| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER-2 positive, resectable gastric cancer |
| cáncer gástrico resecable HER-2 positivo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Her-2 positive, resectable gastric cancer |
| cáncer gástrico resecable HER-2 positivo |
|
| 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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066896 |
| E.1.2 | Term | HER-2 positive gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| 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. |
| Aumentar la mejor tasa de respuesta patológica (< 10% de células tumorales viables) del tratamiento neoadyuvante, mediante la integración de trastuzumab y pertuzumab en la quimioterapia perioperatoria para pacientes con cáncer gástrico resecable HER-2 positivo. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Registration
In Europe, before activation of a site, the institution needs to make a choice between:
Assessment of the HER-2 status of all potentially eligible patients in the central lab OR Assessment of the HER-2 status by IHC in the local lab and mandatory confirmation of the HER-2 positive result in the central lab.
In Korea, all patients are screened locally. Material from patients with a positive HER-2 status has to be sent to the central lab for confirmation.
If a European site selects option a) FFPE blocks or 20x 3-5 µm unstained paraffin sections from all potentially eligible patients must be sent for central assessment of the HER-2 status. If a European site selects option b) and performs local assessment of the HER-2 status by IHC, FFPE blocks or 20x3-5 µm unstained paraffin sections from patients with HER-2 IHC status 1+, 2+ or 3+ must be sent for confirmation to the central lab.
Korean sites are requested to send only FFPE blocks or 20x3-5 µm unstained paraffin sections from HER-2 positive patients if 3+ by IHC or 2+ by IHC and ISH positive by local assessment.
? 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.
? Histologically proven, gastric or GE-junction adenocarcinoma (Siewert I-III, see Appendix J)
? Absence of distant metastases on CT scan of thorax and abdomen
? Patient medically fit for gastrectomy/oesophagectomy as decided by the investigator
? Age ? 18 years
? WHO performance status 0 ? 1
? 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
? 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.
Randomization
? 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).
? Amenable to gastrectomy/oesophagectomy with curative intent as confirmed by a multidisciplinary team discussion
? 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, please refer to chapter 6.3.1 for reporting).
? 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).
? 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
? 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
? 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
? 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.
? 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 (?-human chorionic gonadotropin [?-hCG]) result should be available before randomization and within 7 days from treatment start should be performed. |
Registro
En Europa, antes de activación de sitio, institución deberá elegir entre:
Evaluación estado HER-2 de pacientes potencialmente elegibles en lab central o Evaluación estado HER-2 por inmunohistoquímica (IHC) en lab local y confirmación obligatoria del resultado HER-2 + en lab central.
En Corea, pacientes serán examinados localmente. Material pacientes con estado HER-2 + deberá ser enviado al lab central para su confirmación.
Si centro europeo elige opción a) bloques fijados en formalina y embebidos en parafina o cortes de parafina sin teñir de 20x3-5 µm de pacientes potencialmente elegibles deberán ser enviados para su evaluación central estado HER-2. Si centro europeo elige opción b) y realiza evaluación local estado HER-2 por IHC, bloques fijados en formalina y embebidos en parafina o cortes de parafina sin teñirde 20x3-5 µm de pacientes con HER-2 IHC 1+,2+ o 3+ deberán ser enviados al lab central para su confirmación.
Se solicita a centros coreanos que envíen solamente bloques fijados en formalina y embebidos en parafina o secciones parafinadas en blanco de 20x3-5 µm de pacientes con HER-2-+ 3+ por IHC o 2+ por IHC con ISH + en determinación local.
?Pacientes (HER-2 + y -) deberán registrarse en ensayo lo antes posible vez hayan firmado consentimiento informado para escreeningde acuerdo con ICH/GCP, y regulaciones nacionales y locales.
