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HIPEC + FLOT vs. FLOT Alone in Patients With Gastric Cancer and GEJ (PREVENT) (PREVENT)

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ClinicalTrials.gov Identifier: NCT04447352
Recruitment Status : Recruiting
First Posted : June 25, 2020
Last Update Posted : June 22, 2021
Sponsor:
Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany)
Information provided by (Responsible Party):
Krankenhaus Nordwest

Brief Summary:
This is a multicenter, randomized, controlled, open-label study evaluating efficacy and safety of perioperative FLOT chemotherapy plus intraoperative HIPEC versus FLOT chemotherapy alone in patients with resectable localized and locally advanced diffuse and mixed type adenocarcinoma of the stomach and Type II/III GEJ.

Condition or disease Intervention/treatment Phase
Gastric Cancer Gastroesophageal Junction Adenocarcinoma Drug: 5-Fluorouracil Drug: Leucovorin Drug: Oxaliplatin Drug: Docetaxel Drug: Cisplatin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Preventive HIPEC in Combination With Perioperative FLOT Versus FLOT Alone for Resectable Diffuse Type Gastric and Gastroesophageal Junction Type II/III Adenocarcinoma - The Phase III "PREVENT" Trial of the AIO /CAOGI /ACO
Actual Study Start Date : December 17, 2020
Estimated Primary Completion Date : November 1, 2026
Estimated Study Completion Date : May 1, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A - FLOT

Patients randomized to treatment Arm A already received 3-6 cycles of FLOT in 2-week treatment cycles prior to undergoing surgery. Following surgery, patients will receive four further 2-week cycles FLOT. FLOT can be deescalated to FLO, FLT or FL in case of chemorelated toxicity at any time and at the discretion of investigator.

FLOT = Docetaxel 50 mg/m², Oxaliplatin 85 mg/m², Leucovorin 200 mg/m², 5-FU 2600 mg/m².

Drug: 5-Fluorouracil
Day 1 q2w: 2600 mg/m² IV over 24 hours
Other Name: 5-FU

Drug: Leucovorin
Day 1 q2w: 200 mg/m² IV over 30 minutes
Other Name: Calciumfolinat

Drug: Oxaliplatin
Day 1 q2w: 85 mg/m² IV over 2 hours

Drug: Docetaxel
Day 1 q2w: 50 mg/m² IV over 1 hour

Experimental: Arm B - FLOT/HIPEC

Patients randomized to treatment Arm B already received 3-6 cycles of FLOT in 2-week treatment cycles prior to undergoing surgery including Intraoperative Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) during gastric-/ esophagogastric resection using Cisplatin 75mg/m². Following surgery, patients will receive four further 2-week cycles FLOT. FLOT can be deescalated to FLO, FLT or FL in case of chemorelated toxicity at any time and at the discretion of investigator.

FLOT = Docetaxel 50 mg/m², Oxaliplatin 85 mg/m², Leucovorin 200 mg/m², 5-FU 2600 mg/m².

Drug: 5-Fluorouracil
Day 1 q2w: 2600 mg/m² IV over 24 hours
Other Name: 5-FU

Drug: Leucovorin
Day 1 q2w: 200 mg/m² IV over 30 minutes
Other Name: Calciumfolinat

Drug: Oxaliplatin
Day 1 q2w: 85 mg/m² IV over 2 hours

Drug: Docetaxel
Day 1 q2w: 50 mg/m² IV over 1 hour

Drug: Cisplatin
intraoperative: 75mg/m² intraabdominal solution over 1 hour and 30 minutes




Primary Outcome Measures :
  1. Comparison of progression-/disease-free survival (PFS/DFS) between arms [ Time Frame: from randomization up to 5 years ]
    To compare PFS/DFS in patients with localized and advanced diffuse or mixed type adenocarcinoma of the stomach and Type II/III GEJ (i.e. ≥cT3 any N or any T N-positive) with exclusion of distant metastases and after receiving neoadjuvant FLOT- therapy will be included in this trial after a central review, receiving 3-6 cycles perioperative FLOT versus FLOT alone in the intent to treat population (ITT) and where PFS/DFS is defined as the time from randomization to disease progression or relapse after surgery or death from any cause.


Secondary Outcome Measures :
  1. Comparison of Overall survival (OS) in both arms [ Time Frame: from randomization up to 5 years ]
    Overall survival (OS) where OS is defined as the time from randomization to death from any cause.

