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

Phase 3

Completed

• Conditions: Gastric Cancer
• Interventions: Drug: 5-Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Docetaxel; Drug: Trastuzumab; Drug: sodium folinate; Procedure: Surgery

• Registration Number: NCT02578368
• Lead Sponsor: Krankenhaus Nordwest

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2015-10-12
• Study First Submitted QC: 2015-10-15
• Study First Posted: 2015-10-16
• Study Start: 2016-02
• Primary Completion: 2024-08-27
• Study Completion: 2024-08-27
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-11
• Last Update Posted: 2024-11-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 183

Inclusion Criteria

1. Histologically confirmed limited metastatic gastric or GEJ adenocarcinoma.*

2. Medical and technical operability of the primary.

3. Metastatic lesions are resectable or can be controlled by local ablative procedure (central evaluation).

4. No prior chemotherapy and no prior tumor resection.

5. 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.

6. ECOG (Eastern Cooperative Oncology Group) Performance Status 0 or 1

7. 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

8. Written informed consent of the patient.

(*) Definition of the limited metastatic status is:

1. 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
2. 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

1. Medical inoperability
2. Inability to understand the aims of the study and/or protocol procedures
3. Metastatic disease not fulfilling the criteria of limited disease mentioned in the inclusion criteria or non-metastatic stage (cM0)
4. Cirrhosis of the liver, pronounced alcohol abuse with anticipated detoxification, severe pulmonary infection with considerable reduction of pulmonary function
5. Primary not resectable
6. Hypersensitivity to 5-fluorouracil, leucovorin, oxaliplatin, or docetaxel
7. Contraindication versus 5-fluorouracil, leucovorin, oxaliplatin, or docetaxel (see specific product information)
8. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA (New York Heart Association) III-IV
9. Clinically significant valvular defect
10. 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
11. Known brain metastases
12. Other severe internal disease or acute infection
13. Peripheral polyneuropathy > NCI grade II
14. Serious hepatic impairment (AST/ALT>3.5xULN, AP>6xULN, bilirubin>1.5xULN; ULN = upper limit of normal)
15. Chronic inflammatory bowel disease
16. Any other concurrent antineoplastic treatment including irradiation
17. Participation in another clinical study
18. Pregnancy or lactation

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm B: FLOT chemotherapy alone	sodium folinate	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)
Arm A: FLOT chemotherapy + surgery (OP)	sodium folinate	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)
Arm A: FLOT chemotherapy + surgery (OP)	Surgery	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)
Arm A: FLOT chemotherapy + surgery (OP)	5-Fluorouracil	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)
Arm A: FLOT chemotherapy + surgery (OP)	Leucovorin	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)
Arm A: FLOT chemotherapy + surgery (OP)	Oxaliplatin	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)
Arm A: FLOT chemotherapy + surgery (OP)	Trastuzumab	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)
Arm A: FLOT chemotherapy + surgery (OP)	Docetaxel	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)
Arm B: FLOT chemotherapy alone	5-Fluorouracil	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)
Arm B: FLOT chemotherapy alone	Oxaliplatin	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)
Arm B: FLOT chemotherapy alone	Docetaxel	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)
Arm B: FLOT chemotherapy alone	Trastuzumab	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)
Arm B: FLOT chemotherapy alone	Leucovorin	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)

Primary Outcome Measures

Name	Time	Method
Overall survival (OS)	up to 5 years follow-up

Secondary Outcome Measures

Name	Time	Method
Quality of life (QoL) adjusted OS	up to 5 years follow-up
QoL-response	up to 5 years follow-up
Surgical mortality	up to 2 months after surgery
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
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

Trial Locations

Locations (1)

Krankenhaus Nordwest; 🇩🇪 Frankfurt am Main, Germany