Chemotherapy Alone vs. Chemotherapy + Surgical Resection in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction

Study Overview
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Brief Summary
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Previously untreated patients with limited metastatic stage (see protocol for details on criteria) will receive 4 cycles of FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Patients without disease progression will be randomized 1:1 to receive additional chemotherapy cycles (4-8 cycles of FLOT) or surgical resection followed by subsequent chemotherapy (4-8 cycles of FLOT). Main objective of the study is overall survival. Most important secondary objective is the quality of life under treatment and during follow-up.

Detailed Description
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Patients with potentially limited metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction (GEJ) potentially fulfilling the selection criteria and who gave informed consent will undergo a careful screening and a central review process. 271 patients are to be allocated to the trial, of which at least 176 patients will be randomized. The primary objective is to extend overall survival, while preserving quality of life. The study has an 80% power to detect a statistically significant improvement (hazard ratio, HR 0.65) in overall survival in favor of the bimodal strategy. Quality of life (QoL) under treatment and during follow-up represents the most important secondary endpoint. All patients enrolled will receive four cycles (= 8 weeks) of FLOT. For HER-2 (human epidermal growth factor receptor 2) positive disease, trastuzumab should be added. After the 4th cycle of FLOT, patients will undergo a repeated imaging (esophago-gastro-duodenoscopy, CT/MRI or PET scan of the involved organs). Patients with disease progression will be taken out of the trial. Patients with stable disease, partial or complete remission will be stratified by tumor location (gastric vs. GEJ adenocarcinoma), response to preoperative FLOT (complete or partial remission vs. stable disease) and based on whether they have distant lymph node metastases only or additional organ involvement and will be randomized 1:1 to Arm A (with surgery) or B (no surgery). Arm A: Surgery will be scheduled 4-6 weeks after d1 of the last cycle of preoperative chemotherapy (d1 + 4-6 weeks). The protocol gives detailed recommendations for resection of the primary tumor as well as the metastases. Post-operatively, further 4-8 cycles of FLOT can be administered. Arm B: Patients will be treated with additional 4-8 cycles of FLOT. Surgical interventions are allowed for palliation. In both of the arms, tumor assessments (CT/MRI or PET of the relevant organs) are performed prior to randomization and then every 3 months thereafter until progression/relapse, death or end of follow-up. Quality of life (QoL) will be assessed at baseline, prior to randomization, and every 3 months after randomization during treatment and in the follow-up phase, together with tumor assessments. Survival status and status on relapse/first progress of disease will be assessed every 3 months for up to 5 years after randomization.

Official Title
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Effect of Chemotherapy Alone vs. Chemotherapy Followed by Surgical Resection on Survival and Quality of Life in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction - A Phase III Trial of Arbeitsgemeinschaft Internistische Onkologie/Chirurgische Arbeitsgemeinschaft Onkologie/Chirurgische Arbeitsgemeinschaft für Den Oberen Gastrointestinaltrakt (AIO/CAO-V/CAOGI)

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: 5-Fluorouracil
* Drug: Leucovorin
* Drug: Oxaliplatin
* Drug: Docetaxel
* Drug: Trastuzumab
* Drug: sodium folinate
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed limited metastatic gastric or GEJ adenocarcinoma.* Medical and technical operability of the primary. Metastatic lesions are resectable or can be controlled by local ablative procedure (central evaluation). No prior chemotherapy and no prior tumor resection. Female and male patients ≥ 18 years. Patients in reproductive age must be willing to use adequate contraception during the study and 3 months after the end of the study (appropriate contraception is defined as surgical sterilization (e.g., bilateral tubal ligation, vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any double combination of: intrauterine device, male or female condom with spermicidal gel, diaphragm, sponge, cervical cap)). Female patients with childbearing potential need to have a negative pregnancy test within 7 days before study start. ECOG (Eastern Cooperative Oncology Group) Performance Status 0 or 1 Adequate hematological, hepatic and renal function parameters: Leukocytes ≥ 3000/µl Platelets ≥ 100,000/µl Serum creatinine ≤ 1.5 x upper limit of normal, or glomerular filtration rate (GFR) > 40 ml/min Bilirubin ≤ 1.5 x upper limit of normal AST (aspartate aminotransferase) and ALT (alanine transaminase) ≤ 3.5 x upper limit of normal Alkaline phosphatase ≤ 6 x upper limit of normal Written informed consent of the patient. (*) Definition of the limited metastatic status is: Retroperitoneal lymph node metastases (RPLM) (e.g., para-aortal, intra-aorto-caval, parapancreatic or mesenterial lymph nodes) only (Note: in duodenum invading gastric cancer, retropancreatic nodes are not regarded M1) or/and at maximum one organ involved with or without RPLM according to the following schema: I. Localized potentially operable peritoneal carcinomatosis: stage P1 according to classification of the Japanese Research Society for Gastric Cancer (Clinically visible carcinomatosis of the peritoneum or of the pleura and >P1 peritoneal carcinomatosis are not allowed!) or II. Liver: maximum of 5 metastatic lesions that are potentially resectable or III. Lung: unilateral involvement, potentially resectable or IV. Uni- or bilateral Krukenberg tumors (ovarian met.) in the absence of macroscopic peritoneal carcinomatosis or V. Uni- or bilateral adrenal gland metastases or VI. Extra-abdominal lymph node metastases such as supraclavicular or cervical lymph node involvement or VII. Localized bone involvement (defined as being within one radiation field) or VIII. Other metastatic disease location that is considered limited by the investigator and is confirmed by the review committee Exclusion Criteria: Medical inoperability Inability to understand the aims of the study and/or protocol procedures Metastatic disease not fulfilling the criteria of limited disease mentioned in the inclusion criteria or non-metastatic stage (cM0) Cirrhosis of the liver, pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function Primary not resectable Hypersensitivity to 5-fluorouracil, leucovorin, oxaliplatin, or docetaxel Contraindication versus 5-fluorouracil, leucovorin, oxaliplatin, or docetaxel (see specific product information) Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA (New York Heart Association) III-IV Clinically significant valvular defect Past or current history of other malignancies unless curatively treated and without evidence of disease for more than 3 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix Known brain metastases Other severe internal disease or acute infection Peripheral polyneuropathy > NCI grade II Serious hepatic impairment (AST/ALT>3.5xULN, AP>6xULN, bilirubin>1.5xULN; ULN = upper limit of normal) Chronic inflammatory bowel disease Any other concurrent antineoplastic treatment including irradiation Participation in another clinical study Pregnancy or lactation

