1. Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r) : an Eastern Cooperative Oncology Group Study (E8200) B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology Group Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of Medicine, Greenville; Thomas Jefferson University, Philadelphia; Northwestern University, Chicago

2. Background Gemcitabine is standard for metastatic pancreatic cancer –median survivals of < 6 mo Second cytotoxic or biologic agents do not substantially advance survival EGFR is expressed on PC A phase II trial of gemcitabine plus cetuximab resulted in median survival 6.7 and 1 year survival 32.5%

3. Irinotecan/Docetaxel Phase II Irinotecan and docetaxel are synergistic in preclinical models Cetuximab/irinotecan active in irinotecan-refractory colon cancer A phase II trial of the Murren regimen of weekly irinotecan/docetaxel (I/D) chemotherapy reported a median survival for metastatic patients (pts) of 9 mo and RR 27% We conducted this randomized phase II trial to confirm the activity of this non-gemcitabine regimen, and determine whether combining it with cetuximab was feasible and active

4. E8200 Eligibility Histologically confirmed adenocarcinoma of the pancreas that is metastatic No prior chemotherapy for metastatic disease Prior gemcitabine or 5FU in the neoadjuvant or adjuvant setting permitted if > 6 months have elapsed ECOG 0 or 1

5. E8200 Eligibility AST ≤ 2.5 x ULN if alk phos normal Alk phos ≤ 4 x ULN if transaminases normal Transaminases > 1.5 x ULN and alk phos > 2.5 x ULN -> Ineligible Tissue from core biopsy or open procedure available for IHC (this requirement was removed by amendment midway through the trial to ease accrual)

6. E8200 Study Design Dexamethasone premedication Docetaxel 35 mg/m 2 followed by irinotecan 50 mg/m 2 weekly x 4, q 6 weeks Randomized phase II, 2 arms: –Irinotecan/docetaxel –Irinotecan/docetaxel + cetuximab loading dose of 400 mg/m 2 followed by 250 mg/m 2 weekly All pts receive prophylactic enoxaparin if not on therapeutic anticoagulation

7. Statistical Considerations Primary endpoint response in each arm Secondary endpoints –Time to progression –Overall survival –Toxicity –Rate of thromboembolic events with use of prophylactic enoxaparin –Prospective determination of EGFR expression in population of patients with metastatic pancreatic cancer

8. Statistical Considerations Null hypothesis is RR 5% Response rate of interest 20% 2 responses in first 22 patients required for either arm to proceed to second stage Accrual to Arm B allowed for 3 patients to be replaced in the event of hypersensitivity to cetuximab

9. Disease Evaluation CT scan and tumor markers at baseline. Reevaluate q 2 cycles (ie after 12 weeks). Patients attaining objective response had CT scan and tumor markers repeated after one further cycle of chemotherapy (ie at 18 weeks).

10. E8200 Final accrual 94 patients from 7/31/03 to 8/23/06 8 patients were ineligible –Died prior to receiving therapy, prior chemo, outdated scans, laboratory results out of range, no measurable disease

11. Demographics

12. Treatment Information AB Mean cycle#2.63.3 Median cycle#22 Pts with >4 cycles9.3%20.9%

13. Common Grade 3/4 Toxicity A B N%N% 4645 Neutrophils11 (24)14(31) Fatigue10(22)8(18) Anorexia8(17)4(9) Nausea14(30)9(20) Vomiting6(13)9(20) Diarrhea14(30)20(44) Hyperglycemia3(7)5(11) Hypomagnesemia03(7) Neutropenic Fever/Inf3(6)4(9) Worst33(72)35(78)

14. Bleeding Events A B N%N% 4645 Epistaxis, gd 107(16) Rectal bldg, gd 101(2) Hematemesis, gd 12(4)0 Hematuria, gd 201(2) Hemorrhage/other, gd101(2)

15. Treatment-Related Death AB N4645 Neutropenia with fever or infection11 Diarrhea with sepsis1 Total2.2%4.4%

16. Response AB Unknown4.7%0% PR2.3%7% SD39.5%37.2% PD34.9%25.6% Uneval18.6%30.2%

17. Progression-Free Survival AB Data available, N=4138 Median PFS2.84.5 95% CI2.4,4.82.7,5.3

19. Overall Survival Kaplan-Meier AB Median6.55.3 95% CI5.3-8.64.4-9.5 Known to have died 86.1%93%

21. 50% Decline in CA19-9 AB N3736 50% drop11 (30%)14 (39%) Median PFS without 50% drop2.6m (2.3,3.9)2.9m (2.2,4.9) with 50% drop4.9m (2.9,7.2)5.7m (5.1,8.3) Median OS without 50% drop5.8m (4.1-7.4)4.4 (3.7-11) with 50% drop9.9m (6.5,11.9)9.5 (5.0,15.5)

22. CA19-9-Pooled Data Bsl CA19-9 < median PFS 5.1m (2.9, 5.6) > median PFS 2.6m (2.3,2.9)p*=0.048 Median PFS without 50% drop2.6m (2.3,2.9) with 50% drop5.3m (4.8,6.5)p=0.001 Median OS without 50% drop5.6m (4.1-7.4) with 50% drop9.9m (6.5,12)p=0.02 *2-sided log-rank test

31. Conclusions Non-gemcitabine containing chemotherapy has activity in metastatic pancreatic cancer Response rate by RECIST on a 12 week reassessment schedule is not a useful endpoint in pancreatic cancer in the cooperative group setting –19-30% unevaluable 50% drop in CA19-9 correlates with PFS and OS and may represent a more reproducible endpoint in cooperative group trials in metastatic pancreatic cancer

32. Conclusions The routine use of prophylactic LWM heparin is feasible in patients with metastatic pancreatic cancer, with a low rate of hemorrhage on study Toxicity of irinotecan/docetaxel with or without cetuximab is high –Grade 3/4 diarrhea 33-40% –Treatment related death 2-4% –UGT1A1 testing not performed