| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-Positive Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma and in HER2 Low Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma |
| Adenocarcinoma de la unión gástrica o gastroesofágica (UGE) HER2 positivo y adenocarcinoma de la unión gástrica o gastroesofágica (UGE) con expresión baja de HER2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-Positive Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma and HER2 Low Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma |
| Adenocarcinoma de la unión gástrica o gastroesofágica (UGE) HER2 positivo y adenocarcinoma de la unión gástrica o gastroesofágica (UGE) con expresión baja de HER2 |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Primary Objectives of the trial are:
Arm 1: To assess the efficacy of cinrebafusp alfa in combination with ramucirumab and paclitaxel in patients with HER2-positive gastric or GEJ cancer
Arm 2: To assess the efficacy of cinrebafusp alfa in combination with tucatinib in patients with HER2 low gastric or GEJ cancer |
Grupo 1: evaluar la eficacia de cinrebafusp alfa en combinación con ramucirumab y paclitaxel en pacientes con cáncer gástrico o de la UGE HER2 positivo
Grupo 2: evaluar la eficacia de cinrebafusp alfa en combinación con tucatinib en pacientes con cáncer gástrico o de la UGE con expresión baja de HER2 |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives of the trial are
• To assess other evidence of clinical benefit
• To evaluate the safety and tolerability of the treatment regimens |
• Evaluar otros indicios de beneficio clínico
• Evaluar la seguridad y la tolerabilidad de las pautas de tratamiento |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Key Inclusion Criteria:
• Signed written informed consent obtained prior to performing any study procedure, including screening procedures
• Men and women ≥18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
Disease Characteristics
• Histologically or cytologically confirmed gastric or GEJ adenocarcinoma
• Arm 1: Has received no more than two prior treatment regimens for advanced disease, including a platinum, a fluoropyrimidine, and HER2-directed therapy such as trastuzumab
• Arm 2: Has received at least one prior treatment regimen for advanced disease
• Arm 1: Demonstration of HER2 positivity assessed by a test with appropriate regulatory validation in a current tissue specimen and following guidelines for assessment in gastric or GEJ adenocarcinoma described in Section 4.3 after completion of no more than two prior treatment regimens, including a platinum, a fluoropyrimidine and a HER2-directed therapy such as trastuzumab • Arm 2: Demonstration of HER2 IHC 1+ or IHC 2+ without HER2/neu gene amplification assessed by a test with appropriate regulatory validation in a current tissue specimen and following guidelines for assessment in gastric or GEJ adenocarcinoma described in 4.3 after completion of most recent prior treatment regimen
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 Organ Function
• Adequate organ and hematologic function as defined below:
• Serum AST and ALT ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN in the presence of liver metastases
• Total serum bilirubin ≤1.5 × ULN
• Albumin ≥ 3.0 g/dL
• Serum creatinine ≤1.5 × ULN OR creatinine clearance measured via 24-hour urine collection ≥40 mL/min if serum creatinine is > 1.5X ULN
• Arm 1 only: Urinary protein is ≤ 1+ on dipstick or routine urine analysis; if urine dipstick or urinalysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours
• Hemoglobin ≥9 g/dL; packed red blood cell transfusions are not allowed in the week preceding screening evaluation
• ANC ≥1500/mm3
• Platelet count ≥100,000/mm3
• INR ≤ 1.5 and PT ≤1.5 × ULN and PTT ≤1.5 × ULN.
• Arm 1 only: Patients receiving oral anticoagulants must be switched to low molecular weight anti-coagulants and have achieved stable coagulation profile prior to first dose of protocol therapy.
