FOLFOX6 Versus mFOLFIRINOX as First Line Chemotherapy in Metastatic Gastric Cancer or Esophagogastric Junction Adenocarcinoma (Type II-III)

Study Overview
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Brief Summary
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Patients with metastatic adenocarcinoma of the stomach or the esophagogastric junction (II-III type by Siewert) without previous therapy will be treated with one of two chemotherapy combinations . One half of the patients gets 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin (FOLFOX6), the others 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin and Irinotecan (mFOLFIRINOX). Main objective of the study is progression free survival.

Detailed Description
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This parallel, randomized, open-label study 326 patients with metastatic ( adenocarcinoma of the stomach or the esophagogastric junction without previous therapy will be included in this study. After randomization patients receive 9 cycles FOLFOX6 or mFOLFIRINOX. Stratification factors include ECOG, site of metastasis, age, pathological subtypes. Efficacy will be evaluated every 3 cycles with RECIST. Toxicity will be assessed with WHO CTC 3.0 every 2 weeks.

Official Title
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FOLFOX6 Versus mFOLFIRINOX as First Line Chemotherapy in Metastatic Gastric or Esophagogastric Junction Adenocarcinoma (Type II-III): Open-label Randomized Phase 2/3 Trial

Conditions
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Gastric Carcinoma Stage IV, Esophagogastric Junction Adenocarcinoma Stage IV

Intervention / Treatment
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* Drug: Irinotecan
* Drug: Oxaliplatin
* Drug: 5-FU
* Drug: 5-FU
* Drug: Leucovorin
* Drug: 5-FU
* Drug: 5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically confirmed locally advanced, recurrent or metastatic adenocarcinoma of the esophagogastric junction (Siewert type II-III) or the stomach no prior palliative chemotherapy or radiation therapy Age 18-70 years (female and male) Eastern Cooperative Oncology Group ≤ 2 Neutrophils> 2.000/µl Platelets > 100.000/µl Normal value of Serum Creatinin Albumin level > 29 г/л Aspartate transaminase (AST) or alanine transaminase (ALT) less than 3 times the upper limits of normal (ULN) Total Bilirubin less than 1.5 times the ULN Written informed consent. Exclusion Criteria: Previous palliative cytostatic chemotherapy Cancer relapse Complicated gastric cancer (perforation, bleeding, sub or decompensated stenosis, dysphagia IV) Diarrhea ≥ 2 according to the criteria of Common Terminology Criteria for Adverse Events (CTCAE) version 4.1; Hypersensitivity against 5- Fluorouracil, Leucovorin, Oxaliplatin, irinotecan Existence of contraindications against 5- Fluorouracil, Leucovorin, Oxaliplatin, Irinotecan or Docetaxel Active coronary heart disease, Cardiomyopathy or cardiac insufficiency stage III-IV according to New York Heart Association (NYHA) Severe non-surgical accompanying disease or acute infection (uncontrolled arterial hypertension, diabetes mellitus, stroke less than 6 months old, mental disorders, other tumors and others) Malignant secondary disease, dated back < 5 years (exception: In-situ-carcinoma of the cervix uteri, adequately treated skin basal cell carcinoma) Peripheral polyneuropathy > Grad II Liver dysfunction (AST)/ALT>3,0xULN, ALT>3xULN, Bilirubin>1,5xULN) Serum Creatinin >1,0xULN Chronic inflammable gastro-intestinal disease Inclusion in another clinical trial Pregnancy or lactation Hepatitis B or C in the active stage Human immunodeficiency virus(HIV) infected Serious concomitant somatic and mental illnesses / deviations or territorial causes that may prevent the patient from participating in the protocol and observing the protocol schedule Foreigners or persons with limited legal status

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FOLFOX6<br>5FU 400mg/m2 iv bolus d1, 5-FU 2400 mg/m² d1-2, Leucovorin 400 mg d1, Oxaliplatin 85 mg/m² d1, every two weeks (q2w) 9 cycles | Drug: Oxaliplatin<br>* d1 Oxaliplatin 85 mg/m² every two weeks<br>Drug: Leucovorin<br>* d1 Leucovorin 400 mg every two weeks<br>Drug: 5-FU<br>* d1 5-FU 400 mg/m² every two weeks<br>Drug: 5-FU<br>* d1-2 5-FU 2400 mg/m² every two weeks<br>|
| Experimental: mFOLFIRINOX<br>Irinotecan 180mg/m2 d1, 5FU 250mg/m2 iv bolus d1, 5-FU 2200 mg/m² d1-2, Leucovorin 400 mg d1, Oxaliplatin 85 mg/m² d1, every two weeks (q2w) 9 cycles | Drug: Irinotecan<br>* d1 Irinotecan 180mg/m² every two weeks<br>Drug: Oxaliplatin<br>* d1 Oxaliplatin 85 mg/m² every two weeks<br>Drug: 5-FU<br>* d1-2 5-FU 2200 mg/m² every two weeks<br>Drug: 5-FU<br>* d1 5-FU 250 mg/m² every two weeks<br>Drug: Leucovorin<br>* d1 Leucovorin 400 mg every two weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | PFS is defined as the time from the date of randomization to the date of the first documentation of progressive disease or date of death, whichever occurs first. For target lesions (TL), PD was defined as at least a 20 percent (%) increase in the sum of the longest diameter (SLD) of TLs, taking as a reference the smallest SLD recorded since the treatment started, or the appearance of one or more lesions. For non-target lesions (NTL), PD was defined as an unequivocal progression of existing NTLs. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log or the date of last follow-up | 60 months | 
| Percentage of Participants With Confirmed Complete Response (CR) or Partial Response (PR) Determined by Response Evaluation Criteria in Solid Tumors (RECIST) |  | 12 months | 
| Duration of Response |  | 12 months | 
| Treatment associated toxicities | WHO CTC 3.0 | 12 months |