| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive adenocarcinoma of the stomach or gastroesophageal junction |
| Adenomacarcinoma de estómago o unión gastroesofágica HER2-positiva |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive advanced gastric cancer |
| Cáncer gástrico avanzado HER2-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 | 14.0 |
| E.1.2 | Level | LLT |
| 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 estimate the minimum (trough) pertuzumab concentration
(Cmin) at Day 43 for two dose levels of pertuzumab in order to
identify a dose that produces a steady-state Cmin of ? 20 ?g/mL in 90% of patients receiving pertuzumab and trastuzumab plus chemotherapy as first-line treatment for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction
? To evaluate the safety and tolerability of two dose levels of pertuzumab in combination with trastuzumab and chemotherapy administered every 3 weeks to patients with HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction |
? Calcular la concentración mínima (?valle?) (Cmin) de pertuzumab alcanzada el día 43 con dos niveles de dosis de pertuzumab, con objeto de identificar una dosis que proporcione una Cmin en estado de equilibrio de ? 20 ?g/ml en el 90% de los pacientes que reciben pertuzumab en combinación con trastuzumab y quimioterapia como tratamiento de primera línea del adenocarcinoma gástrico o de la unión gastroesofágica HER2-positivo, localmente avanzado o recurrente y/o metastásico e inoperable
? Evaluar la seguridad y la tolerancia de dos niveles de dosis de pertuzumab en combinación con trastuzumab y quimioterapia, administrados cada 3 semanas a pacientes con adenocarcinoma gástrico o de la unión gastroesofágica HER2-positivo, localmente avanzado o recurrente y/o metastásico e inoperable |
|
| E.2.2 | Secondary objectives of the trial |
To make an exploratory assessment of the anti-tumor activity of
pertuzumab in combination with trastuzumab and chemotherapy in
patients with HER2 positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction |
| Realizar una evaluación exploratoria de la actividad antitumoral de pertuzumab en combinación con trastuzumab y quimioterapia en pacientes con adenocarcinoma gástrico o de la unión gastroesofágica HER2-positivo, localmente avanzado o recurrente y/o metastásico e inoperable |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease-Specific Inclusion Criteria
? Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with inoperable locally advanced or metastatic disease, not amenable to curative therapy. Patients with advanced disease who present with a recurrence post operatively (when intent of surgery was cure) are also eligible for entry.
? Measurable disease, according to the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1, assessed using imaging techniques (CT or MRI), or non-measurable disease that can be followed
? HER2 positive tumor defined as either IHC 3+ or IHC 2+ in combination with ISH +, as assessed by central laboratory on primary or metastatic tumor ISH positivity is defined as a ratio of >= 2.0 for the number of HER2 gene copies to the number of signals for CEP17.
Availability of formalin-fixed paraffin-embedded (FFPE) tissue with at least 5 mm of invasive tumor for central confirmation of HER2 eligibility is mandatory.
? Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
? Baseline LVEF >= 55% (measured by ECHO or MUGA)
? Life expectancy of at least 3 months.
General Inclusion Criteria
? Male or female
? Age >= 18 years
? Signed informed consent
? For women of childbearing potential and male participants with partners of childbearing potential: agreement to use a highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner (see Section 7.2.6 for details). Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study medication. |
- Presentar adenocarcinoma gástrico o de la unión gastroesofágica confirmado histológicamente, con enfermedad localmente avanzada o metastásica e inoperable, que no se pueda tratar con intención curativa.
Los pacientes con enfermedad avanzada que manifiesten recurrencia postoperatoria (cuando la intención de la cirugía era curativa) también son aptos para la inclusión en el estudio.
Enfermedad medible, de acuerdo con los Criterios de Evaluación de la Respuesta en
Tumores Sólidos (RECIST), v1.1, evaluada mediante técnicas de diagnóstico por
imágenes ( TAC o RM, o enfermedad no medible que pueda ser seguida
Tumores HER2 positivo, que se definen como IHC 3+ o IHC 2+ en combinación con ISH +, basándose en la evaluación del tumor primario o metastásico realizada en el laboratorio central
La positividad en ISH se define como una relación para el número de copias del gen HER2 al número de señales en CEP17 de ? 2,0
Es obligatorio que haya tejido disponible fijado en formalina e incluido en parafina (FFPE) que contenga una muestra de tumor invasivo de 5 mm, como mínimo, para la confirmación del estado de HER2 en el laboratorio central.
