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

NCT ID: NCT04447352

Last Updated: 2024-11-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

200 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-12-17

Study Completion Date

2027-05-01

Brief Summary

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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.

Detailed Description

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This is a multicenter, randomized, controlled, open-label study including patients with localized and locally advanced diffuse and mixed type adenocarcinoma of the stomach and Type II/III GEJ scheduled to receive perioperative chemotherapy combined with intraoperative HIPEC procedure.

The scope of the trial is to evaluate the efficacy as well as the safety and tolerability of the combination of perioperative chemotherapy combined with an intraoperative HIPEC for resectable diffuse and mixed type gastric and GEJ (types II/III) adenocarcinoma. Intraoperative hyperthermic chemoperfusion is summarized under the abbreviation HIPEC in the following.

Patients with localized and locally 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.

All enrolled patients will have received 3-6 pre-operative cycles (de-escalation or dose modification allowed) of biweekly FLOT (Docetaxel 50 mg/m² in 250 ml NaCl 0.9%, iv over 1 h; Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h; Leucovorin 200 mg/m² in 250 ml NaCl 0.9%, iv over 30 min; 5-FU 2600 mg/m², iv over 24 h, q2wk) in the preoperative treatment phase.

After completion of neoadjuvant FLOT- therapy followed by pre-operative tumor assessment, (also including diagnostic laparoscopy prior to start of FLOT), patients without disease progression (expected to be approximately 90% of the patients) will be included into the trial, stratified by initial clinical stage (N- vs. N+), histological type of tumor (Lauren classification diffuse vs. mixed) and study site.

Patients will be randomized 1:1 to receive either postoperative FLOT (Arm A) or postoperative FLOT + intraoperative HIPEC (Arm B).

Arm A (FLOT) Surgery in Arm A is planned to occur 4 to 6 weeks after d1 of last FLOT. Surgery is carried out in kind of gastrectomy, transhiatal extended gastrectomy. Following surgery, patients will receive four further 2-week treatment cycles FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.

Arm B (FLOT/ HIPEC) Surgery in Arm B is planned to occur 4 to 6 weeks after d1 of last FLOT. Surgery is carried out in kind of gastrectomy, transhiatal extended gastrectomy. Surgery will be combined with an intraoperative Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) including cisplatin solution administered at a temperature of 42°C for 90 minutes. Following surgery, patients will receive four further 2-week treatment cycles FLOT in the post-operative treatment phase. Post-operative treatment should start 6 to 8 weeks, but at maximum 12 weeks after surgery.

In both of the arms, tumor assessments (CT or MRI) are performed before randomization prior to surgery, and then every 3 months (radiological tumor assessment) thereafter until progression/relapse, death or end of follow-up. A change from CT into MRI in the follow up period is possible at any time.

During treatment, clinical visits (blood cell counts, detection of toxicity) occur prior to every treatment dose. Safety of FLOT/ HIPEC will be monitored continuously by careful monitoring of all adverse events (AEs) and serious adverse events (SAEs) reported.

The phase III design starts with a safety run-in phase. After 20 patients had curatively intended resection in Arm B, an interim safety analysis is performed that shows feasibility, safety, and tolerability of Arm B planned at the time 8 weeks after the 20th patient in Arm B had curatively intended resection. It is not planned to discontinue recruitment for the interim safety analysis.

Conditions

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Gastric Cancer Gastroesophageal Junction Adenocarcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

5-Fluorouracil

Intervention Type DRUG

Day 1 q2w: 2600 mg/m² IV over 24 hours

Leucovorin

Intervention Type DRUG

Day 1 q2w: 200 mg/m² IV over 30 minutes

Oxaliplatin

Intervention Type DRUG

Day 1 q2w: 85 mg/m² IV over 2 hours

Docetaxel

Intervention Type DRUG

Day 1 q2w: 50 mg/m² IV over 1 hour

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.

