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 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

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

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 Nogué M, et al. Anticancer Drugs Bauknecht T, et al. Int J Gynecol Cancer Markman M, et al. J Clin Oncol 2003.

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.

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

Study Design Induction GC Gemcitabine 1000 mg/m 2 D1,8 Carboplatin AUC 5 D1 x 6 cycles q21 days RANDOMIZE Induction TC Paclitaxel 175 mg/m 2 D1 Carboplatin AUC 6 D1 x 6 cycles q21 days Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover (CO-T) Paclitaxel 175 mg/m 2 D1, q21 days Single-agent crossover (CO-G) Gemcitabine 1000 mg/m 2 D1, D8; q21 days Elective Tcon therapy Paclitaxel 135 mg/m 2 q28 days for 12 cycles 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.

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.

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. Methods…continued Abbreviations: GCIG, Gynecologic Cancer Intergroup; NCI, National Cancer Institute; RECIST, Response Evaluation Criteria in Solid Tumors.

Patient Disposition Abbreviations: N, number of patients enrolled; n, number of patients in group; NA, not available. Patients randomly assigned (n = 916) Allocated to GC (n = 417) Received GC(n = 411) Withdrew(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) Allocated to TC(n = 414) Received TC(n = 409) Withdrew(n = 5) Enrolled (N = 919) 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) Excluded(n = 3) Not meeting inclusion criteria(NA) Other(NA) Received Tcon (n = 169)Received Tcon (n = 183) Received CO-G (n = 78) Excluded (clerical errors) (n = 85) Received CO-T (n = 77)

Patient Characteristics Parameter GC N=417 TC N=414 P-value Age Median age, years (range)60 (22-84)61 (22-86)0.439 Age ≤65 years, n (%)282 (67.6)274 (66.2) Age >65 years, n (%)135 (32.4)139 (33.6) Race, n (%) Caucasian379 (90.9)379 (91.5) Black12 (2.9)13 (3.1) Asian5 (1.2) Native American2 (0.5)1 (0.2) Other19 (4.6)16 (3.9) Zubrod performance status, n (%) 0239 (57.3)232 (56.0) 1139 (33.3)157 (37.9) (6.5)16 (3.9)

Patient Characteristics…continued Parameter GC N=417 TC N=414 P-value Origin of disease, n (%) Ovary355 (85.1)362 (87.4) Peritoneum56 (13.4)50 (12.1) Extent of residual disease, n (%) Measurable139 (33.3)114 (27.5) Non-measurable276 (66.2)300 (72.5) FIGO stage at initial surgery, n (%) IC21 (5.0)22 (5.3) II44 (10.6)39 (9.4) III284 (68.1)289 (69.8) IV68 (16.3)63 (15.2) Tumor size after debulking, n (%) <2 cm309 (74.1)314 (75.8) ≥2 cm102 (24.5)96 (23.2) Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.

Patient Characteristics…continued Parameter GC N=417 TC N=414 P-value Histology, n (%) Mucinous10 (2.4) Serous283 (63.2)276 (66.7) Endometroid44 (10.6)40 (9.7) Undifferentiated7 (1.7) Clear cell21 (5.0)23 (5.6)0.960 Mixed epithelial9 (2.2)13 (3.1) Transitional cell3 (0.7)1 (0.2) Adenocarcinoma22 (5.3)23 (5.6) Other17 (4.1)21 (5.1) CA-125 Patients evaluated, n Baseline, mean U/ml ± SD492.8 ± ± Abbreviation: SD, standard deviation.

Adverse Events – Induction Adverse event, n (%) GC N=412 TC N=408 P-value Grade 3-4 anemia113 (27.4)31 (7.6)  Grade 3/4 thrombocytopenia 165 (40.0) 114 (27.7) 39 (9.6) 9 (2.2)  * Platelet transfusion11 (2.7)0 (0.0)  Grade 2 neuropathy 9 (2.2)57 (14.0)< Grade 2-3 alopecia30 (7.3)208 (51.0)< Grade 3-4 neutropenia332 (80.6)321 (78.7)0.544 Grade 3-4 febrile neutropenia7 (1.7)12 (2.9)0.256 Grade 3-4 fatigue23 (5.6)15 (3.7)0.245 Grade 3-4 nausea21 (5.1)18 (4.4)0.743 Grade 3-4 vomiting16 (3.9)17 (4.2)0.861 Grade 3-4 myalgia1 (0.2)3 (0.7)0.372 Red blood cell transfusion15 (3.6)9 (2.2)0.300 * P-value compares combined Grade 3-4 thrombocytopenia between groups.

Adverse Events – Consolidation Adverse event, n (%) Tcon-G N=169 Tcon-T N=183 P-value  Grade 2 neuropathy 25 (14.8)50 (27.3)0.004 Grade 3-4 neutropenia29 (17.2)30 (16.4)0.887 Grade 3-4 febrile neutropenia0 (0.0) - Grade 3/4 thrombocytopenia 3 (1.8) 1 (0.6) 0 (0.0) 0.052* Grade 3-4 anemia2 (1.2)0 (0.0)0.230 Grade 3-4 fatigue3 (1.8)2 (1.1)0.674 Grade 3-4 nausea1 (0.6)0 (0.0)0.480 Grade 3-4 vomiting2 (1.2)0 (0.0)0.230 Grade 3-4 myalgia1 (0.6)0 (0.0)0.480 Grade 2-3 alopecia76 (45.0)67 (36.6)0.128 Red blood cell transfusion1 (0.6)0 (0.0)0.480 Platelet transfusion1 (0.6)0 (0.0)0.480 * P-value compares combined Grade 3-4 thrombocytopenia between groups. Abbreviations: Tcon-G, paclitaxel consolidation after GC; Tcon-T, paclitaxel consolidation after TC.