  2. Comparison of Overall survival rates at 3 and 5 years in both arms [ Time Frame: 3 and 5 years after randomization ]
    OS rates at 3 & 5 years defined as the percentage patients known to be alive after 3 and 5 years referring to the total number of patients randomized into the respective treatment arm

  3. Comparison of peritoneal relapse rate at 2 and 3 years in both arms [ Time Frame: 2 and 3 years after surgery ]
    Peritoneal relapse rate defined as the percentage of patients with peritoneal relapse referring to the total number of patients randomized into the respective treatment arm

  4. PFS/DFS rates at 2, 3 & 5 years [ Time Frame: 2, 3 & 5 years after randomization ]
    PFS/DFS rates at 2, 3 & 5 years defined as the percentage of patients without disease progression or relapse after surgery or death from any cause after 2, 3 and 5 years referring to the total number of patients randomized into the respective treatment arm

  5. Rate of surgical serious adverse events (SAEs) [ Time Frame: After randomization of the patient until 30 days after last study-specific treatment ]
    Rate of surgical serious adverse events, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0) grade ≥ 3 adverse events and grade ≥ 3 laboratory toxicities.

  6. OS and PFS/DFS (medians and rates) according to subgroup (diffuse vs. mixed and gastric vs. GEJ type II/III) [ Time Frame: from randomization up to 5 years ]
    PFS/DFS is defined as the time from randomization to disease progression or relapse after surgery or death from any cause and OS is defined as the time from randomization to death from any cause. OS and PFS/DFS rates are defined as the percentage of patients known to be alive or without disease progression or relapse after surgery or death from any cause, respectively, at specific timepoints and referring to the total number of patients in defined subgroups (diffuse vs. mixed and gastric vs. GEJ type II/III).

  7. Patient reported outcomes: Quality of life EORTC QLQ C30 questionnaire [ Time Frame: From date of screening until the date of first documented progression or last visit before date of death from any cause, whichever came first, assessed 8 weeks +/- 7 days until EOT, afterwards every 3 months up to 2 years after last patient in ]

    The QoL analyses will include QoL mean values, QoL response and time to symptom deterioration (TTSD) defined as the time interval between randomization and the first decrease by ≥ 10-points. All randomly assigned patients with a baseline and at least one post-baseline assessment will be included in TTSD analyses. Patients without observed deterioration will be censored at the time of their last QoL assessment. Questionnaires given to the patients (validated quality of life questionnaires EORTC QLQ C30).

    EORTC QLQ C30 contains 30 questions:

    28 questions regarding body fitness, daily routines, restrictions at work and hobby, appetite, fatigue, cough, breathlessness, pain, tiredness, and body conditions from (1) to (4); 1 (not a bit), 2 (little), 3 (moderate), 4 (much).

    2 questions regarding state of health and Quality of life with a horizontal rating from 1 to 7; 1 (very bad), 7 (excellent).


  8. Patient reported outcomes: Quality of life EORTC QLQ STO22 questionnaire [ Time Frame: From date of screening until the date of first documented progression or last visit before date of death from any cause, whichever came first, assessed 8 weeks +/- 7 days until EOT, afterwards every 3 months up to 2 years after last patient in ]

    The QoL analyses will include QoL mean values, QoL response and time to symptom deterioration (TTSD) defined as the time interval between randomization and the first decrease by ≥ 10-points. All randomly assigned patients with a baseline and at least one post-baseline assessment will be included in TTSD analyses. Patients without observed deterioration will be censored at the time of their last QoL assessment. Questionnaires given to the patients (validated quality of life questionnaires EORTC QLQ STO22).

    The EORTC QLQ-STO 22 module contains 22 items in a similar layout and response format to the EORTC QLQ-C30. The hypothesised scale structure of the module consists of five scales (dysphagia, eating restrictions, pain, reflux and anxiety) and three single items (dry mouth, body image and hair loss).


  9. Patient reported outcomes: VAS pain assessment form [ Time Frame: From date of screening until the date of first documented progression or last visit before date of death from any cause, whichever came first, assessed 8 weeks +/- 7 days until EOT, afterwards every 3 months up to 2 years after last patient in ]
    The patient´s assessment of their current level of pain on a 100-mm horizontal VAS. The left-hand extreme of the line should be described as "no pain" and the right-hand as "unbearable pain".

  10. Rate of post-operative morbidity/mortality at day 30 after surgery acc. to Clavien-Dindo classification [ Time Frame: at day 30 after surgery ]
    Rate of post-operative morbidity/mortality will be assessed at day 30 after surgery acc. to Clavien-Dindo classification.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed, medically operable, resectable diffuse or mixed type (according to Lauren's classification) adenocarcinoma of the gastroesophageal junction (AEG II-III) or the stomach (uT3, uT4a, any N category, M0), or any T N+ M0 patient
  2. Patient has received 3 to 6 cycles of neoadjuvant FLOT (de-escalation or dose modification allowed)
  3. No preceding cytotoxic or targeted therapy other than neoadjuvant FLOT (including de-escalated or dose reduced schema) therapy
  4. No prior partial or complete tumor resection
  5. Female and male patient ≥ 18 and ≤ 75 years. Female patient with childbearing potential needs to have a negative pregnancy test within 7 days prior to study start. Males and females of reproductive potential must agree to practice highly effective contraceptive measures* during the study. Male patients must also agree to refrain from father a child during treatment and additionally to use a condom during treatment period. Their female partner of childbearing potential must also agree to use an adequate contraceptive measure.