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: FLOT chemotherapy + surgery (OP)<br>4 cycles (8 weeks) FLOT pre-OP - surgery - 4-8 cycles FLOT (8-16 weeks) post-OP Docetaxel (50 mg/m2) in 250 ml sodium chloride (NaCl) 0.9% i.v. for 1 h, d1; Oxaliplatin (85 mg/m2) in 500 ml G5% (glucose 5%) i.v. for 2 h, d1; Leucovorin (Ca-folinate) (200 mg/m2) in 250 ml NaCl 0.9% i.v. for 1 h, d1*; 5-FU (2600 mg/m2) continuous infusion for 24 h, d1; Repeated every two weeks (qd15). * Leucovorin can be replaced by sodium folinate. Dose adjustment necessary if levo-leucovorin is used instead of racemic leucovorin mixture. For HER-2 positive disease, trastuzumab should be added: Trastuzumab 4 mg/kg body weight (6 mg loading dose at 1st administration), i.v. for 1 h, d1 For PD-L1 positive disease (CPS ≥ 5), nivolumab can be added according to SmPC: Nivolumab 240 mg i.v. for 30 min, d1, repeated every two weeks (q15d) | Drug: 5-Fluorouracil<br>* 2600 mg/m², d1 i.v., every 2 weeks<br>* Other names: 5-FU;Drug: Leucovorin<br>* 200 mg/m², d1, i.v., every 2 weeks<br>* Other names: calcium folinate;Drug: Oxaliplatin<br>* 85 mg/m², d1, i.v., every 2 weeks<br>Drug: Docetaxel<br>* 50mg/m², d1, i.v., every 2 weeks<br>Drug: Trastuzumab<br>* 4 mg/kg BW (6 mg loading dose at 1st administration), i.v. for 1 h, d1, i.v., every two weeks<br>Drug: sodium folinate<br>* can be used to replace leucovorin (calcium folinate)<br>Procedure: Surgery<br>* Aim of surgical resection is a complete (R0) resection of the primary tumor and the metastases or a complete macroscopic cytoreduction of the metastases.<br>|
| Active Comparator: Arm B: FLOT chemotherapy alone<br>4 cycles (8 weeks) FLOT followed by further 4-8 cycles FLOT (8-16 weeks) Docetaxel (50 mg/m2) in 250 ml sodium chloride (NaCl) 0.9% i.v. for 1 h, d1; Oxaliplatin (85 mg/m2) in 500 ml G5% (glucose 5%) i.v. for 2 h, d1; Leucovorin (Ca-folinate) (200 mg/m2) in 250 ml NaCl 0.9% i.v. for 1 h, d1*; 5-FU (2600 mg/m2) continuous infusion for 24 h, d1; Repeated every two weeks (qd15). * Leucovorin can be replaced by sodium folinate. Dose adjustment necessary if levo-leucovorin is used instead of racemic leucovorin mixture. For HER-2 positive disease, trastuzumab should be added: Trastuzumab 4 mg/kg body weight (6 mg loading dose at 1st administration), i.v. for 1 h, d1 For PD-L1 positive disease (CPS ≥ 5), nivolumab can be added according to SmPC: Nivolumab 240 mg i.v. for 30 min, d1, repeated every two weeks (q15d) | Drug: 5-Fluorouracil<br>* 2600 mg/m², d1 i.v., every 2 weeks<br>* Other names: 5-FU;Drug: Leucovorin<br>* 200 mg/m², d1, i.v., every 2 weeks<br>* Other names: calcium folinate;Drug: Oxaliplatin<br>* 85 mg/m², d1, i.v., every 2 weeks<br>Drug: Docetaxel<br>* 50mg/m², d1, i.v., every 2 weeks<br>Drug: Trastuzumab<br>* 4 mg/kg BW (6 mg loading dose at 1st administration), i.v. for 1 h, d1, i.v., every two weeks<br>Drug: sodium folinate<br>* can be used to replace leucovorin (calcium folinate)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | up to 5 years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life (QoL) adjusted OS |  | up to 5 years follow-up | 
| QoL-response |  | up to 5 years follow-up | 
| QoL mean scores |  | up to 5 years follow-up | 
| OS in patients with lymph node metastases only |  | up to 5 years follow-up | 
| Progression free survival (PFS) |  | up to 5 years follow-up | 
| Surgical morbidity |  | up to 2 months after surgery | 
| Surgical mortality |  | up to 2 months after surgery | 
| Toxicity - Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | From signature of the informed consent form (ICF) up to 30 days after last administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gastric cancer, perioperative, FLOT, limited metastatic, GEJ cancer