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M. Teneriello 1 , A. Gordon 2 , P. Lim 3 , M. Janicek 4

Phase III Trial of Induction Gemcitabine (G) or Paclitaxel (T) Plus Carboplatin (C) Followed by Elective T Consolidation in Ovarian Cancer (OC), Stages IC to IV: Final Safety and Efficacy Report. M. Teneriello 1 , A. Gordon 2 , P. Lim 3 , M. Janicek 4

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M. Teneriello 1 , A. Gordon 2 , P. Lim 3 , M. Janicek 4

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  1. Phase III Trial of Induction Gemcitabine (G) or Paclitaxel (T) Plus Carboplatin (C) Followed by Elective T Consolidation in Ovarian Cancer (OC), Stages IC to IV: Final Safety and Efficacy Report M. Teneriello1, A. Gordon2, P. Lim3, M. Janicek4 1 US Oncology, Houston, TX and Texas Oncology, Austin, TX 2 MD Anderson Cancer Center Orlando, Orlando, FL 3 Center of Hope at Renown Regional Medical Center, Reno, NV 4 OncoGyne, Scottsdale, AZ

  2. Disclosure Information The authors have no conflicts of interest to report. This study was sponsored by Eli Lilly and Company.

  3. Background • Induction chemotherapy with a platinum agent and paclitaxel (T) is a standard of care for Stage IC-IV ovarian cancer (OC). • Combination gemcitabine and carboplatin (GC) is approved for use in recurrent platinum-sensitive OC. • Phase II trials have previously shown the combination of G plus cisplatin to be active as first-line therapy for OC.1-3 • Evidence suggests (SWOG 9701/GOG 178) that 12‑month T consolidation (Tcon) improves progression-free survival (PFS).4 • The current study was designed to compare GC to standard first-line therapy, followed by Tcon. • 1 Belpomme D, et al.Gynecol Oncol 2003. • 2 Nogué M, et al. Anticancer Drugs 2002. • 3 Bauknecht T, et al. Int J Gynecol Cancer 2003. • 4 Markman M, et al. J Clin Oncol 2003.

  4. Background • The study was initiated in October 2002 as a multi- center, open-label, dual-arm, randomized, Phase III, superiority trial. • In June 2004, Tcon was changed from mandatory to elective after 362 patients had been enrolled. • Planned enrollment was 1208 patients. In August 2006, the protocol was modified to allow PFS as primary endpoint. Subsequently, enrollment was stopped at 919 patients, an adequate sample size for estimation of PFS. • The trial was stopped in October 2009 after an ad hoc futility analysis showed low probability of a positive PFS result.

  5. Objectives • Primary Objective • To compare PFS in the experimental arm (GC) to the control arm, paclitaxel and carboplatin (TC) • Secondary Objectives • To compare efficacy of the two regimens with respect to response rate and OS • To compare adverse events related to each regimen

  6. RANDOMIZE Induction GC Gemcitabine 1000 mg/m2 D1,8 Carboplatin AUC 5 D1 x 6 cycles q21 days Induction TC Paclitaxel 175 mg/m2 D1 Carboplatin AUC 6 D1 x 6 cycles q21 days Clinical CR Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Elective Tcon therapy Paclitaxel 135 mg/m2 q28 days for 12 cycles Single-agent crossover (CO-T) Paclitaxel 175 mg/m2 D1, q21 days Single-agent crossover (CO-G) Gemcitabine 1000 mg/m2 D1, D8; q21 days Study Design Abbreviations: AUC, area under curve; CO-T, crossover to paclitaxel; CO-G, crossover to gemcitabine; CR, complete response; D, day; PD, progressive disease; PR, partial response; q, every; SD, stable disease; Tcon, paclitaxel consolidation.

  7. Methods • IRB approval was required at all sites. • Surgery had to be ≤12 weeks prior to enrollment and performance status (PS) was 0, 1, or 2. • A pathologic diagnosis of primary peritoneal, epithelial ovarian, or fallopian tube carcinoma was required, Stage IC, II, III, or IV. • No prior gemcitabine (G), prior radiation, or prior chemotherapy for any abdominal or pelvic tumor. Abbreviations: IRB, Institutional Review Board.

  8. Methods…continued • Best tumor response was assessed in patients with measurable disease using RECIST criteria. • CA-125 assessments in patients with non-measurable disease followed GCIG criteria. • Adverse events were assessed using the NCI Common Toxicity Criteria (v 2.0). • The 2-sided Fisher’s exact test was used to determine P-values for response and toxicity. • Survival was assessed using Kaplan-Meier method and log rank test for P-values. Abbreviations: GCIG, Gynecologic Cancer Intergroup; NCI, National Cancer Institute; RECIST, Response Evaluation Criteria in Solid Tumors.

