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-EE

Lead Sponsor: European Organisation for 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 the determination of the HER-2 status, European sites will have the
choice, patient by patient, between the two following options:
a) Assessment of the HER-2 status of the potentially eligible patient in the
central lab
or
b) Assessment of the HER-2 status by IHC only in the local lab and
mandatory confirmation of the HER-2 positive result in the central lab.
Important note:
Despite excellent pathologists and quality-controlled testing in local
pathology laboratories, potential discrepancies between the peripheral
and central lab in the interpretation of IHC results are well known. In
order not to lose potentially eligible patients for the trial it is mandatory
that the material from all patients with any HER-2 positivity (IHC 1+ or
more) in the local lab must be sent to the central pathology laboratory
as specified below:
? 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 tumor (7th edition) 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 heparin (LMWH) in equivalent doses before treatment start, or if on oral anticoagulations &unwilling to switch to LMWH, patients have to be treated with mandatory 5-FU i.v. instead of capecitabine
? Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with study protocol & follow-up schedule; those conditions should be discussed with the patient before registration in trial
? For women who are not postmenopausal (> 12 months of non- therapy induced amenorrhea)or surgi

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
Main Objective: To increase the major pathological response rate (< 10% vital tumor cells) to neoadjuvant treatment by integrating both trastuzumab and pertuzumab into perioperative chemotherapy for HER-2 positive, resectable gastric cancer. ;Secondary Objective: Not applicable;Primary end point(s): The primary endpoint of the phase II study is the major pathological response rate (< 10% vital tumor cells).;Timepoint(s) of evaluation of this end point: Post surgery.<br>The analysis of the primary endpoint will occur:<br>1. 30 days after all patients have undergone surgery<br>2. the trial is mature for the analysis of the primary endpoint as defined in the protocol<br>3. the database has been fully cleaned and frozen for the analysis

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1 - R0 resection rate<br>2 - Pathological complete response<br>3 - Locoregional failure<br>4 - Distant failure <br>5 - Progression-free survival (according to Recist v1.1)<br>6 - Recurrence-free-survival (from surgery)<br>7 - Overall survival<br>8 - Adverse event assessment according to CTCAE v 4.0;Timepoint(s) of evaluation of this end point: 1 & 2 - Post Surgery<br>3, 4, 5 & 6 - Disease evaluation will be performed with contrast-enhanced CT-scan and/or MRI of thorax and abdomen every 6 months since the date of surgery for the first 2 years, and every 12 months for the subsequent 4 years (thus for at least 6 years). <br>7 - Patients will be followed up for at least 6 years following end of treatment or until death.<br>8 - AEs will be collected until 30 days after end of treatment and during follow-up (as specified in protocol)

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