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

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ClinicalTrials.gov Identifier: NCT02578368
Recruitment Status : Recruiting
First Posted : October 16, 2015
Last Update Posted : April 7, 2016
Sponsor:
Collaborators:
German Research Foundation
Arbeitsgemeinschaft fur Internistische Onkologie
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Gastric Cancer Drug: 5-Fluorouracil Drug: Leucovorin Drug: Oxaliplatin Drug: Docetaxel Drug: Trastuzumab Drug: sodium folinate Procedure: Surgery Phase 3

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 271 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : February 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


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

Drug: 5-Fluorouracil
2600 mg/m², d1 i.v., every 2 weeks
Other Name: 5-FU

Drug: Leucovorin
200 mg/m², d1, i.v., every 2 weeks
Other Name: calcium folinate

Drug: Oxaliplatin
85 mg/m², d1, i.v., every 2 weeks

Drug: Docetaxel
50mg/m², d1, i.v., every 2 weeks

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

Drug: sodium folinate
can be used to replace leucovorin (calcium folinate)

Procedure: Surgery
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

Drug: 5-Fluorouracil
2600 mg/m², d1 i.v., every 2 weeks
Other Name: 5-FU

Drug: Leucovorin
200 mg/m², d1, i.v., every 2 weeks
Other Name: calcium folinate

Drug: Oxaliplatin
85 mg/m², d1, i.v., every 2 weeks

Drug: Docetaxel
50mg/m², d1, i.v., every 2 weeks

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

Drug: sodium folinate
can be used to replace leucovorin (calcium folinate)




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: up to 5 years follow-up ]

Secondary Outcome Measures :
  1. Quality of life (QoL) adjusted OS [ Time Frame: up to 5 years follow-up ]
  2. QoL-response [ Time Frame: up to 5 years follow-up ]
  3. QoL mean scores [ Time Frame: up to 5 years follow-up ]
  4. OS in patients with lymph node metastases only [ Time Frame: up to 5 years follow-up ]
  5. Progression free survival (PFS) [ Time Frame: up to 5 years follow-up ]
  6. Surgical morbidity [ Time Frame: up to 2 months after surgery ]
  7. Surgical mortality [ Time Frame: up to 2 months after surgery ]
  8. 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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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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, docetaxel, or trastuzumab (in HER-2 positive tumors)
  7. Contraindication versus 5-fluorouracil, leucovorin, oxaliplatin, docetaxel (see specific product information), or trastuzumab (in HER-2 positive tumors)
  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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02578368


Contacts
Contact: Claudia Pauligk, PhD 069 7601 ext 3906 pauligk.claudia@khnw.de
Contact: Daniel W. Mueller, PhD 069 7601 ext 4125 mueller.daniel@khnw.de

Locations
Germany
Krankenhaus Nordwest Recruiting
Frankfurt am Main, Germany, 60488
Contact: Salah-Eddin Al-Batran, MD    +496976014420    albatran@aol.com   
Contact: Claudia Pauligk, PhD    +496976013906    pauligk.claudia@khnw.de   
Principal Investigator: Salah-Eddin Al-Batran, MD         
Sponsors and Collaborators
Krankenhaus Nordwest
German Research Foundation
Arbeitsgemeinschaft fur Internistische Onkologie
Investigators
Study Director: Salah-Eddin Al-Batran, MD Institute of Clinical Cancer Research (IKF), Krankenhaus Nordwest; University Cancer Center Frankfurt (UCT)

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Krankenhaus Nordwest
ClinicalTrials.gov Identifier: NCT02578368     History of Changes
Other Study ID Numbers: RENAISSANCE
First Posted: October 16, 2015    Key Record Dates
Last Update Posted: April 7, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Krankenhaus Nordwest:
gastric cancer
perioperative
FLOT
limited metastatic
GEJ cancer

Additional relevant MeSH terms:
Adenocarcinoma
Stomach Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Docetaxel
Oxaliplatin
Trastuzumab
Fluorouracil
Levoleucovorin
Leucovorin
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antidotes
Protective Agents