INNOVATION: INtegratioN of trastuzumab, with or without pertuzumab, into periOperatiVe chemotherApy of HER-2 posiTIve stOmach caNcer
Indication :

Cancer de l'estomac HER-2 positif


Sponsor :

EORTC


Phase :

II


Ligne :

1ère ligne


Traitement :

Cisplatine + Capécitabine +/- Trastuzumab +/- Pertuzumab


Spécificités :
  • HER2+
  • Adénocarcinome gastrique ou de la jonction gastro-oesophagienne histologiquement prouvé
  • Candidat pour une gastrectomie/oesophagectomie
  • Pas de chimio/immuno-thérapie antérieure

Site :

CHUV, HUG


Contact(s) :
Dr Thibaud KOESSLER
Investigateur Principal

HUG
Oncologie

Rue Gabrielle Perret-Gentil, 4
1211
Geneva

+41795532409
Thibaud.Kossler@hcuge.ch
Christelle Trembleau
Coordinatrice

HUG
Oncologie

4 rue Gabrielle-Perret-Gentil
Genève
1211

079 553 53 91
Christelle.Trembleau@hcuge.ch
Anna-Dorothea Wagner
Investigateur Principal

CHUV
Oncologie

Rue du Bugnon 46
Lausanne
1011

+41 (0)79 556 18 89
dorothea.wagner@chuv.ch

Primary objective :

The main objective of the trial is to increase the major pathological response rate (< 10% vital tumor cells) after neoadjuvant treatment by integrating either trastuzumab or both trastuzumab and pertuzumab into perioperative chemotherapy for HER-2 positive, resectable gastric cancer


Inclusion criteria :
  1. All patients (HER-2 positive and negative) should be registered in the trial as soon as possible after written informed consent for screening according to ICH/GCP, and national/local regulations.
  2. Histologically proven, gastric or GE-junction adenocarcinoma (Siewert I-III)
  3. Absence of distant metastases on CT scan of thorax and abdomen
  4. Patient medically fit for gastrectomy/oesophagectomy as decided by the investigator
  5. Age ≥ 18 years
  6. WHO performance status 0 – 1
  7. HER2 status
    • For European patients if site chooses option (b): Availability of local HER-2 IHC test results
    • For Korean patients: Availability of local HER-2 IHC+/- ISH test results
  8. Availability of the paraffin block or sufficient (ideally 20 slides, but exceptionally minimum 15 slides is acceptable) unstained paraffin sections from the diagnostic endoscopic biopsies for centralized HER-2 assessment/confirmation.
  9. HER-2 overexpression, as determined by central testing using immunohistochemistry (IHC 3+) or the combination of IHC 2+ and HER-2 FISH positive (please see pathology guidelines).
  10. Amenable to gastrectomy/oesophagectomy with curative intent as confirmed by a multidisciplinary team discussion
  11. UICC tumor stage Ib to III, as defined by CT (CT should be assessed within 35 days prior to start of treatment). Endosonography (EUS) is recommended, but not mandatory. EUS should especially be considered to distinguish T1 and T2 tumors and to evaluate local resectability. (In case of conflicting results of CT and endoscopic ultrasound, the final decision on which finding the staging is based should be taken by the multidisciplinary team
  12. No prior chemo- or antibody therapy
  13. No history of significant cardiac disease defined as:
    • Symptomatic CHF (NYHA classes II-IV)
    • High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular
    tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
    • History of myocardial infarction within 6 months prior to randomization
    • Clinically significant valvular heart disease
    • Angina pectoris requiring anti-anginal treatment
    • No current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg)
    • The cardiac ejection fraction (LVEF), as determined by echocardiography, MUGA or cardiac MRI should be at least 55% (assessed within 14
    days prior to randomization)
  14. Adequate organ function (assessed within 7 days prior to randomization):
    • White blood cell count (WBC) > 3 x 109/L
    • Absolute neutrophil count (ANC) > 1.5 x 109/L
    • Platelets ≥ 100 x 109/L
    • Hemoglobin ≥ 9 g/dL
    • Estimated glomerular filtration rate (eGFR) according to MDRD (see Appendix G) should be > 60 ml/min
    • Total bilirubin within normal limits (if the patient has documented Gilbert’s disease ≤ 1.5 × ULN or direct bilirubin ≤ ULN)
    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN
  15. No known hypersensitivity to the components of trastuzumab, pertuzumab, cisplatin, 5-FU or capecitabine
  16. No known dihydropyrimidine dehydrogenase (DPD) deficiency
  17. No ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
  18. No chronic treatment with high-dose intravenous corticosteroids
  19. Investigator and patient have to agree to replace any oral anticoagulations by subcutaneous administration of low-molecular weight heparin (LMWH) in equivalent doses before treatment start, or if on oral anticoagulations and unwilling to switch to LMWH, patients have to be treated with mandatory 5-FU i.v. instead of capecitabine.
  20. No previous malignancy within the last 5 years, with the exception of adequately treated cervical carcinoma in situ, localized non-melanoma skin cancer, or other curatively treated cancer without impact on the patient’s overall prognosis according to the judgment of the investigator.
  21. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  22. For women who are not postmenopausal (> 12 months of non-therapy induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last treatment dose
  23. For men: agreement to remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods for contraception.
  24. For all female patients who are not confirmed postmenopausal (> 12 months of non-therapy induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus) a negative serum pregnancy test (β-human chorionic gonadotropin [β-hCG]) result should be available before randomization and within 7 days from treatment start should be performed. Female patients should not be breast feeding.
  25. Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.