Estado funcional del Eastern Cooperative Oncology Group (ECOG) 0 o 1
Fracción de eyección ventricular izquierda (FEVI) basal ? 55% (medida en ecocardiograma [ECO] o angiografía radioisotópica [MUGA])
Esperanza de vida de 3 meses, como mínimo
Varones o mujeres
Edad ? 18 años
Consentimiento informado firmado
Las mujeres potencialmente fértiles y los varones participantes cuya pareja sea potencialmente fértil deben comprometerse a utilizar, por su parte y/o la de su pareja, un método anticonceptivo no hormonal altamente eficaz o dos métodos anticonceptivos no hormonales eficaces
Las medidas anticonceptivas deben seguir utilizándose durante todo el tratamiento del estudio y, como mínimo, hasta 6 meses después de administrar la última dosis de la medicación del estudio. |
|
| E.4 | Principal exclusion criteria |
Cancer-Related Exclusion Criteria
? Previous chemotherapy for advanced or metastatic disease, except that prior adjuvant or neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant or neoadjuvant therapy and enrollment in the study. Adjuvant or neoadjuvant treatment with platinum-based therapy is not allowed.
? Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome (e.g., patients with partial or total gastrectomy can enter the study, but not those with a jejunostomy probe)
? Active (significant or uncontrolled) gastrointestinal bleeding
? Residual relevant toxicity resulting from previous therapy (e.g., neurological toxicity of >= Grade >= 2 [NCI CTCAE]), with the exception of alopecia
? Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
Exclusion Criteria Related to Hematological, Biochemical, and Organ Function
? Any of the following abnormal laboratory tests immediately prior to randomization:
Serum total bilirubin > 1.5 times the upper limit of normal (ULN) or, for patients with known Gilberts syndrome, serum total bilirubin > 2 × ULN
For patients with no liver and no bone metastases:
AST or ALT > 2.5 × ULN, and alkaline phosphatase (ALP) > 2.5 × ULN
In patients with liver metastases and no bone metastases:
AST or ALT > 5 × ULN, and ALP > 2.5 × ULN
In patients with liver metastases and bone metastases:
AST or ALT > 5 × ULN, and ALP > 10 × ULN;
In patients with bone metastases and no liver metastases:
AST or ALT > 2.5 × ULN, and ALP > 10 × ULN
Albumin < 25 g/L
Creatinine clearance < 60 mL/min
Total WBC count < 2500/?L (< 2.5 × 109/L)
Absolute neutrophil count (ANC) < 1500/?L (<1.5 × 109/L)
Platelets < 100,000/?L (<100 × 109/L).
Other Study Drug?Related Exclusion Criteria
? Serious cardiac illness or medical conditions including but not confined to:
History of documented heart failure or systolic dysfunction (LVEF < 50%)
High-risk uncontrolled arrhythmias, such as 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 II] or third-degree AV block)
Angina pectoris requiring anti-anginal medication
Clinically significant valvular heart disease
Evidence of transmural infarction on ECG
Poorly controlled hypertension (e.g., systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg)
? Dyspnea at rest due to complications of advanced malignancy or other disease, or requirement for supportive oxygen therapy
? Treatment with chronic or high-dose corticosteroid therapy.
Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed.
? Clinically significant hearing abnormality
? Known dihydropyrimidine dehydrogenase deficiency.
General Exclusion Criteria
? History or clinical evidence of brain metastases
? Serious uncontrolled systemic intercurrent illness (e.g., infections or poorly controlled diabetes)
? Pregnant or lactating. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization, irrespective of the method of contraception used.
? Radiotherapy within 4 weeks prior to start of study treatment, or within 2 weeks prior to start of study treatment if palliative radiotherapy is given to bone metastatic site peripherally and patient recovers from any acute toxicity
? Major surgery within 4 weeks prior to start of study treatment, without complete recovery
? Known active infection with HIV, hepatitis B virus, or hepatitis C virus
? Known hypersensitivity to any of the study drugs
? Inability to comply with follow-up testing or procedures, as determined by the investigator. |
Administración de quimioterapia previa para la enfermedad avanzada o metastásica, con la siguiente excepción: está permitida la administración de terapia adyuvante o neoadyuvante previa siempre que hayan transcurrido un mínimo de 6 meses desde la terminación de dicho tratamiento y la inclusión en el estudio
No está permitida la administración de terapia adyuvante o neoadyuvante con un compuesto de platino.
?
Falta de integridad física del tracto gastrointestinal superior o síndrome de malabsorción (p. ej. los pacientes con gastrectomía parcial o total pueden ser incluidos en el estudio, pero no los que utilicen una sonda de yeyunostomía).
