Epirubicin Hydrochloride, Cisplatin, and Fluorouracil or Capecitabine With or Without Lapatinib Ditosylate as First-Line Therapy in Treating Patients With Stomach Cancer or Gastroesophageal Junction Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as epirubicin hydrochloride, cisplatin, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving combination chemotherapy together with or without lapatinib ditosylate is more effective in treating patients with cancer of the stomach or gastroesophageal junction. PURPOSE: This randomized phase II trial is studying how well epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine works when given together with or without lapatinib ditosylate as first-line therapy in treating patients with stomach cancer or gastroesophageal junction cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To determine the activity of first-line treatment comprising epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine with or without lapatinib ditosylate in patients with adenocarcinoma of the stomach or esophagogastric junction that is metastatic or not amenable to curative surgery according to HER2 and EGFR status. Secondary To explore the activity of this regimen in patients who are HER2 negative by FISH, but HER2 positive by IHC (2+ and 3+) as well as patients who are HER2 positive or negative by FISH and negative by IHC (0 or 1+), but EGFR positive by FISH or by IHC (2+ and 3+). To assess the concordance of HER2 determination by FISH and IHC. OUTLINE: This is a multicenter study. Patients are stratified according to institution and the combination of EGFR/HER2 status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) assays (HER2 positive by FISH/HER2 positive by IHC 2/3+ vs HER2 negative by FISH/HER2 positive by IHC 2/3+ vs HER2 negative by IHC 0/1+/EGFR positive by FISH or by IHC 2/3+). Patients are randomized to 1 of 2 treatment arms. Arm I (experimental): Patients receive epirubicin hydrochloride IV and cisplatin IV on day 1; fluorouracil IV continuously on days 1-21 or oral capecitabine twice daily on days 1-21; and oral lapatinib ditosylate once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Arm II (control): Patients receive epirubicin hydrochloride, cisplatin, and fluorouracil or capecitabine as in arm I. Patients also receive oral placebo once daily on days 1-21. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 8 weeks, every 3 months for 2 years, and then every 6 months thereafter.

Official Title
-----------------
Effectiveness of First Line Treatment With Lapatinib and ECF/X in Histologically Proven Adenocarcinoma of the Stomach or the Esophagogastric Junction, Metastatic or Not Amenable to Curative Surgery According to HER2 and EGFR Status: a Randomized Phase II Trial

Conditions
-----------------
Adenocarcinoma of the Gastroesophageal Junction, Gastric Cancer

Intervention / Treatment
-----------------
* Drug: capecitabine
* Drug: cisplatin
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Drug: lapatinib ditosylate


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the stomach or the esophagogastric junction Metastatic disease OR not amenable to curative surgery Tissue material for HER2 and EGFR assessment must be available Positive HER2 status by immunohistochemistry (IHC) OR positive EGFR by either fluorescence in situ hybridization (FISH) or IHC at time of randomization No clinical signs of CNS involvement PATIENT CHARACTERISTICS: WHO performance status 0-1 WBC > 3 x 10^9/L Absolute neutrophil count > 1.5 x 10^9/L Platelet count > 100 x 10^9/L Hemoglobin > 9 g/dL Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST/ALT ≤ 3 times ULN (≤ 5 times ULN in case of liver metastases) Serum creatinine ≤ 2.0 mg/dL Creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 1 month after completion of study therapy LVEF normal by MUGA scan or ECHO No serious cardiac illness within the past 6 months No previous or concurrent malignancies except for adequately treated cone-biopsied carcinoma in situ of the cervix or basal cell carcinoma of the skin Able to swallow and retain oral medication No history or evidence of interstitial pneumonitis or pulmonary fibrosis No uncontrolled infections or serious illnesses, malabsorption syndrome, or medical conditions including chronic alcohol abuse, hepatitis, HIV, and/or cirrhosis No psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or follow-up schedule PRIOR CONCURRENT THERAPY: At least 12 months since prior neoadjuvant or adjuvant chemotherapy No other investigational drugs from 28 days prior to the first dose of study treatment until 30 days after the last dose of study treatment At least 30 days since prior and no concurrent drugs or herbal constituents known to be inducers or inhibitors of CYP3A4 No prior palliative systemic chemotherapy No prior EGFR pathway-targeting therapy (e.g., antibodies or tyrosine kinase inhibitors) No concurrent traditional Chinese medicines No concurrent non-drug therapies such as radiotherapy (other than for pain relief) or surgery No other concurrent anticancer therapy or investigational agents No concurrent grapefruit or its juice

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib<br>Chemotherapy + lapatinib | Drug: capecitabine<br> <br> Drug: cisplatin<br> <br> Drug: epirubicin hydrochloride<br> <br> Drug: fluorouracil<br> <br> Drug: lapatinib ditosylate<br> <br> |
| Placebo Comparator: Placebo<br>Chemotherapy + placebo | Drug: capecitabine<br> <br> Drug: cisplatin<br> <br> Drug: epirubicin hydrochloride<br> <br> Drug: fluorouracil<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate |  |  | 
| Overall survival |  |  | 
| Toxicity |  |  | 
| Concordance of diagnostic tests |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the gastroesophageal junction, adenocarcinoma of the stomach, stage IIIA gastric cancer, stage IIIB gastric cancer, stage IIIC gastric cancer, stage IV gastric cancer