- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02578368
Chemotherapy Alone vs. Chemotherapy + Surgical Resection in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction (FLOT5)
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)
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Claudia Pauligk, PhD
- Phone Number: 3906 069 7601
- Email: pauligk.claudia@khnw.de
Study Contact Backup
- Name: Ulli S Bankstahl
- Phone Number: 4596 069 7601
- Email: bankstahl.ulli@khnw.de
Study Locations
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-
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Frankfurt am Main, Germany, 60488
- Krankenhaus Nordwest
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Arm A: FLOT chemotherapy + surgery (OP)
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) |
2600 mg/m², d1 i.v., every 2 weeks
Other Names:
200 mg/m², d1, i.v., every 2 weeks
Other Names:
85 mg/m², d1, i.v., every 2 weeks
50mg/m², d1, i.v., every 2 weeks
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)
Aim of surgical resection is a complete (R0) resection of the primary tumor and the metastases or a complete macroscopic cytoreduction of the metastases.
|
Active Comparator: Arm B: FLOT chemotherapy alone
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) |
2600 mg/m², d1 i.v., every 2 weeks
Other Names:
200 mg/m², d1, i.v., every 2 weeks
Other Names:
85 mg/m², d1, i.v., every 2 weeks
50mg/m², d1, i.v., every 2 weeks
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)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Overall survival (OS)
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Quality of life (QoL) adjusted OS
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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QoL-response
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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QoL mean scores
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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OS in patients with lymph node metastases only
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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Progression free survival (PFS)
Time Frame: up to 5 years follow-up
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up to 5 years follow-up
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Surgical morbidity
Time Frame: up to 2 months after surgery
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up to 2 months after surgery
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Surgical mortality
Time Frame: up to 2 months after surgery
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up to 2 months after surgery
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Toxicity - Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: From signature of the informed consent form (ICF) up to 30 days after last administration
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From signature of the informed consent form (ICF) up to 30 days after last administration
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Salah-Eddin Al-Batran, MD, Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest; University Cancer Center Frankfurt (UCT)
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Digestive System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Gastrointestinal Neoplasms
- Digestive System Neoplasms
- Gastrointestinal Diseases
- Stomach Diseases
- Stomach Neoplasms
- Adenocarcinoma
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Protective Agents
- Antineoplastic Agents, Immunological
- Micronutrients
- Vitamins
- Antidotes
- Vitamin B Complex
- Docetaxel
- Trastuzumab
- Fluorouracil
- Oxaliplatin
- Leucovorin
- Levoleucovorin
Other Study ID Numbers
- RENAISSANCE
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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