Hemorragia gastrointestinal activa (significativa o no controlada)
Toxicidad residual importante a consecuencia de la terapia previa (p. ej. toxicidad neurológica de grado ? 2 [NCI-CTCAE]), excepto alopecia
Otras neoplasias en los 5 últimos años, excepto carcinoma in situ de cervix o carcinoma basocelular
Cualquiera de los valores anómalos siguientes de las pruebas de laboratorio realizadas inmediatamente antes de la randomización:
Bilirrubina sérica total > 1,5 veces el límite superior de normalidad (LSN) o > 2 × LSN en pacientes con síndrome de Gilberts confirmado
En pacientes sin metástasis hepáticas ni óseas:
AST o ALT > 2,5 × LSN y fosfatasa alcalina (FA) > 2,5 × LSN
En pacientes con metástasis hepáticas y sin metástasis óseas: AST o ALT > 5 × LSN y FA > 2,5 × LSN
En pacientes con metástasis hepáticas y óseas: AST o ALT > 5 × LSN y FA > 10 × LSN;
En pacientes con metástasis óseas y sin metástasis hepáticas: AST o ALT > 2,5 × LSN y FA > 10 × LSN
Albúmina < 25 g/l
Aclaramiento de creatinina < 60 ml/min
Recuento total de leucocitos < 2500/?l (? 2,5 × 109/l)
Recuento absoluto de neutrófilos (RAN) < 1500/?l (? 1,5 × 109/l)
Recuento de plaquetas < 100.000/?l (? 100 × 109/l)
Enfermedades o trastornos cardíacos graves, incluyendo los siguientes aunque no exclusivamente:
Antecedentes de insuficiencia cardíaca o disfunción sistólica (FEVI < 50%) documentadas
Arritmias de alto riesgo no controladas, tales como taquicardia auricular con una frecuencia cardíaca ? 100/min en reposo, arritmias ventriculares significativas (taquicardia ventricular) o bloqueo AV de grado más alto (bloqueo AV de segundo grado tipo 2 [Mobitz II] o bloqueo AV de tercer grado)
Angina de pecho que requiera medicación antianginosa
Valvulopatía clínicamente significativa
Evidencia de infarto transmural en ECG
Hipertensión mal controlada (p. ej. presión arterial sistólica > 180 mm Hg o diastólica > 100 mm Hg)
Disnea en reposo debido a complicaciones de la enfermedad neoplásica avanzada u otras enfermedades o pacientes que precisen oxigenoterapia de soporte
Tratamiento corticosteroide crónico o a dosis altas: está permitido el uso de esteroides por vía inhalatoria y la administración de ciclos cortos de tratamiento con esteroides orales para la prevención de la emesis o para estimular el apetito.
Anomalías auditivas clínicamente significativas
Deficiencia de dihidropirimidina deshidrogenasa confirmada
Antecedentes o evidencia clínica de metástasis cerebrales
Enfermedades intercurrentes sistémicas graves no controladas (p. ej. infecciones o diabetes mal controlada)
Embarazo o lactancia: las mujeres potencialmente fértiles deben presentar un resultado negativo en la prueba de embarazo en suero realizada en los 7 días previos a la randomización, independientemente del método anticonceptivo utilizado.
Administración de radioterapia en las 4 semanas previas al inicio del tratamiento del estudio, aunque se permite la radioterapia paliativa en las 2 semanas previas si se ha administrado en metástasis óseas periféricas y el paciente se ha recuperado de la toxicidad aguda de la terapia
Cirugía mayor en las 4 semanas previas al inicio del tratamiento del estudio, sin que el paciente se haya recuperado por completo
Infección activa confirmada por VIH o virus de la hepatitis B o C
Hipersensibilidad confirmada a cualquiera de los fármacos del estudio
Incapacidad para cumplir las evaluaciones o los procedimientos del seguimiento, de acuerdo con el criterio del investigador |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Minimum (trough) serum concentration (Cmin) for pertuzumab |
| Concentración mínima (?valle?) (Cmin) de pertuzumab |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| This study is not designed or powered to provide an accurate evaluation of efficacy. Thus, efficacy analyses are exploratory and no comparisons between dose levels will be made. Investigator-assessed tumor response will be used to summarize best overall response at the end of Cycles 3 and 6 for each treatment arm, defined as patients with a complete or partial response as determined by RECIST. |
| Este estudio no está diseñado para proporcionar una evaluación precisa de la eficacia. Por lo tanto los análisis de eficacia son exploratorios y no se realizarán comparaciones entre los niveles de dosis. Evaluados por el investigador la respuesta del tumor se utiliza para resumir mejor respuesta general al final de los ciclos de 3 y 6 para cada grupo de tratamiento, definida como pacientes con respuesta completa o parcial según lo determinado por RECIST. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of cyles 3 and 6 |
| Al final de 3er y 6º ciclo |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Se compararan entre si dos esquemas de dosificación diferentes de pertuzumab |
| Two different dosing schemes of pertuzumab will be compared to each other |
|
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| European Union |
| Korea, Republic of |
|
| 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
|
| The end of study will be when progressive disease has occurred in all patients, or all patients have withdrawn or discontinued from the study, whichever is earlier. |
| El estudio terminará cuando todos los pacientes hayan manifestado progresión de la enfermedad o se hayan retirado o terminado prematuramente el estudio, dependiendo de lo que ocurra primero. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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