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

Phase 1

Conditions: HER-2 positive, resectable gastric cancer
MedDRA version: 23.0Level: PTClassification code 10066896Term: HER2 positive gastric cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2014-000722-38-DE

Lead Sponsor: European Organization for the Research and Treatment of Cancer

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 215

Inclusion Criteria

1) REGISTRATION
For determination of the HER-2 status, European sites will have the choice, patient by patient, between the two options:
a) Assessment of HER-2 status of potentially eligible patient in the central lab OR
b) Assessment of HER-2 status by IHC only in the local lab& mandatory confirmation of the HER-2 positive result in central lab

In EUROPE: if the site selects option a) FFPE blocks or 20 x 3-5 µm (ideally 20 slides but exceptionally minimum of 15 slides is acceptable) unstained paraffin sections from the diagnostic endoscopic biopsies for all potentially eligible patients must be sent to the central lab. If site selects option b) & performs local assessment of the HER-2 status by IHC, FFPE blocks or 20 x 3-5 µm(ideally 20 slides, but exceptionally a minimum of 15 slides is acceptable)unstained paraffin sections for all patients with HER-2 IHC status 1+, 2+ or 3+ must be sent for confirmation to central lab
In ASIA all patients are screened locally. Material from patients with a positive HER-2 status (2+ or 3+ by IHC) has to be sent to central lab for confirmation
Asian sites are requested to send only FFPE blocks or 20 x 3-5 µm (ideally 20 slides, but exceptionally a minimum of 15 slides is acceptable) unstained paraffin tissue sections from diagnostic endoscopic biopsies for HER-2 positive patients if 2+ or 3+ by IHC as per local assessment
? All patients (HER-2 positive and negative) should be registered in the trial asap after written informed consent for screening according to ICH/GCP & national/local regulations
? Histologically proven, gastric or GE-junction adenocarcinoma (Siewert I-III)
? Absence of distant metastases on CT scan of thorax & abdomen
? Patient medically fit for gastrectomy/oesophagectomy as decided by investigator
? Age = 18 years
? WHO performance status 0 – 1

2) RANDOMIZATION
? HER-2 overexpression, as determined by central testing using immunohistochemistry (IHC 3+) or the combination of IHC 2+ & HER-2 FISH positive (please see pathology guidelines)
? Amenable to gastrectomy/oesophagectomy with curative intent confirmed by multidisciplinary team discussion
? UICC (Edition 7th) tumor stage Ib to III, as defined by CT scan and/or MRI Endosonography (EUS) is recommended but not mandatory. EUS should especially be considered to distinguish T1&T2 tumors & to evaluate local resectability. (In case of conflicting results of CT scan and/or MRI and endoscopic ultrasound, the final decision on which finding the staging is based should be taken by the multidisciplinary team
? The cardiac ejection fraction (LVEF) as determined by echocardiography, MUGA or cardiac MRI should be at least 55%
? Adequate organ function:
? 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 (transfusions are permitted to reach this value)
? Estimated glomerular filtration rate (eGFR) according to MDRD should be > 50 ml/min (for patients treated with oxaliplatin-based regimens upfront)
NOTE: For patients that will receive CISPLATIN upfront a GFR > 60 ml/min is required
? Total bilirubin within normal limits (if the patient has documented Gilbert’s disease = 1.5 × ULN or direct bilirubin = ULN)
? Aspartate transaminase (AST) & alanine transaminase (ALT) = 2.5 × ULN
? Absence of preexisting neuropathy > grade I
? Investigator and patient have to agree to replace any oral anticoagulations by subcutaneous administration of low-molecular weight

Exclusion Criteria

2) Randomization
?Prior chemo- or antibody therapy
?History of significant cardiac disease defined as:
-Symptomatic CHF (NYHA classes II-IV, see Appendix D)
-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
?Central nervous system metastasis or leptomeningeal tumor spread. For patients without any neurological symptoms, a brain MRI is recommended, but not obligatory. For patients with any clinical symptoms, which may be attributed to brain metastases, a brain MRI is compulsory to rule out cerebral metastases.
?Known hypersensitivity to the components of trastuzumab, pertuzumab, oxaliplatin, docetaxel, 5-FU or capecitabine
?Patients with interstitial lung disease
?Known dihydropyrimidine dehydrogenase (DPD) deficiency (testing not required). In case of specific recommendations due to institutional and/or national guidelines please proceed accordingly
?Ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
?Chronic treatment with high-dose intravenous corticosteroids (> 10 mg/day prednisone equivalents)
?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.
? Female patients should NOT be breast feeding

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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