• Arm 2 only: patients receiving oral anti-coagulants must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
• Left ventricular ejection fraction (LVEF) of ≥50% as determined by echocardiogram or multigated acquisition scan
Previous Therapy
•Resolution to Grade ≤1 by NCI CTCAE v5.0 of all clinically significant toxicities associated with prior therapy or procedures Contraception
• If sexually active, the patient must be post-menopausal, surgically sterile or using highly effective contraception. Highly effective contraception for women of child-bearing potential and males with female partners of child-bearing potential is defined as 1 barrier method (e.g., condom) and 1 additional method (e.g., hormonal) of contraception during the study and for at least three months from the last study treatment or recommended contraceptive period according to the local label of the concomitant drug if greater than 3 months
• Women of child-bearing potential may not be breastfeeding and must have a negative serum pregnancy test within 96 hours prior to start of study treatment |
General
1. Consentimiento informado por escrito y firmado obtenido antes de realizar cualquier procedimiento del estudio, incluidos los procedimientos de selección
2. Hombres y mujeres ≥18 años de edad.
3. Estado general 0 o 1, de la Escala del Grupo Oncológico Cooperativo del Este (ECOG).
Características de la enfermedad
4. Adenocarcinoma gástrico o de la UGE confirmado histológica o citológicamente
5. Grupo 1: no haber recibido más de dos pautas previas de tratamiento para la enfermedad avanzada, incluidas una con platino, una con fluoropirimidina y un tratamiento dirigido al HER2 como trastuzumab.
Grupo 2: Haber recibido al menos una pauta de tratamiento previo para la enfermedad avanzada.
6. Grupo 1: Demostración de HER2 positivo evaluada mediante una prueba con validación normativa vigente en una muestra de tejido actual y siguiendo las directrices para la evaluación del adenocarcinoma gástrico o de la UGE descrito en el apartado 4.3 después de recibir no más de dos pautas de tratamiento previo, incluidas una con platino, una con fluoropirimidina y un tratamiento dirigido a HER2 como trastuzumab.
Grupo 2: Demostración de la amplificación de HER2 IHQ 1+ o IHQ 2+ sin HER2/neu evaluada mediante una prueba con validación normativa adecuada en una muestra de tejido actual y siguiendo las directrices para la evaluación del adenocarcinoma gástrico o de la UGE descritas en el apartado 4.3 tras la finalización de la pauta de tratamiento previa más reciente.
7. Enfermedad medible según los criterios de evaluación de la respuesta en tumores sólidos (RECIST) 1.1
Funcionamiento de los órganos
8. Función hematológica y de los órganos adecuada definida como sigue:
• AST y ALT en suero ≤2,5 veces el límite superior de la normalidad (LSN) o ≤5 veces el LSN en
presencia de metástasis hepáticas
• Bilirrubina sérica total ≤1,5 veces el LSN
• Albúmina sérica ≥3 g/dl
• Creatinina sérica ≤1,5 veces el LSN O aclaramiento de creatinina medido mediante
recogida de orina de 24 horas ≥40 ml/min si la creatinina sérica es >1,5 veces el LSN
• Grupo 1 solamente: Proteína urinaria ≤1+ en la tira reactiva o el análisis de orina rutinario; si la tira reactiva o el análisis de orina es ≥2+, la recogida de orina de 24 horas para proteínas debe demostrar <1 000 mg de proteínas en 24 horas
• Hemoglobina ≥9 g/dl; no se permiten las transfusiones de concentrados de eritrocitos en la semana anterior a la evaluación de la selección
• RAN ≥1500/mm3
• Recuento de plaquetas ≥100 000/mm3
• INR ≤1,5 y TP ≤1,5 veces el LSN y TTP ≤1,5 veces el LSN. Grupo 1 solamente: Se debe cambiar el tratamiento a los pacientes que estén recibiendo anticoagulantes orales a anticoagulantes de bajo peso molecular y tienen que haber alcanzado un perfil de coagulación estable antes de la primera dosis del tratamiento según el protocolo. Grupo 2 solamente: Se debe cambiar el tratamiento a los pacientes que estén recibiendo anticoagulantes orales a heparina de bajo peso molecular y tienen que haber alcanzado un perfil de coagulación estable antes de la primera dosis del tratamiento según el protocolo.
