5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) Versus Epirubicin, Cisplatin and 5-FU (ECF) in Patients With Locally Advanced, Resectable Gastric Cancer

• ClinicalTrials.gov Identifier: NCT01216644
• Recruitment Status: Completed
• First Posted: October 7, 2010
• Last Update Posted: June 19, 2019
• Sponsor: Krankenhaus Nordwest
• Information provided by (Responsible Party): Prof. Dr. S.E. Al-Batran, Krankenhaus Nordwest

Tracking Information

• First Submitted Date: June 30, 2010
• First Posted Date: October 7, 2010
• Last Update Posted Date: June 19, 2019
• Actual Study Start Date: August 2010
• Actual Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 12, 2014): median overall survival [ Time Frame: 2 years follow-up ]
• Original Primary Outcome Measures (submitted: October 6, 2010): Pathologic Complete Response Rate (pCR) [ Time Frame: 6 weeks after surgery ]

Current Secondary Outcome Measures (submitted: May 12, 2014)

• histopathological regression rate [ Time Frame: 6 weeks after surgery ]
• disease free survival (DFS) [ Time Frame: 2 years follow-up ]
• correlation of pCR and DFS with survival [ Time Frame: 2 years follow-up ]
• Perioperative Morbidity and Mortality [ Time Frame: up to 2 months after surgery ]
• R0-Resection rate [ Time Frame: 2 months after surgery ]

Original Secondary Outcome Measures (submitted: October 6, 2010)

• disease free survival (DFS) [ Time Frame: 2 years follow-up ]
• overall survival (OS) [ Time Frame: 2 years follow-up (maximum 5 years) ]
• correlation of pCR and DFS with survival [ Time Frame: 2 years follow-up ]
• Perioperative Morbidity and Mortality [ Time Frame: up to 2 months after surgery ]
• R0-Resection rate [ Time Frame: 2 months after surgery ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) Versus Epirubicin, Cisplatin and 5-FU (ECF) in Patients With Locally Advanced, Resectable Gastric Cancer
• Official Title: A Randomized Multicenter Phase II/III Study Comparing 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) Versus Epirubicin, Cisplatin and 5-FU (ECF) in Patients With Locally Advanced Resectable Adenocarcinoma of the Esophagogastreal Junction or the Stomach
• Brief Summary: Patients with locally advanced resectable adenocarcinoma of the stomach or the esophagogastreal junction without previous therapy will be treated with one of two chemotherapy combinations before and after surgery. One half of the patients gets 5-Fluorouracil (5-FU), Leucovorin, Oxaliplatin and Docetaxel (FLOT), the others Epirubicin, Cisplatin and 5-FU (ECF). Main objective of the study is median overall survival.
• Detailed Description: 714 Patients with locally advanced resectable (T2-4 and/or N+, M0) adenocarcinoma of the stomach or the esophagogastreal junction without previous therapy will be included in this study. After randomization patients receive perioperatively 4 cycles FLOT or 3 cycles ECF, followed by a restaging of the tumour status and surgery. Subsequently another 4 cycles of FLOT or 3 cycles ECF are applicated. Then a central validation of the pathological remission rate is scheduled. Primary endpoint is overall survival, secondary endpoints are disease free survival, perioperative morbidity and mortality, histopathologic regression rate and R0-resection rate.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Gastric Cancer

Intervention

• Drug: 5-Fluorouracil
  2600 mg/m²d1 i.v. every 2 weeks
• Drug: Leucovorin
  200 mg/m², d1, i.v., every 2 weeks
• Drug: Oxaliplatin
  85 mg/m², d1, i.v., every 2 weeks
• Drug: Docetaxel
  50mg/m2, d1, i.v., every 2 weeks
• Drug: Epirubicin
  50 mg/m2, d1, i.v., every 3 weeks
• Drug: Cisplatin
  60 mg/m², d1, i.v., every 3 weeks
• Drug: 5-fluorouracil
  200 mg/m², d1-d21, i.v., every 3 weeks

Study Arms

• Experimental: FLOT
  Docetaxel 50mg/m2, d1 5-FU 2600 mg/m², d1 Leucovorin 200 mg/m², d1 Oxaliplatin 85 mg/m², d1 every two weeks (q2w) 4 cycles (8 weeks) pre-OP and 4 cycles (8 weeks) post-OP
  Interventions:

