prior platinum therapy • 11 refractory or resistant (<6 mo) • 13 sensitive (>6 mo) • Overall response rate = 38% Hochster et al. J Clin Oncol. 1999;17:2553.

  18. Ongoing Clinical StudiesWith Topotecan 0.4 mg/m2/dx 21 q28d(N = 24) 1.5 mg/m2/dx 5 q21d(N = 112) Outcome Response rate (%)Platinum-refractory 33 8.8Platinum-resistant 40 19.2Platinum-sensitive 38 28.8 Median TTP (wk) 26 18.9 Grade IV neutropenia (% of cycles) 4 37 Grade IV thrombocytopenia (% of cycles) 4 10

  19. Proposed GOG Replacement Study Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 • Randomization • All patients • Equal proportions on each regimen • Primary end points: PFI,OS, RR Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.5 mg/m2/d IV d 1-3 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimens I and II: 8 cycles, 21-d cycle interval. Regimens IV and V: 4 cycles, 21-d cycle interval.