9. Fracción de eyección ventricular izquierda (FEVI) ≥50 % determinada mediante ecocardiograma o ventriculografía isotópica
Tratamiento previo
10. Resolución a grado ≤1 según los CTCAE del NCI v5.0 de todas las toxicidades clínicamente significativas asociadas al tratamiento o los procedimientos previos
Anticoncepción
11. Si es sexualmente activa, la paciente debe ser posmenopáusica, estar esterilizada quirúrgicamente o utilizar un método anticonceptivo altamente eficaz. Un método anticonceptivo altamente eficaz para las mujeres en edad fértil y los hombres con parejas femeninas en edad fértil se define como 1 método de barrera (p. ej., preservativo) y 1 método anticonceptivo adicional (p. ej., hormonal) durante el estudio y durante al menos tres meses desde el último tratamiento del estudio o el periodo de anticoncepción recomendado según la ficha técnica local del fármaco concomitante si es superior a 3 meses
12. Las mujeres en edad fértil no pueden estar en periodo de lactancia y deben tener una prueba de embarazo en suero negativa en las 96 horas anteriores al inicio del tratamiento del estudio |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria
• Disease of squamous or undifferentiated histology
• History or evidence of known active CNS metastases or carcinomatous meningitis.
•Patients with brain metastases are eligible provided they have shown clinical and radiographic stable disease for at least 4 weeks after definitive therapy and have not used steroids (> 10 mg/day of prednisone or equivalent) for at least 2 weeks prior to the first dose of study treatment
•Arm 1 only: Receipt of any previous systemic therapy (including investigational agents) targeting the VEGF or the VEGFR signaling pathways
• Intolerance to trastuzumab or other HER2-directed agent in prior treatment regimen
Coagulation Considerations
• History of deep vein thrombosis (DVT), pulmonary embolism (PE) or any other significant thromboembolism during the three months prior to first dose of study treatment; venous port or catheter thrombosis or superficial venous thrombosis are not considered significant (Arm 1 only). For patients in Arm 2, the investigator is referred to Exclusion Criterion 21 and should consult with the Medical Monitor in the case of a history of these or similar events. • Chronic therapy with nonsteroidal anti-inflammatory drugs or other antiplatelet
• Significant bleeding disorders, vasculitis or a significant bleeding episode from the GI tract within 3 months prior to study entry • Arterial thromboembolic event within 6 months prior to study entry
• History of acute coronary syndromes, including myocardial infarction, coronary artery bypass graft, unstable angina, coronary angioplasty or stenting within past 24 weeks
•History of or current Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system or symptomatic or poorly controlled cardiac arrhythmia •History of ejection fraction drop below the lower limit of normal with trastuzumab or other HER2directed therapy
•Uncontrolled or poorly-controlled hypertension (arterial hypertension ≥150 mm Hg or diastolic ≥90 mmHg) for > four weeks despite standard medical management; the patient may be re-screened after treatment for hypertension
•Any arterial thromboembolic event, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident or unstable angina, within six months prior to first dose of study treatment
•Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn’s disease, ulcerative colitis or chronic diarrhea
•Gastrointestinal perforation or fistula within 6 months prior to study entry or have risk factors for perforation
•Grade 3 or Grade 4 GI bleeding within 3 months prior to first study treatment
•Arm 2 only: Inability to swallow pills or presence of any significant gastrointestinal disease which would preclude the adequate absorption of an oral medication Hepatic Cirrhosis at a level of Child-Pugh B or worse OR cirrhosis of any degree
Serious or non-healing wound, ulcer or bone fracture within 28 days prior to first study treatment
Any medical, psychiatric, cognitive or other condition that compromises the patient’s ability to understand information,
Arm 2 only: Prior anthracycline exposure (epirubicin > 720 mg/m2) Arm 2 only: Having used a strong cytochrome P450 CYP2C8 inhibitor within three elimination halflives of the inhibitor
Patients on the strong CYP2C8 inhibitor gemfibrozil at screening must discontinue its use at least 24 hours before the first dose of study drug and if needed, substitute an alternate lipid-lowering agent.
