RAD001 in Advanced Gastric Cancer Who Failed Standard First-line Treatment With pS6 Ser 240/4 Expression

Study Overview
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Brief Summary
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This is a phase II study to evaluate RAD001 (Everolimus) in terms of 4-month progression-free survival rate (primary end-point) and response rate, toxicity, overall survival and biomarker assessment (secondary end-points) in patients with metastatic or recurrent gastric cancer with pS6 Ser 240/4 expression. Eligibility criteria include pathologically proven non-resectable adenocarcinoma of stomach with measurable disease who failed previous first-line palliative chemotherapy including fluoropyrimidine and platinum with high expression of pS6 Ser 240/4. Oral RAD001 (everolimus) 10mg daily will be administered and the dose will be adjusted according to the observed clinical toxicities. Treatment will be continued until disease progression or patient's intolerability to the study drug. A study requires 40 assessable subjects to decide whether the proportion of patients who are free from progression at 4 months (16 weeks), P, is less than or equal to 0.1 or greater than or equal to 0.25 with a target error rate of 0.05 and β of 0.2. If the number of responses is 7 or less, the hypothesis that P >= 0.250 is rejected with a target error rate of 0.200 and an actual error rate of 0.182. If the investigators assume that drop-out rate is 10%, total accrual patient will be 45.

Detailed Description
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Methodology: Prospective, non blinded, open label, single center phase II study Criteria for evaluation: Assessment of response will be assessed radiologically according to RECIST criteria after completion of the two cycles. Evaluation will be by physical examination, chest X-ray, abdomen-pelvis CT scan Safety criteria: Physical examination, vital signs, performance status, CBC, serum chemistry, NCI CTC V.3.0

Official Title
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A Phase II Trial of RAD001 (Everolimus) for 2nd Line Treatment After Failure of Fluoropyrimidine Plus Platinum Chemotherapy in Patients With Metastatic or Recurrent Gastric Cancer With pS6 Ser 240/4 Expression

Conditions
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Stomach Neoplasm

Intervention / Treatment
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* Drug: RAD001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically or cytologically documented stomach adenocarcinoma including adenocarcinoma of the esophagogastric junction non-resectable disease by metastasis or recurrent disease after curative surgical resection (See Appendix A) with uni-dimensionally measurable disease failure of 1st line chemotherapy including fluoropyrimidine (capecitabine, S1, or 5-FU,) and platinum (cisplatin or oxaliplatin) in palliative setting; progression during or within 6 months after chemotherapy High expression of pS6 Ser 240/4 (proportion of pS6 Ser 240/4 positive cancer cells by immunohistochemistry > 10%) Age 20 to 75 years old Estimated life expectancy of more than 3 months ECOG performance status of 2 or lower Adequate bone marrow function Adequate kidney function Adequate liver function Fasting serum cholesterol ≤ 300 mg/dL AND fasting triglyceride ≤ 2.5 X ULN No prior radiation therapy to more than 25% of BM psychological, familial, sociological or geographical conditions which do not permit medical follow-up and compliance with this study Women of childbearing potential must have a negative pregnancy test on admission Written informed consent Exclusion Criteria: Other tumor type than adenocarcinoma CNS metastases or prior radiation for CNS metastases Gastric outlet obstruction or intestinal obstruction Evidence of active gastrointestinal bleeding Bone lesions as the sole evaluable disease Past or concurrent history of neoplasm other than stomach cancer Pregnant or lactating women, women of childbearing potential not employing adequate contraception Other serious illness or medical conditions Concomitant or with a 4-week period administration of any other experimental drug under investigation Concomitant chemotherapy, hormonal therapy, or immunotherapy Any preexisting medical condition of sufficient severity to prevent full compliance with the study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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: RAD001 (everolimus)<br> | Drug: RAD001<br>* RAD001 (everolimus) 10 mg daily, orally without interruption. 1 cycle is equal to 4-week treatment. Treatment will be continued unless disease progression or intolerability.<br>* Other names: everolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4-month progression-free survival | Progression-free survival is defined as the time from the first treatment to the onset of progressive disease per RECIST criteria or to the date of death whichever comes first. For patients who do not experience progressive disease or death, the progression-free survival duration will be right censored on the last disease assessment date. | up to 3years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | evaluated with abdominal and pelvic dynamic CT scan every 8 weeks, using RECIST version 1.0 | Up to 1year | 
| Number of participants with adverse events | Adverse events will be graded according to Common Terminology Criteria for Adverse events version 4.0 | Monitoring of adverse events will be contineud for at least 28days following the last dose of study treatment | 
| Overall survival | Overall survival duration is calculated as time from the first treatment to the date of death. For patients who are still alive at the cut-off date for statistical reporting, the overall survival duration will be right censored on the last known alive date. | Up to 3years | 
| Biomarker assessment | Tumor tissues obtained by tumor tissues can be used for immunohistochemistry(IHC) of pS6 Ser 240/4. In patients who did not receive gastrectomy tumor biopsies will be obtained at screening(before everolimus treatment) and after two cycles of treatment. Scoring of all IHC results is based on the percentage of positive cells. The percentage of positive cells is scored as: 0 (0%); 1 (≤10%); 2 (11-33%); 3 (34-66%); 4 (≥67%). | 24months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pS6 Ser 240/4, RAD001 (everolimus), second-line treatment, advanced gastric cancer