?Adenocarcinoma gástrico o de unión gastroesofágica histológicamente demostrado (Siewert I-III)
?Ausencia de metástasis a distancia en TC toracoabdominal
?Paciente médicamente apto para práctica gastrecctomía/esofaguectomía a criterio del investigador
?Edad ? 18 años
?Estado funcional OMS (PS) 0 ? 1
?Estado HER2
?Para pacientes europeos si centro elige opción (b): Dispo resultados de determinación local de HER-2 IHC
?Para pacientes coreanos: Dispo resultados de determinación local de HER-2 IHC+/- ISH
?Dispo bloque de parafina o suficientes (idealmente 20 laminillas, aunque excepcionalmente se aceptará un mínimo de 15) cortes de parafina sin teñirde biopsias endoscópicas diagnósticas para análisis o confirmación centralizada de HER-2.
Randomización
?Sobreexpresión HER-2, según determinación centralmediante inmunohistoquímica (IHC 3+) o combinación de IHC 2+ y HER-2 FISH positivo
?Paciente apto para gastrectomía/esofaguectomía con intención curativa en base a decisión multidisciplinar.
?Estadio UICC Ib a III, definido por TC (TC deberá realizarsedentro de los 35 días previos al inicio del tratamiento). EUS es recomendable, pero no obligatoria. EUS debe ser especialmente considerada para diferenciar entre tumores T1 y T2 para valorar posibilidad de resecciónlocal. (En caso de que TC y EUS muestrenresultados contradictorios, estadio definitivo determinará equipo multidisciplinary).
?FEVI, determinada porecocardiograma, ventriculografía isotópica (MUGA) o resonancia magnética cardiaca debe ser de menos un 55% (evaluado dentro de los 14 días previos a la randomización).
?Función orgánica adecuada (evaluado dentro de los 7 días anteriores randomización):
?Recuento de leucocitos (WBC) > 3 x 109/L
?Recuento absoluto de neutrófilos (ANC)> 1,5 x 109/L
?Plaquetas ? 100 x 109/L
?Hemoglobina ? 9 g / dlL
?FGe según MDRD debe ser> 60 ml / min
?Bilirrubina total dentro de límites normales (si paciente ha documentado enfermedad de Gilbert ? 1,5 x LSN o bilirrubina directa ? LSN)
?AST y ALT ? 2,5 x LSN
?No presentar condición psicológica, familiar, sociológica o geográfica que pueda obstaculizar cumplimiento del protocolo estudio y programa de seguimiento. Estas condiciones sedeberán analizar con paciente antes de su inclusión en ensayo.
?En caso de mujeres no posmenopáusicas (> 12 meses de amenorrea no inducida por terapia) o quirúrgicamente estériles (ausencia de ovarios o útero): se deberá acordar permanecer en abstinencia o uso de métodos anticonceptivos simples o combinados que conlleven tasa de fracaso de <1 % por año durante período de tratamiento y durante por lo menos 7 meses después de última dosis de tratamiento.
?En caso de hombres: se deberá acordar permanecer en abstinencia o usar preservativo además de método anticonceptivo adicional que juntos den como resultado tasa de fracaso de <1% por año durante período de tratamiento y durante por lo menos 7 meses después de última dosis del tratamiento del estudio. Abstinencia es solamente aceptable si es acorde al estilo de vida habitual del paciente. Abstinencia periódica (por ejemplo, métodos de calendario, ovulación, métodos de temperatura o postovulación) y retirada no son métodos aceptables para anticoncepción.
?Todas los pacientes de sexo femenino que no sean posmenopáusicas (> 12 meses de amenorrea no inducida por terapia) o quirúrgicamente estériles (ausencia de ovarios o útero) deberán disponer de resultado de prueba de embarazo en suero negativo (? -gonadotropina coriónica humana [?-hCG]) antes de randomización y en plazo de 7 días desde inicio del tratamiento. |
|
| E.4 | Principal exclusion criteria |
?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
? Angina pectoris requiring anti-anginal treatment
?current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg)
?known hypersensitivity to the components of trastuzumab, pertuzumab, cisplatin, 5-FU or capecitabine
?known dihydropyrimidine dehydrogenase (DPD) deficiency
?ongoing or concomitant use of the antiviral drug sorivudine or its chemically related analogs, such as brivudine
?chronic treatment with high-dose intravenous corticosteroids
? 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.