  9. Patient Disposition Enrolled (N = 919) Excluded (n = 3) Not meeting inclusion criteria (NA) Other (NA) Patients randomly assigned (n = 916) Excluded (clerical errors) (n = 85) Allocated to GC (n = 417) Received GC (n = 411) Withdrew (n = 6) Allocated to TC (n = 414) Received TC (n = 409) Withdrew (n = 5) Discontinued (n = 148) Patient request (n = 39) Toxicity (n = 37) Physician request (n = 11) Death (n = 8) >5 week therapy delay (n = 7) Progressive disease (n = 6) Other (n = 19) Unknown (n = 6) Discontinued (n = 165) Patient request (n = 58) Toxicity (n = 26) Physician request (n = 20) Death (n = 6) >5 week therapy delay (n = 5) Progressive disease (n = 5) Other (n = 33) Unknown (n = 12) Received CO-G (n = 78) Received Tcon (n = 169) Received Tcon (n = 183) Received CO-T (n = 77) Abbreviations: N, number of patients enrolled; n, number of patients in group; NA, not available.

  10. Patient Characteristics

  11. Patient Characteristics…continued Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.

  12. Patient Characteristics…continued Abbreviation: SD, standard deviation.

  13. Adverse Events – Induction * P-value compares combined Grade 3-4 thrombocytopenia between groups.

  14. Adverse Events – Consolidation * P-value compares combined Grade 3-4 thrombocytopenia between groups. Abbreviations: Tcon-G, paclitaxel consolidation after GC; Tcon-T, paclitaxel consolidation after TC.

  15. Response: Induction (Measurable Disease) * CR required a normalized CA-125. Abbreviations: ORR, Overall Response Rate; DCR, Disease Control Rate.

  16. Response: Crossover (Measurable Disease) * CR required a normalized CA-125.

  17. Progression-Free Survival (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Survival Probability 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Survival Time (months) Abbreviations: CI, confidence interval; ITT, intent-to-treat.

  18. Progression-Free Survival: Further Analyses

  19. Overall Survival * Cox regression analysis was performed using baseline patient characteristics: performance status, tumor size after debulking, FIGO stage, and histology.

  20. Summary • In 2006 the protocol was modified to allow PFS as primary endpoint and enrollment was stopped at 919 patients. • Demographics were well balanced between arms. • Toxicity profiles were consistent with prior clinical experience. • Response results were not statistically different comparing the two induction or crossover arms.

  21. Summary • For PFS, the primary endpoint, there was no difference for induction, consolidation, and crossover groups. • Adjusting for significant covariates, there was no significant difference in OS between the two arms. • Subset analysis suggested that OS may be improved for patients receiving Tcon after achieving CR. • The OS analysis was severely limited by: early study closure, the high rate of censored data, unrecoverable data, and non-randomization for the consolidation treatment.

  22. Conclusions • GC did not offer an advantage over standard of care TC for first-line chemotherapy in OC. • Paclitaxel consolidation may have improved OS, but analysis was limited by study design and high censorship. • The utility of paclitaxel consolidation cannot be answered by this trial.

  23. Acknowledgements • We thank... • The 85 trial Investigators at 63 sites in the United States. • The Lilly Medical team. • Our patients.

  24. Phase III Trial of Induction Gemcitabine (G) or Paclitaxel (T) Plus Carboplatin (C) Followed by Elective T Consolidation in Ovarian Cancer (OC), Stages IC to IV: Final Safety and Efficacy Report M. Teneriello1, A. Gordon2, P. Lim3, M. Janicek4 1 US Oncology, Houston, TX and Texas Oncology, Austin, TX 2 MD Anderson Cancer Center Orlando, Orlando, FL 3 Center of Hope at Renown Regional Medical Center, Reno, NV 4 OncoGyne, Scottsdale, AZ

  25. Discussion Slides

  26. Drug Administration Abbreviations: Tcon-G, paclitaxel consolidation after GC; Tcon-T, paclitaxel consolidation after TC.

  27. Adverse Events – Crossover * P-value compares combined Grade 3-4 thrombocytopenia between groups.

  28. Overall Survival: Further Analyses

  29. Patient Accrual S302 Planned Accrual Actual Accrual Cumulative Patients, n 10/2002 9/2005 8/2006 29

  30. Cumulative PFS Events S302 636 Planned PFS Events Cumulative Events 30

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