  • Drug: 5-Fluorouracil
  • Drug: Leucovorin
  • Drug: Oxaliplatin
  • Drug: Docetaxel
• Active Comparator: ECF
  Epirubicin 50 mg/m2, d1 Cisplatin 60 mg/m², d1 5-FU 200 mg/m², d1-d21 every 3 weeks (q3w) 3 cycles (9 weeks) pre-OP and 3 cycles (9 weeks) post-OP
  Interventions:

  • Drug: Epirubicin
  • Drug: Cisplatin
  • Drug: 5-fluorouracil

Publications *

• Zeng H, Wang C, Song LY, Jia SJ, Zeng X, Liu Q. Economic evaluation of FLOT and ECF/ECX perioperative chemotherapy in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. BMJ Open. 2022 Nov 14;12(11):e060983. doi: 10.1136/bmjopen-2022-060983.
• Koch C, Reitz C, Schreckenbach T, Eichler K, Filmann N, Al-Batran SE, Gotze T, Zeuzem S, Bechstein WO, Kraus T, Bojunga J, Dux M, Trojan J, Blumenstein I. Sarcopenia as a prognostic factor for survival in patients with locally advanced gastroesophageal adenocarcinoma. PLoS One. 2019 Oct 22;14(10):e0223613. doi: 10.1371/journal.pone.0223613. eCollection 2019.
• Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Lohr C, Bernhard H, Schuch G, Rethwisch V, von Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Weniger J, Belle S, Gaiser T, Oduncu FS, Guntner M, Hozaeel W, Reichart A, Jager E, Kraus T, Monig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957. doi: 10.1016/S0140-6736(18)32557-1. Epub 2019 Apr 11.
• Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Konigsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jager E, Monig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. doi: 10.1016/S1470-2045(16)30531-9. Epub 2016 Oct 22.
• Lorenzen S, Thuss-Patience P, Al-Batran SE, Lordick F, Haller B, Schuster T, Pauligk C, Luley K, Bichev D, Schumacher G, Homann N. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann Oncol. 2013 Aug;24(8):2068-73. doi: 10.1093/annonc/mdt141. Epub 2013 Apr 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 5, 2016): 716
• Original Estimated Enrollment (submitted: October 6, 2010): 300
• Actual Study Completion Date: May 2019
• Actual Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. locally advanced (>T1) and/or nodal positive (N+) histologically proven adenocarcinoma of the esophagogastreal junction (AEG I-III) or the stomach without distant metastases (M0) and without infiltration of adjacent structures and organs
2. no previous surgical resection
3. no previous cytostatic chemotherapy
4. Age > 18 years (female and male)
5. ECOG ≤ 2
6. surgical resectability
7. Exclusion of peritoneal carcinomatosis (if clinically suspected) via laparoscopy
8. Leucocytes > 3.000/µl
9. Platelets > 100.000/µl
10. Serum creatinin ≤ 1.5x of normal value, or Creatinin-Clearance > 50 ml/min
11. written informed consent.
12. Ejection fraction > 50% in echocardiography before start of therapy

Exclusion Criteria:

1. distant metastases or infiltration of adjacent structures or organs and all primarily not resectable stages
2. relapse
3. Hypersensitivity against 5- Fluorouracil, Leucovorin, Oxaliplatin, Cisplatin. Epirubicin and Docetaxel
4. Existence of contraindications against 5- Fluorouracil, Leucovorin, Oxaliplatin, Cisplatin, Epirubicin or Docetaxel
5. Active CHD, Cardiomyopathy or cardiac insufficiency stage III-IV according to NYHA
6. malignant secondary disease, dated back < 5 years (exception: In-situ-carcinoma of the cervix uteri, adequately treated skin basal cell carcinoma)
7. severe non-surgical accompanying disease or acute infection
8. peripheral polyneuropathy > NCI Grad II
9. severe liver dysfunction (AST/ALT>3,5xULN, AP>6xULN, Bilirubin>1,5xULN)
10. chronic inflammable gastro-intestinal disease
11. inclusion in another clinical trial
12. pregnancy or lactation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT01216644
• Other Study ID Numbers: FLOT4
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Prof. Dr. S.E. Al-Batran, Krankenhaus Nordwest
• Original Responsible Party: PD Dr. Salah-Eddin Al-Batran, Krankenhaus Nordwest
• Current Study Sponsor: Krankenhaus Nordwest
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Salah-Eddin Al-Batran, MD; Institute of Clinical Cancer Research (IKF), UCT - University Cancer Center, Frankfurt, Germany

• PRS Account: Krankenhaus Nordwest
• Verification Date: June 2019