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Folic Acid

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Folinic Acid

Folate

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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)

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)

5-Fluorouracil

4 mg/kg BW (6 mg loading dose at 1st administration), i.v. for 1 h, d1, i.v., every two weeks

can be used to replace leucovorin (calcium folinate)

sodium folinate

Aim of surgical resection is a complete (R0) resection of the primary tumor and the metastases or a complete macroscopic cytoreduction of the metastases.

Surgery

Salah-Eddin Al-Batran, MD

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.

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.

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

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)

German Research Foundation

Arbeitsgemeinschaft fur Internistische Onkologie

Krankenhaus Nordwest

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