1. A Phase II Study of Sorafenib Combining with Docetaxel and Cisplatin in the Treatment of Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma (ECOG 5203) Weijing Sun, Mark Powell, Peter J O’Dwyer, R. H. Ansari, Al B. Benson University of Pennsylvania, Philadelphia, PA; Dana Farber Cancer Institute, Boston, Massachusett, Boston, MA; Memorial Hospital of South Bend, South Bend, IN; Northwestern University, Chicago, IL

2. Adenocarcinoma of the stomach and gastroesophageal junction (GEJ) is a highly virulent disease and remains a leading cause of death worldwide. Alterations of the ras/raf pathway may contribute to the pathogenesis of the disease. Sorafenib is a potent inhibitor of raf tyrosine kinase and of several receptor tyrosine kinases (RTKs) that are involved in tumor progression (e.g. VEGFR-2, VEGFR-3, PDGFR-β ). The combination of docetaxel and cisplatin is commonly used in the treatment of gastric cancer. This study tested the efficacy and tolerability of combining sorafenib with docetaxel and cisplatin in patients with metastatic or advanced unresectable gastric/GEJ adenocarcinoma. INTRODUCTION

3. OBJECTIVES and Design The design for this protocol is a single-stage design -To evaluate objective response rate of the Combination of Sorafenib with docetaxel and cisplatin [a true response rate (CR + PR) of 40% or more will be taken as evidence of activity.] - To evaluate the PFS and OS - To evaluate the toxicities of the combination - To evaluate raf status in the tumor and to correlate response and TTP

4. Schema/METHODS Stratification Factors Disease site or tumor location (Type I, II or III) 2) Locally advanced unresectable vs. distal metastatic disease Sorafenib 400 mg, BID for 28 21 days Docetaxel 75 mg/m 2 IV over 1 hour on day 1 of each 21-day cycle Cisplatin 75 mg/m 2 IV over 1-2 hours on day 1 of each 21-day cycle Treatment continues until progression

5. STUDY Open: 10/28/05 First Registration: 3/13/2006 Finish Enrollment: 8/28/06 - 44 patients.

6. Patient Demographics N (44)% Gender male3784% female716% AgeAverage (60)Range (28-86) Race White (non-his)3988.6% White (his)49.1% African American12.3% PS 02761.4% 11738.6% Disease status Distal Metastatic3579.5% Advanced Unresectable920.5%

7. ECOG 5203: Efficacy N= 44% RR1840.9% SD1431.8% Progression36.8% Unevaluble^ 920.5% months (90% CI) mPFS*5.8(5.4 – 7.4) mOS*13.6(8.6 – 16.1) ^Most are due to improperly timed or conducted scans * As of 5/9/08

8. Progression-Free Survival

9. Overall Survival

10. ECOG 5203: Toxicity N=44Gr. 3 ( #20)Gr. 4 (#18)Gr. 5 (#2) Leukopenia810- Lymphocytopenia11- Neutropenia1117- Febrile Neutropenia3-- Infection311* Thrombocytopenia2-- Hemorrhage11** Thrombosis/ Thrombusembolism 12- *The pt died due to infection with NL ANC during 8 th cycle of treatment, each of the 3 study drug was deemed ‘probable cause’, adenoCa at GEJ as a definite cause. ** the pt died of hemorrhage (tumor site) 3 days after completing 4 cycles of treatment, sorafenib was deemed as possible cause, adenoCa at GEJ as a definite cause.

11. ECOG 5203: Toxicity N=44Gr. 3 ( #20)Gr. 4 (#18)Gr. 5 (#2) Rectal Perforation1-- Hypotension2-- Hand-Foot Reaction7-- Rash/Desquamation22 Fatigue7-- Anorexia6-- Dehydration81- Diarrhea6-- Nausea7-- Vomiting2--

12. ECOG 5203: Toxicity N=44Gr. 3 ( #20)Gr. 4 (#18)Gr. 5 (#2) Allergic reaction1-- Seizure1-- Atria fibrillation1-- Confusion1- Hypoxia1-- Ataxia1-- Neuropathy (Sensory) 3-- Headache1-- Syncope2-- Esophageal Pain1-- Scalp pain1--

13. ECOG 5203: Toxicity N=44Gr. 3 ( #20)Gr. 4 (#18)Gr. 5 (#2) Hypoalbuminemia2-- Alk Phos1-- ALT (SGPT)2-- AST (SGOT)2-- Bilirubin1-- Hypocalcemia2-- Creatinine1-- Hyperglycemia3-- Hypomagnesemia11- Hypophosphatemia1-- Hypokalemia31- Hyponatremia41- Renal failure-1-

14. The efficacy thiscombination is very encouraging with median overall survival of 13.6 months (RR of 40.9 %, SD 31.8 % and PFS of 5.8 months). There is no obvious increased toxicity by adding sorafenib to docetaxel and cisplatin combination Further phase III study with the combination should be considered. Conclusion