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, TX2 MD Anderson Cancer Center Orlando, Orlando, FL3 Center of Hope at Renown Regional Medical Center, Reno, NV4 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 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.

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 GCGemcitabine 1000 mg/m2 D1,8

Carboplatin AUC 5 D1x 6 cycles q21 days

RANDOMIZE

Induction TCPaclitaxel 175 mg/m2 D1Carboplatin 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/m2

D1, q21 days

Single-agent crossover (CO-G)Gemcitabine 1000 mg/m2

D1, D8; q21 days

Elective Tcon therapyPaclitaxel 135 mg/m2 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, ResponseEvaluation 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

ParameterGC

N=417 TC

N=414P-value

Age

Median age, years (range) 60 (22-84) 61 (22-86) 0.439

Age ≤65 years, n (%) 282 (67.6) 274 (66.2)0.695

Age >65 years, n (%) 135 (32.4) 139 (33.6)

Race, n (%)

Caucasian 379 (90.9) 379 (91.5)

0.961

Black 12 (2.9) 13 (3.1)

Asian 5 (1.2) 5 (1.2)

Native American 2 (0.5) 1 (0.2)

Other 19 (4.6) 16 (3.9)

Zubrod performance status, n (%)

0 239 (57.3) 232 (56.0)

1 139 (33.3) 157 (37.9) 0.887

2 27 (6.5) 16 (3.9)

Patient Characteristics…continued

ParameterGC

N=417 TC

N=414P-value

Origin of disease, n (%)

Ovary 355 (85.1) 362 (87.4)0.524

Peritoneum 56 (13.4) 50 (12.1)

Extent of residual disease, n (%)

Measurable 139 (33.3) 114 (27.5)0.063

Non-measurable 276 (66.2) 300 (72.5)

FIGO stage at initial surgery, n (%)

IC 21 (5.0) 22 (5.3)

0.929 II 44 (10.6) 39 (9.4)

III 284 (68.1) 289 (69.8)

IV 68 (16.3) 63 (15.2)

Tumor size after debulking, n (%)

<2 cm 309 (74.1) 314 (75.8)0.638

≥2 cm 102 (24.5) 96 (23.2)

Abbreviation: FIGO, International Federation of Gynecology and Obstetrics.

Patient Characteristics…continued

ParameterGC

N=417 TC

N=414P-value

Histology, n (%)

Mucinous 10 (2.4) 10 (2.4)

Serous 283 (63.2) 276 (66.7)

Endometroid 44 (10.6) 40 (9.7)

Undifferentiated 7 (1.7) 7 (1.7)

Clear cell 21 (5.0) 23 (5.6) 0.960

Mixed epithelial 9 (2.2) 13 (3.1)

Transitional cell 3 (0.7) 1 (0.2)

Adenocarcinoma 22 (5.3) 23 (5.6)

Other 17 (4.1) 21 (5.1)

CA-125

Patients evaluated, n 416 4140.869

Baseline, mean U/ml ± SD 492.8 ± 1138.6 479.8 ± 1117.0

Abbreviation: SD, standard deviation.

Adverse Events – Induction

Adverse event, n (%)GC

N=412TC

N=408P-value

Grade 3-4 anemia 113 (27.4) 31 (7.6) 0.00010.0001

Grade 3/4 thrombocytopenia165 (40.0)114 (27.7)

39 (9.6)9 (2.2)

0.00010.0001**

Platelet transfusion 11 (2.7) 0 (0.0) 0.00090.0009

Grade 2 neuropathy 9 (2.2) 57 (14.0) <0.0001<0.0001

Grade 2-3 alopecia 30 (7.3) 208 (51.0) <0.0001<0.0001

Grade 3-4 neutropenia 332 (80.6) 321 (78.7) 0.544

Grade 3-4 febrile neutropenia 7 (1.7) 12 (2.9) 0.256

Grade 3-4 fatigue 23 (5.6) 15 (3.7) 0.245

Grade 3-4 nausea 21 (5.1) 18 (4.4) 0.743

Grade 3-4 vomiting 16 (3.9) 17 (4.2) 0.861

Grade 3-4 myalgia 1 (0.2) 3 (0.7) 0.372

Red blood cell transfusion 15 (3.6) 9 (2.2) 0.300

* P-value compares combined Grade 3-4 thrombocytopenia between groups.

