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Background

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).

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Background

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  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 GroupStudy(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/m2 followed by irinotecan 50 mg/m2 weekly x 4, q 6 weeks • Randomized phase II, 2 arms: • Irinotecan/docetaxel • Irinotecan/docetaxel + cetuximab loading dose of 400 mg/m2 followed by 250 mg/m2 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 A B Mean cycle# 2.6 3.3 Median cycle# 2 2 Pts with >4 cycles 9.3% 20.9%

  13. Common Grade 3/4 Toxicity A B N % N % 46 45 Neutrophils 11 (24) 14 (31) Fatigue 10 (22) 8 (18) Anorexia 8 (17) 4 (9) Nausea 14 (30) 9 (20) Vomiting 6 (13) 9 (20) Diarrhea 14 (30) 20 (44) Hyperglycemia 3 (7) 5 (11) Hypomagnesemia 0 3 (7) Neutropenic Fever/Inf 3 (6) 4 (9) Worst 33 (72) 35 (78)

  14. Bleeding Events A B N % N % 46 45 Epistaxis, gd 1 0 7 (16) Rectal bldg, gd 1 0 1 (2) Hematemesis, gd 1 2 (4) 0 Hematuria, gd 2 0 1 (2) Hemorrhage/other, gd1 0 1 (2)

  15. Treatment-Related Death A B N 46 45 Neutropenia with fever or infection 1 1 Diarrhea with sepsis 1 Total 2.2% 4.4%

  16. Response A B Unknown 4.7% 0% PR 2.3% 7% SD 39.5% 37.2% PD 34.9% 25.6% Uneval 18.6% 30.2%

  17. Progression-Free Survival A B Data available, N= 41 38 Median PFS 2.8 4.5 95% CI 2.4,4.8 2.7,5.3

  18. Overall SurvivalKaplan-Meier A B Median 6.5 5.3 95% CI 5.3-8.6 4.4-9.5 Known to have died 86.1% 93%

  19. 50% Decline in CA19-9 A B N 37 36 50% drop 11 (30%) 14 (39%) Median PFS without 50% drop 2.6m (2.3,3.9) 2.9m (2.2,4.9) with 50% drop 4.9m (2.9,7.2) 5.7m (5.1,8.3) Median OS without 50% drop 5.8m (4.1-7.4) 4.4 (3.7-11) with 50% drop 9.9m (6.5,11.9) 9.5 (5.0,15.5)

  20. CA19-9-Pooled Data Bsl CA19-9 < median PFS 5.1m (2.9, 5.6) > medianPFS 2.6m (2.3,2.9) p*=0.048 Median PFS without 50% drop 2.6m (2.3,2.9) with 50% drop 5.3m (4.8,6.5) p=0.001 Median OS without 50% drop 5.6m (4.1-7.4) with 50% drop 9.9m (6.5,12) p=0.02 *2-sided log-rank test

  21. 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

  22. 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

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