S-1, Gemcitabine and Erlotinib for Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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This study will conduct a phase II study of gemcitabine, erlotinib, and S-1 as first-line chemotherapy in patients with advanced pancreatic cancer and evaluate the EGFR expression, KRAS mutation, and BRAF mutation as predictive or prognostic markers

Detailed Description
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Pancreatic ductal adenocarcinoma, also known as pancreatic cancer, is an eighth cause of cancer-related deaths in the world. The estimated worldwide incidence of pancreatic cancer was 277,000 cases and an estimated 266,000 patients died from the disease in 20081. Pancreatic cancer is more common in elderly persons than in younger persons, and characterised by early locoregional spread and distant metastasis. As a result, less than 20% of patients are diagnosed with localized, potentially curable disease, and the median survival is no longer than 3-4 months without effective treatment2. Single-agent chemotherapy with gemcitabine was considered as standard of care for patients with advanced pancreatic cancer, since Burris et al. demonstrated superiority of gemcitabine over 5-fluorouracil (5-FU) in respect of a survival benefit as well as an improvement in disease related symptoms in a randomized study3. Nevertheless, the activity of gemcitabine monotherapy in pancreatic cancer was modest, and there was a clear need to improve its efficacy by combining it with other anticancer drugs. Multiple agents such as 5-FU4, capecitabine5,6, cisplatin7,8, oxaliplatin9, pemetrexed10, irinotecan11, cetuximab12, and bevacizumab13, in combination with gemcitabine have been tested in clinical trials, however, they have failed to improve the outcome. The only agent that, in combination with gemcitabine, has shown a small, but statistically significant improvement, with a hazard ratio (HR) of 0.82, the absolute improvement in median overall survival (OS) of 5.9 months with gemcitabine versus 6.2 months with the combination, is erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR)14. Considering the modest improvement in survival by adding erlotinib to gemcitabine, new combination therapy that have a great impact is urgently needed. S-1 is an oral fluoropyrimidine derivative that combines tegafur (FT) with two modulators; 5-chloro-2, 4-dihydroxypyridine (CDHP) and oteracil potassium (Oxo) in a 1:0.4:1 molar concentration ratio. The phase II trials of a combination of gemcitabine and S-1 have demonstrated objective response rates of 32-48% and median survival of 8-12 months 15-17. Therefore, we will conduct a phase II study of gemcitabine, erlotinib, and S-1 as first-line chemotherapy in patients with advanced pancreatic cancer and evaluate the EGFR expression, KRAS mutation, and BRAF mutation as predictive or prognostic markers.

Official Title
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A Phase II Study of S-1 in Combination With Gemcitabine and Erlotinib in Patients With Advanced or Metastatic Pancreatic Cancer

Conditions
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Pancreas Neoplasms

Intervention / Treatment
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* Drug: GES (Gemcitabine, Erlotinib, S-1)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed locally advanced unresectable, recurrent or metastatic adenocarcinoma of pancreas (Stage III-IV ; TNM staging system) Measurable or evaluable disease by RECIST criteria 1.1 Minimum age of 18 years ECOG Performance status 0-1 Prior adjuvant chemotherapy without gemcitabine, erlotinib or S-1 is allowed if more than 4 weeks elapsed since completion of chemotherapy. More than 4 weeks since completion of prior radiotherapy (measurable or evaluable lesions should be outside the radiation field) Adequate organ functions Patients must sign an informed consent indicating that they are aware of the investigational nature of the study in keeping with the policy of the hospital. Exclusion Criteria: Patients treated previously with gemcitabine, erlotinib, or S-1 as adjuvant chemotherapy. Patients with CNS metastases Patients with active infection, severe heart disease, uncontrollable hypertension or diabetes mellitus, myocardial infarction during the preceding 6 months, pregnancy, or breast feeding Any previous or concurrent malignancy other than non-melanoma skin cancer or in situ cancer of uterine cervix Known history of cerebral or leptomeningeal metastases or neurologic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GES (Gemcitabine, Erlotinib, S-1)<br>Treatment will be delivered as a 3-week cycle. Gemcitabine 1000 mg/m² IV on day 1, 8 Erlotinib 100 mg/day PO on day 1 S-1 60 mg/m²/day PO on day 1-14 | Drug: GES (Gemcitabine, Erlotinib, S-1)<br>* Treatment will be delivered as a 3-week cycle. Gemcitabine 1000 mg/m² IV on day 1, 8 Erlotinib 100 mg/day PO on day 1 S-1 60 mg/m²/day PO on day 1-14<br>* Other names: TS-1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Objective response rate will be measured from the rate of complete response (disappearance of disease) and partial response (decrease at least 30% in the sum of the longest diameters of target lesions) by RECIST (response evaluation criteria in solid tumors) guidelines. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival time will be measured from the start of study treatment until documented tumor progression, or death due to any cause | 1.5 years | 
| Overall survival | Overall survival time will be measured from the start of study treatment until death due to any cause | 1.5 years | 
| Disease control rate | Disease control rate will be measured from the rate of complete response (disappearance of disease), partial response (decrease at least 30% in the sum of the longest diameters of target lesions), and stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) by RECIST (response evaluation criteria in solid tumors) guidelines. | 1.5 years | 
| Toxicity profiles | Adverse events will be descripted and graded using NCI-CTCAE version 4.0 | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreas neoplasm, gemcitabine, erlotinib, S-1