Response: Induction (Measurable Disease) Best response, n (%) GC N=139 TC N=114 P-value ORR (CR+PR)94 (67.6)81 (71.1)0.771 DCR (CR+PR+SD)116 (83.5)97 (85.1)  Complete response (CR)*57 (41.0)50 (43.9)0.795 Partial response (PR)37 (26.6)31 (27.2)- Stable disease (SD)22 (15.8)16 (14.0)- Progressive disease (PD)14 (10.1)11 (9.6)- Data not available9 (6.5)6 (5.3)- Abbreviations: ORR, Overall Response Rate; DCR, Disease Control Rate. * CR required a normalized CA-125.

Response: Crossover (Measurable Disease) Best response, n (%) CO-G N=28 CO-T N=33 P-value ORR (CR+PR)10 (35.7)10 (30.3)0.784 DCR (CR+PR+SD)14 (50.0)15 (45.5)0.796 Complete response (CR)*5 (17.9)1 (3.0)0.084 Partial response (PR)5 (17.9)9 (27.3)- Stable disease (SD)4 (14.3)5 (15.2)- Progressive disease (PD)13 (46.4)16 (48.5)- Data not available1 (3.5)2 (6.0)- * CR required a normalized CA-125.

Progression-Free Survival (ITT) Survival Time (months) Survival Probability PFS  GC (N=417)  TC (N=414)P-value Patients censored, n (%)122 (29.3)134 (32.4) Median, months (95% CI)20.0 (17.9, 22.2)22.2 (19.0, 25.7)0.199 Abbreviations: CI, confidence interval; ITT, intent-to-treat.

Progression-Free Survival: Further Analyses CR after induction+ Tcon (N=342)– Tcon (N=175)P-value Median, months (95% CI)30.0 (25.7, 33.9)23.7 (19.8, 36.7)0.295 CR - with consolidationGC (N=163)TC (N=179) Median, months (95% CI)27.2 (23.9, 36.1)30.6 (26.0, 36.5)0.803 CR - no consolidationGC (N=97)TC (N=78) Median, months (95% CI)23.4 (17.8, 36.7)27.4 (15.8, 43.8)0.793 CrossoverCO-G (N=78)CO-T (N=77) Median, months (95% CI)9.3 (7.7, 11.8)10.2 (7.2, 12.5)0.918

Overall Survival Intent-to-treatGC (N=417)TC (N=414)P-value Patients censored, n (%)220 (52.8)254 (61.4) Median, months (95% CI)43.8 (38.8, 48.4)57.3 (48.5, 64.0)0.013 Adjusted by covariates*GC (N=400)TC (N=395) Hazard ratio (95% CI)1.22 (0.99, 1.52)0.067 CR after induction+ Tcon (N=342)– Tcon (N=175) Patients censored, n (%)228 (66.7)118 (67.4) Median, months (95% CI)65.6 (54.7, - )51.4 (48.4, - )0.041 * Cox regression analysis was performed using baseline patient characteristics: performance status, tumor size after debulking, FIGO stage, and histology.

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.

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.

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.

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

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 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

Discussion Slides

Drug Administration Parameter GC N=412 TC N=408 Tcon-G N=169 Tcon-T N=183 CO-G N=78 CO-T N=77 Total cycles administered, n Mean cycles administered, n Median cycles administered, n Cycles with dose reduction, n/(%) 312 (14.0) 107 (4.9) 23 (1.4) 40 (2.3) 32 (7.7) 25 (4.9) Abbreviations: Tcon-G, paclitaxel consolidation after GC; Tcon-T, paclitaxel consolidation after TC.

Adverse Events – Crossover Adverse event, n (%) CO-G N=78 CO-T N=77 P-value Grade 3-4 neutropenia52 (66.7)30 (39.0) Grade 3/4 thrombocytopenia 12 (15.4) 5 (6.4) 3 (3.9) 1 (1.3) 0.004*  Grade 2 neuropathy 7 (9.0)22 (28.6) Grade 3-4 febrile neutropenia2 (2.6) >0.999 Grade 3-4 anemia2 (2.6) >0.999 Grade 3-4 fatigue5 (6.4)3 (3.9)0.719 Grade 3-4 nausea0 (0.0)1 (1.3)0.497 Grade 3-4 vomiting1 (1.3) >0.999 Grade 3-4 myalgia1 (1.3)3 (3.9)0.367 Grade 2-3 alopecia30 (38.5)38 (49.4)0.077 Red blood cell transfusion2 (2.6)0 (0.0)0.497 Platelet transfusion0 (0.0) - * P-value compares combined Grade 3-4 thrombocytopenia between groups.

Overall Survival: Further Analyses CR after induction+ Tcon (N=342)– Tcon (N=175)P-value Patients censored, n (%)228 (66.7)118 (67.4) Median, months (95% CI)65.6 (54.7, - )51.4 (48.4, - )0.041 CR - with consolidationGC (N=163)TC (N=179) Patients censored, n (%)98 (60.1)130 (72.6) Median, months (95% CI)56.1 (47.3, - )- ( -, - )0.035 CR - no consolidationGC (N=97)TC (N=78) Patients censored, n (%)63 (64.9)55 (70.5) Median, months (95% CI)- ( -, - )64.0 (48.4, - )0.191 CrossoverCO-G (N=78)CO-T (N=77) Patients censored, n (%)30 (38.5)23 (29.9) Median, months (95% CI)26.4 (21.3, 37.1)25.7 (20.6, 34.2)0.735

29 Patient Accrual S302 Planned Accrual Cumulative Patients, n 10/20028/2006 Actual Accrual 9/2005

30 Cumulative Events 636 Planned PFS Events Cumulative PFS Events S302