Adverse Events – Consolidation

Adverse event, n (%)Tcon-GN=169

Tcon-TN=183

P-value

Grade 2 neuropathy 25 (14.8) 50 (27.3) 0.0040.004

Grade 3-4 neutropenia 29 (17.2) 30 (16.4) 0.887

Grade 3-4 febrile neutropenia 0 (0.0) 0 (0.0) -

Grade 3/4 thrombocytopenia3 (1.8)1 (0.6)

0 (0.0)0 (0.0)

0.052*

Grade 3-4 anemia 2 (1.2) 0 (0.0) 0.230

Grade 3-4 fatigue 3 (1.8) 2 (1.1) 0.674

Grade 3-4 nausea 1 (0.6) 0 (0.0) 0.480

Grade 3-4 vomiting 2 (1.2) 0 (0.0) 0.230

Grade 3-4 myalgia 1 (0.6) 0 (0.0) 0.480

Grade 2-3 alopecia 76 (45.0) 67 (36.6) 0.128

Red blood cell transfusion 1 (0.6) 0 (0.0) 0.480

Platelet transfusion 1 (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=139TC

N=114P-value

ORR (CR+PR) 94 (67.6) 81 (71.1) 0.771

DCR (CR+PR+SD) 116 (83.5) 97 (85.1) 0.999

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 available 9 (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-GN=28

CO-TN=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 available 1 (3.5) 2 (6.0) -

* CR required a normalized CA-125.

Progression-Free Survival (ITT)

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Survival Time (months)

Su

rviv

al P

rob

abil

ity

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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 consolidation GC (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 consolidation GC (N=97) TC (N=78)

Median, months (95% CI) 23.4 (17.8, 36.7) 27.4 (15.8, 43.8) 0.793

Crossover CO-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-treat GC (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) 0.0130.013

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, - ) 0.0410.041

* 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. Teneriello1, A. Gordon2, P. Lim3, M. Janicek4

1 US Oncology, Houston, TX and Texas Oncology, Austin, TX2 MD Anderson Cancer Center Orlando, Orlando, FL3 Center of Hope at Renown Regional Medical Center, Reno, NV4 OncoGyne, Scottsdale, AZ

Discussion Slides

Drug Administration

ParameterGC

N=412TC

N=408

Tcon-G

N=169

Tcon-TN=183

CO-GN=78

CO-TN=77

Total cycles administered, n 2221 2194 1583 1760 417 513

Mean cycles administered, n 5.4 5.4 9.4 9.6 5.3 6.7

Median cycles administered, n 6 6 12 12 5 6

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-GN=78

CO-TN=77

P-value

Grade 3-4 neutropenia 52 (66.7) 30 (39.0) 0.00070.0007

Grade 3/4 thrombocytopenia12 (15.4)

5 (6.4)3 (3.9)1 (1.3) 0.0040.004**

Grade 2 neuropathy 7 (9.0) 22 (28.6) 0.00190.0019

Grade 3-4 febrile neutropenia 2 (2.6) 2 (2.6) >0.999

Grade 3-4 anemia 2 (2.6) 2 (2.6) >0.999

Grade 3-4 fatigue 5 (6.4) 3 (3.9) 0.719

Grade 3-4 nausea 0 (0.0) 1 (1.3) 0.497

Grade 3-4 vomiting 1 (1.3) 1 (1.3) >0.999

Grade 3-4 myalgia 1 (1.3) 3 (3.9) 0.367

Grade 2-3 alopecia 30 (38.5) 38 (49.4) 0.077

Red blood cell transfusion 2 (2.6) 0 (0.0) 0.497

Platelet transfusion 0 (0.0) 0 (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, - ) 0.0410.041

CR - with consolidation GC (N=163) TC (N=179)

Patients censored, n (%) 98 (60.1) 130 (72.6)

Median, months (95% CI) 56.1 (47.3, - ) - ( - , - ) 0.0350.035

CR - no consolidation GC (N=97) TC (N=78)

Patients censored, n (%) 63 (64.9) 55 (70.5)

Median, months (95% CI) - ( - , - ) 64.0 (48.4, - ) 0.1910.191

Crossover CO-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) 0.7350.735

29

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