Group Type EXPERIMENTAL

5-Fluorouracil

Intervention Type DRUG

Day 1 q2w: 2600 mg/m² IV over 24 hours

Leucovorin

Intervention Type DRUG

Day 1 q2w: 200 mg/m² IV over 30 minutes

Oxaliplatin

Intervention Type DRUG

Day 1 q2w: 85 mg/m² IV over 2 hours

Docetaxel

Intervention Type DRUG

Day 1 q2w: 50 mg/m² IV over 1 hour

Cisplatin

Intervention Type DRUG

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

Interventions

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5-Fluorouracil

Day 1 q2w: 2600 mg/m² IV over 24 hours

Intervention Type DRUG

Leucovorin

Day 1 q2w: 200 mg/m² IV over 30 minutes

Intervention Type DRUG

Oxaliplatin

Day 1 q2w: 85 mg/m² IV over 2 hours

Intervention Type DRUG

Docetaxel

Day 1 q2w: 50 mg/m² IV over 1 hour

Intervention Type DRUG

Cisplatin

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

Intervention Type DRUG

Other Intervention Names

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5-FU Calciumfolinat

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Deutsche Krebshilfe e.V., Bonn (Germany)

OTHER

Sponsor Role collaborator

Krankenhaus Nordwest

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Thorsten O Götze, MD

Role: PRINCIPAL_INVESTIGATOR

Lead Coordinating Investigator

Locations

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Uniklinik RWTH Aachen, AöR, Medizinische Klinik III, Studienzentrum Viszeralmedizin

Aachen, , Germany

Site Status RECRUITING

Universitätsklinikum, Klinik und Poliklinik für Viszeral-, Thorax- und Gefäßchirurgie

Dresden, , Germany

Site Status RECRUITING

Institute of Clinical Cancer Research (IKF), UCT - University Cancer Center, Frankfurt, Germany

Frankfurt, , Germany

Site Status RECRUITING

Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Viszerale, Gefäß- und Endokrine Chirurgie

Halle, , Germany

Site Status RECRUITING

Universitätsklinikum Leipzig, Klinik und Poliklinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie

Leipzig, , Germany

Site Status RECRUITING

Klinikum Ludwigsburg, Klinik für Innere Medizin, Gastroenterologie, Hämato-Onkologie, Pneumologie, Diabetologie und Infektiologie

Ludwigsburg, , Germany

Site Status RECRUITING

Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Klinik für Chirurgie

Lübeck, , Germany

Site Status RECRUITING

Universitätsklinikum Magdeburg

Magdeburg, , Germany

Site Status RECRUITING

Klinikum rechts der Isar der TU München, Klinik und Poliklinik für Innere Medizin III

München, , Germany

Site Status RECRUITING

Universitätsklinikum Münster, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie

Münster, , Germany

Site Status RECRUITING

Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie

Regensburg, , Germany

Site Status RECRUITING

Klinikum Südstadt Rostock, Klinik für Innere Medizin III

Rostock, , Germany

Site Status RECRUITING

Universitätsklinikum Tübingen, Universitätsklinik für Allgemeine, Viszeral- und Transplantationschirurgie Chirurgische Studienzentrale

Tübingen, , Germany

Site Status RECRUITING

Marien-Hospital Witten

Witten, , Germany

Site Status RECRUITING

Universitätsklinikum Würzburg, Chirurgische Klinik I, Chirurgisches Studienzentrum

Würzburg, , Germany

Site Status RECRUITING

Countries

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Germany

Central Contacts

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Thorsten O Götze, MD

Role: CONTACT

+4969 7601 ext. 4187

Claudia Pauligk, PhD

Role: CONTACT

+4969 7601 ext. 3906

Facility Contacts

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Thorsten O Goetze, MD

Role: primary

+496976014187

Claudia Pauligk

Role: backup

+496976013906

References

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Gotze TO, Piso P, Lorenzen S, Bankstahl US, Pauligk C, Elshafei M, Amato G, Reim D, Bechstein WO, Konigsrainer A, Monig SP, Rau B, Schwarzbach M, Al-Batran SE. 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"- (FLOT9) trial of the AIO /CAOGI /ACO. BMC Cancer. 2021 Oct 29;21(1):1158. doi: 10.1186/s12885-021-08872-8.

Reference Type DERIVED
PMID: 34715810 (View on PubMed)

Other Identifiers

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AIO-STO-0319/ass

Identifier Type: OTHER

Identifier Source: secondary_id

HIPEC/FLOT9

Identifier Type: -

Identifier Source: org_study_id

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