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Chemotherapy Alone vs. Chemotherapy + Surgical Resection in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction (FLOT5)

Primary Purpose

Gastric Cancer

Status
Recruiting
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
5-Fluorouracil
Leucovorin
Oxaliplatin
Docetaxel
Trastuzumab
sodium folinate
Surgery
Sponsored by
Krankenhaus Nordwest
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gastric Cancer focused on measuring gastric cancer, perioperative, FLOT, limited metastatic, GEJ cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Krankenhaus NordwestRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Arm A: FLOT chemotherapy + surgery (OP)

Arm B: FLOT chemotherapy alone

Arm Description

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)

Outcomes

Primary Outcome Measures

Overall survival (OS)

Secondary Outcome Measures

Quality of life (QoL) adjusted OS
QoL-response
QoL mean scores
OS in patients with lymph node metastases only
Progression free survival (PFS)
Surgical morbidity
Surgical mortality
Toxicity - Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Full Information

First Posted
October 12, 2015
Last Updated
February 21, 2022
Sponsor
Krankenhaus Nordwest
Collaborators
German Research Foundation, Arbeitsgemeinschaft fur Internistische Onkologie
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1. Study Identification

Unique Protocol Identification Number
NCT02578368
Brief Title
Chemotherapy Alone vs. Chemotherapy + Surgical Resection in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction
Acronym
FLOT5
Official Title
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 Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Recruiting
Study Start Date
February 2016 (Actual)
Primary Completion Date
February 2026 (Anticipated)
Study Completion Date
February 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Krankenhaus Nordwest
Collaborators
German Research Foundation, Arbeitsgemeinschaft fur Internistische Onkologie

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gastric Cancer
Keywords
gastric cancer, perioperative, FLOT, limited metastatic, GEJ cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
271 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A: FLOT chemotherapy + surgery (OP)
Arm Type
Experimental
Arm Description
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 Title
Arm B: FLOT chemotherapy alone
Arm Type
Active Comparator
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
5-Fluorouracil
Other Intervention Name(s)
5-FU
Intervention Description
2600 mg/m², d1 i.v., every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
calcium folinate
Intervention Description
200 mg/m², d1, i.v., every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Intervention Description
85 mg/m², d1, i.v., every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Intervention Description
50mg/m², d1, i.v., every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Trastuzumab
Intervention Description
4 mg/kg BW (6 mg loading dose at 1st administration), i.v. for 1 h, d1, i.v., every two weeks
Intervention Type
Drug
Intervention Name(s)
sodium folinate
Intervention Description
can be used to replace leucovorin (calcium folinate)
Intervention Type
Procedure
Intervention Name(s)
Surgery
Intervention Description
Aim of surgical resection is a complete (R0) resection of the primary tumor and the metastases or a complete macroscopic cytoreduction of the metastases.
Primary Outcome Measure Information:
Title
Overall survival (OS)
Time Frame
up to 5 years follow-up
Secondary Outcome Measure Information:
Title
Quality of life (QoL) adjusted OS
Time Frame
up to 5 years follow-up
Title
QoL-response
Time Frame
up to 5 years follow-up
Title
QoL mean scores
Time Frame
up to 5 years follow-up
Title
OS in patients with lymph node metastases only
Time Frame
up to 5 years follow-up
Title
Progression free survival (PFS)
Time Frame
up to 5 years follow-up
Title
Surgical morbidity
Time Frame
up to 2 months after surgery
Title
Surgical mortality
Time Frame
up to 2 months after surgery
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Claudia Pauligk, PhD
Phone
069 7601
Ext
3906
Email
pauligk.claudia@khnw.de
First Name & Middle Initial & Last Name or Official Title & Degree
Ulli S Bankstahl
Phone
069 7601
Ext
4596
Email
bankstahl.ulli@khnw.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Salah-Eddin Al-Batran, MD
Organizational Affiliation
Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest; University Cancer Center Frankfurt (UCT)
Official's Role
Study Director
Facility Information:
Facility Name
Krankenhaus Nordwest
City
Frankfurt am Main
ZIP/Postal Code
60488
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Salah-Eddin Al-Batran, MD
Phone
+496976014420
Email
albatran@aol.com
First Name & Middle Initial & Last Name & Degree
Claudia Pauligk, PhD
Phone
+496976013906
Email
pauligk.claudia@khnw.de
First Name & Middle Initial & Last Name & Degree
Salah-Eddin Al-Batran, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
No IPD will be shared
Citations:
PubMed Identifier
29282088
Citation
Al-Batran SE, Goetze TO, Mueller DW, Vogel A, Winkler M, Lorenzen S, Novotny A, Pauligk C, Homann N, Jungbluth T, Reissfelder C, Caca K, Retter S, Horndasch E, Gumpp J, Bolling C, Fuchs KH, Blau W, Padberg W, Pohl M, Wunsch A, Michl P, Mannes F, Schwarzbach M, Schmalenberg H, Hohaus M, Scholz C, Benckert C, Knorrenschild JR, Kanngiesser V, Zander T, Alakus H, Hofheinz RD, Roedel C, Shah MA, Sasako M, Lorenz D, Izbicki J, Bechstein WO, Lang H, Moenig SP. The RENAISSANCE (AIO-FLOT5) trial: 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 the German AIO/CAO-V/CAOGI. BMC Cancer. 2017 Dec 28;17(1):893. doi: 10.1186/s12885-017-3918-9.
Results Reference
derived
Links:
URL
http://www.ikf-nordwest.de/
Description
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Chemotherapy Alone vs. Chemotherapy + Surgical Resection in Patients With Limited-metastatic Adenocarcinoma of the Stomach or Esophagogastric Junction

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