| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| locally advanced resectable diffuse type adenocarcinoma of the oesophagogastric junction or the stomach |
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| E.1.1.1 | Medical condition in easily understood language |
| locally advanced resectable diffuse type gastric cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062878 |
| E.1.2 | Term | Gastrooesophageal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary efficacy objective of the study is to compare progression/disease-free survival (PFS/DFS), defined as first occurrence of progression or recurrence, as determined by the investigator using RECIST criteria. The duration of PFS/DFS will be determined by measuring time interval from randomization until disease progression or disease recurrence after surgery or death of any cause.
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| E.2.2 | Secondary objectives of the trial |
• To compare OS in both trial arms where OS is defined as the time from randomization to death from any cause
• To compare the rates of peritoneal relapse after 2 and 3 years in both arms
• To determine the safety of perioperative FLOT + HIPEC
• To evaluate the safety and tolerability of intraoperative HIPEC + perioperative FLOT compared with perioperative FLOT alone in patients with diffuse type (diffuse and mixed type acc. to Lauren- classification) adenocarcinoma of the stomach and Type II/III gastroesophageal junction (GEJ), focusing on surgical serious adverse events, according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0) Grade greater than equal 3 adverse events, and Grade greater than equal 3 laboratory toxicities
• To evaluate the perioperative morbidity and mortality of the regimens described above
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
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| E.4 | Principal 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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-/Disease-free Survival, defined as the time from randomization to disease progression or relapse after surgery or death from any cause.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| continuously, tumor assessment every 3 months |
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| E.5.2 | Secondary end point(s) |
• OS, defined as the time from randomization to death from any cause If no event is observed OS is censored at the day of last subject contact.
• Rate of patients with peritoneal relapse at 2 and 3 years in both arms
• 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
• 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
• 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.
• OS and PFS/DFS (medians and rates) according to subgroup (diffuse vs. mixed and gastric vs. GEJ type II/III)
• Quality of life (QoL) – EORTC QLQ C30 and EORTC QLQ STO22 questionnaire
• Post-operative morbidity/mortality at day 30 after surgery acc. to Clavien–Dindo classification
• Post-operative Pain according to VAS (visual analog scale): 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”.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OS: continuously and at 3 & 5 years
- Rate of peritoneal relapse at 2 & 3 years
- PFS/DFS rate: at 2, 3 & 5 years
- Safety analysis of the combination of perioperative chemotherapy combined with intraoperative HIPEC: after surgery
- Quality of life (QoL): prior to and after surgery, and approx. every 8 weeks (±7 days) until EOT, afterwards every 3 months until progression/relapse
- post-operative morbidity/mortality: at day 30 after surgery
- Post-operative pain according to VAS (Visual analog scale): prior to and after surgery, and approx. every 8 weeks (±7 days) until EOT, afterwards every 3 months until progression/relapse |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Database closure is defined as the end of the trial: Site need to collect survival data of the patients and are involved in the data cleaning process actively (e.g. additional source data may be requested and additional monitoring visits may be necessary). Therefore, database closure is considered at the end of ther trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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