    *highly effective (i.e. failure rate of <1% per year when used consistently and correctly) methods: intravaginal and transdermal combined (estrogen and progestogen containing) hormonal contraception; injectable and implantable progestogen-only hormonal contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner; sexual abstinence (complete abstinence is defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments).

  6. ECOG ≤ 1
  7. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI
  8. Laparoscopic exclusion of peritoneal carcinomatosis at initial staging, before start of FLOT chemotherapy
  9. Hematological, hepatic and renal function parameters adequate to allow surgical procedure and HIPEC at investigator´s discretion
  10. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures

Exclusion Criteria:

  1. Patient without neoadjuvant therapy or those who received a neoadjuvant therapy other than FLOT
  2. Known hypersensitivity against 5-FU, leucovorin, oxaliplatin, or docetaxel
  3. Other known contraindications against, 5-FU, leucovorin, oxaliplatin, or docetaxel
  4. Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV
  5. Clinically significant valvular defect
  6. Past or current history of other malignancies not 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
  7. Criteria of primary unresectability, e.g.:

    • Radiologically documented evidence of major blood vessel invasion or invasion of adjacent organs (T4b).
    • Patients with involved retroperitoneal (e.g. para-aortal, paracaval or interaortocaval lymph nodes) or mesenterial lymph nodes (distant metastases!)
  8. Other severe internal disease or acute infection
  9. Patient has undergone major surgery within 28 days prior to enrollment
  10. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites.
  11. On-treatment participation in another interventional clinical study in the period 30 days prior to inclusion and during the study
  12. Patient pregnant or breast feeding, or planning to become pregnant
  13. Patient in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
  14. Any other concurrent antineoplastic treatment including irradiation
  15. Known intraabdominal adhesion situs
  16. Pre-existing peritoneal seeding

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): NCT04447352


Contacts
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Contact: Thorsten O Götze, MD +4969 7601 ext 4187 goetze.thorsten@khnw.de
Contact: Claudia Pauligk, PhD +4969 7601 ext 3906 pauligk.claudia@khnw.de

Locations
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Germany
Uniklinik RWTH Aachen, AöR, Medizinische Klinik III, Studienzentrum Viszeralmedizin Recruiting
Aachen, Germany, 52074
Universitätsklinikum, Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie Recruiting
Dresden, Germany, 01307
Institute of Clinical Cancer Research (IKF), UCT - University Cancer Center, Frankfurt, Germany Recruiting
Frankfurt, Germany, 60488
Contact: Thorsten O Goetze, MD    +496976014187      
Contact: Claudia Pauligk    +496976013906    pauligk.claudia@khnw.de   
Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Viszerale, Gefäß- und Endokrine Chirurgie Recruiting
Halle, Germany, 06120
Universitätsklinikum Leipzig, Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie Recruiting
Leipzig, Germany, 04103
Klinikum Ludwigsburg, Klinik für Innere Medizin, Gastroenterologie, Hämato-Onkologie, Pneumologie, Diabetologie und Infektiologie Recruiting
Ludwigsburg, Germany, 71640
Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Chirurgie Recruiting
Lübeck, Germany, 23538
Universitätsklinikum Magdeburg Recruiting
Magdeburg, Germany, 39120
Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Innere Medizin III Recruiting
München, Germany, 81675
Universitätsklinikum Münster, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie Recruiting
Münster, Germany, 48149
Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie Recruiting
Regensburg, Germany, 93049
Klinikum Südstadt Rostock, Klinik für Innere Medizin III Recruiting
Rostock, Germany, 18059
Universitätsklinikum Tübingen, Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Chirurgische Studienzentrale Recruiting
Tübingen, Germany, 72076
Marien-Hospital Witten Recruiting
Witten, Germany, 58452
Universitätsklinikum Würzburg, Chirurgische Klinik I, Chirurgisches Studienzentrum Recruiting
Würzburg, Germany, 97080
Sponsors and Collaborators
Krankenhaus Nordwest
Deutsche Krebshilfe e.V., Bonn (Germany)
Investigators
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Principal Investigator: Thorsten O Götze, MD Lead Coordinating Investigator
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Krankenhaus Nordwest
ClinicalTrials.gov Identifier: NCT04447352    
Other Study ID Numbers: HIPEC/FLOT9
AIO-STO-0319/ass ( Other Identifier: AIO number )
First Posted: June 25, 2020    Key Record Dates
Last Update Posted: June 22, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD will be shared.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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
Leucovorin
Docetaxel
Fluorouracil
Oxaliplatin
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
Vitamin B Complex
Vitamins