?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. |
?Quimioterapia o terapia de anticuerpos previa.
?Presentar historial de enfermedad cardíaca significativa definida como:
CHF sintomática (NYHA II-IV)
Arritmias no controladas de alto riesgo, es decir, taquicardia auricular con una frecuencia cardíaca > 100/min en reposo, arritmia ventricular significativa (taquicardia ventricular) o bloqueo auriculoventricular de alto grado (bloqueo auriculoventricular de segundo grado Tipo 2 [Mobitz 2] o bloqueo auriculoventricular de tercer grado).
Antecedentes de infarto del miocardio en los 6 meses previos a la randomizacion.
Enfermedad cardíaca valvular significativa clínicamente.
Angina de pecho que requiere tratamiento antianginoso.
?Hipertensión arterial no controlada (sistólica> 180 mmHg o diastólica> 100 mmHg persistente).
?Hipersensibilidad conocida a los componentes de trastuzumab, pertuzumab, cisplatino, 5-FU o capecitabina.
?Déficit de dihidropirimidina deshidrogenasa (DPD) conocido.
?Uso concomitante de fármacos antivirales como sorivudina o sus análogos como brivudina..
?Tratamiento crónico con dosis altas de corticosteroides de forma intravenosa
?El investigador y el paciente deben ponerse de acuerdo para reemplazar cualquier anticoagulante oral por heparina de bajo peso molecular (HBPM) de administración subcutáneaen dosis equivalentes antes de comenzar el tratamiento, o si toma anticoagulantes orales y no está dispuesto a cambiar a HBPM, los pacientes tienen que ser tratados obligatoriamente con 5-FU i.v. en lugar de capecitabina.
?Haber tenido otrostumores malignos dentro de los últimos 5 años, a excepción de cáncer de cérvix in situ tratado adecuadamente, cáncer de piel no melanoma localizado, u otro tipo de cáncer tratado de forma curativa y sin impacto en el pronóstico general del paciente a criterio del investigador.
?Las pacientes de sexo femenino no deben estar en periodo de lactancia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the phase II study is the major pathological response rate (< 10% vital tumor cells). |
| El Objetivo principal es una mayor tasa de respuesta patológica (< 10% de células tumorales residuales). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Post surgery.
The analysis of the primary endpoint will occur:
1. 30 days after all patients have undergone surgery
2. the trial is mature for the analysis of the primary endpoint as defined in the protocol
3. the database has been fully cleaned and frozen for the analysis |
|
| E.5.2 | Secondary end point(s) |
1 - R0 resection rate
2 -Pathological complete response
3 - Locoregional failure
4 - Distant failure
5 - Progression-free survival
6 - Recurrence-free-survival
7 - Overall survival
8 - Adverse event assessment according to CTCAE v 4.0 |
1- Tasa de resección R0
2- Respuesta patológica completa
3- Tasa de recidiva locorregional
4- Tasa de recidiva a distancia
5- Supervivencia libre de progresión
6- Supervivencia libre de recidiva
7- Supervivencia global
8- Evaluación de eventos adversos según CTCAE v 4.0 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 & 2 - Post Surgery
3, 4, 5 & 6 - Tumor evaluations will be done at end of neoadjuvant treatment and every 6 months since surgery for the first 2 years and every 12 months for the subsequent 3 years (thus for at least 5 years).
5 & 6 - Both rates at 3 years will be displayed by treatment arm together with their 95% confidence interval. the 3-year cumulative incidence rates of locoregional failures and distant failures will be calculated together with their 95% confidence intervals.
7 - Patients will be followed up for at least 5 years following randomization or until death.
8 - AEs will be collected until 30 days after end of treatment and during follow-up (as specified in protocol treatment) |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Elderly Minimal Dataset Comprehensive Geriatric Assessment for patients ? 70 years of age at 28 days after end of treatment. |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Estonia |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. All patients have been followed up for at least 5 years from randomization
3. The database has been fully cleaned and frozen for the analysis of secondary endpoints. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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