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

• 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

OBJECTIVES and DesignThe 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

Schema/METHODS

Stratification FactorsDisease 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/m2 IV over 1 hour on day 1 of each 21-day cycle

Cisplatin 75 mg/m2 IV over 1-2 hours on day 1 of each 21-day cycle

Treatment continues until progression

STUDY

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

Patient DemographicsPatient DemographicsN (44) %

Gendermale 37 84%

female 7 16%Age Average (60) Range (28-86)Race

White (non-his) 39 88.6%White (his) 4 9.1%

African American 1 2.3%PS

0 27 61.4%1 17 38.6%

Disease statusDistal Metastatic 35 79.5%

Advanced Unresectable 9 20.5%

ECOG 5203: Efficacy

N= 44 %RR 18 40.9%SD 14 31.8%Progression 3 6.8%Unevaluble^ 9 20.5%

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

Treatment Arm CENSOREDPFS-EVENT MEDIANTOTALA 44 38 6 5.8

Prob

abilit

yPFS - E5203

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Progression-Free Survival (Months)0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Progression-Free Survival

Treatment Arm ALIVEDEAD MEDIANTOTALA 44 32 12 13.6

Prob

abilit

yOverall Survival - E5203

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival (Months)0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Overall Survival

ECOG 5203: ToxicityN=44 Gr. 3 ( #20) Gr. 4 (#18) Gr. 5 (#2)

Leukopenia 8 10 -

Lymphocytopenia 1 1 -

Neutropenia 11 17 -

Febrile Neutropenia 3 - -

Infection 3 1 1*

Thrombocytopenia 2 - -

Hemorrhage 1 1**

Thrombosis/Thrombusembolism

1 2 -

*The pt died due to infection with NL ANC during 8th 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.

ECOG 5203: Toxicity

N=44 Gr. 3 ( #20) Gr. 4 (#18) Gr. 5 (#2)Rectal Perforation 1 - -Hypotension 2 - -Hand-Foot Reaction 7 - -

Rash/Desquamation 2 2Fatigue 7 - -Anorexia 6 - -Dehydration 8 1 -Diarrhea 6 - -Nausea 7 - -Vomiting 2 - -

ECOG 5203: ToxicityN=44 Gr. 3 ( #20) Gr. 4 (#18) Gr. 5 (#2)Allergic reaction 1 - -Seizure 1 - -Atria fibrillation 1 - -Confusion 1 -Hypoxia 1 - -Ataxia 1 - -Neuropathy

(Sensory)3 - -

Headache 1 - -Syncope 2 - -Esophageal Pain 1 - -Scalp pain 1 - -

ECOG 5203: ToxicityN=44 Gr. 3 ( #20) Gr. 4 (#18) Gr. 5 (#2)Hypoalbuminemia 2 - -

Alk Phos 1 - -

ALT (SGPT) 2 - -

AST (SGOT) 2 - -

Bilirubin 1 - -

Hypocalcemia 2 - -

Creatinine 1 - -

Hyperglycemia 3 - -

Hypomagnesemia 1 1 -

Hypophosphatemia 1 - -

Hypokalemia 3 1 -

Hyponatremia 4 1 -

Renal failure - 1 -

• 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