Active human immunodeficiency virus (HIV) disease, hepatitis B, or hepatitis C
Any severe infection within 28 days prior to study start or requirement for oral or intravenous antibiotics within 14 days prior to study start
Administration of live, attenuated vaccines within 28 days prior to start of treatment or anticipated need for vaccination with live attenuated vaccine during the study.
Vaccination for SARS-CoV-2 is permitted and guidelines for administration of vaccine are provided in Section 5.9.
History of infusion or other reactions to any component/excipient of cinrebafusp alfa (Arm 1 and Arm 2), ramucirumab or paclitaxel (Arm 1) or tucatinib (Arm 2); Arm 2 only: history of allergic reactions to tucatinib or compounds chemically or biologically similar to |
Enfermedad y tratamiento previo
1. Enfermedad de histología epidermoide o indiferenciada
2. Antecedentes o indicios conocidos de metástasis activa en el SNC o meningitis carcinomatosa. Los pacientes con metástasis cerebrales son aptos siempre que hayan mostrado enfermedad estable clínica y radiográfica durante al menos 4 semanas después del tratamiento definitivo y no hayan utilizado corticoesteroides (>10 mg/día de prednisona o equivalente) durante al menos 2 semanas antes de la primera dosis del tratamiento del estudio
3. Grupo 1 solamente: Haber recibido cualquier tratamiento sistémico previo (incluidos fármacos en investigación) dirigido contra el VEGF o las vías de señalización del VEGFR
4. Intolerancia a trastuzumab u otro fármaco dirigido a HER2 en una pauta de tratamiento previa
Consideraciones sobre coagulación
5. Antecedentes de trombosis venosa profunda (TVP), embolia pulmonar (EP) o cualquier otra tromboembolia significativa durante los tres meses anteriores a
la primera dosis del tratamiento del estudio; la trombosis relacionada con el puerto o el catéter venoso o la trombosis venosa superficial no se consideran significativas (grupo 1 solamente). En el caso de los pacientes del grupo 2, el investigador se refiere al criterio de exclusión 21 y debe consultar con el monitor médico en caso de antecedentes de estos acontecimientos o acontecimientos similares.
6. Tratamiento crónico con fármacos antinflamatorios no esteroideos (AINE; p. ej., indometacina, ibuprofeno, naproxeno o fármacos similares) u otros antiagregantes plaquetarios (p. ej., clopidogrel, ticlopidina, dipiridamol, anagrelida); se permite el uso de aspirina hasta 325 mg al día
7. Trastornos hemorrágicos significativos, vasculitis o un episodio hemorrágico significativo del tubo GI en los 3 meses previos a la entrada al estudio
8. Acontecimiento tromboembólico arterial en un plazo de 6 meses antes de la entrada al estudio
Hacemos referencia a los criterios de exclusión por especialidad en la sinopsis debido a falta de caracteres en el formulario. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) as defined by RECIST version 1.1 |
| Tasa de respuesta global (TRG), definida mediante RECIST versión 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Objective disease status using RECIST v1.1 criteria will be assessed every eight weeks for the first six months and then every 12 weeks thereafter. |
| El estado objetivo de la enfermedad utilizando los criterios RECIST v1.1 se evaluará cada ocho semanas durante los primeros seis meses y luego cada 12 semanas a partir de entonces. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
• Progression-free survival (PFS), disease control rate (DCR, CR+PR+SD), duration of response (DOR), time to progression (TTP), overall survival (OS)
• Overall safety profile as assessed by the type, frequency, severity, timing and causal relationship of any AEs, changes in vital signs, ECGs, serum chemistry or other laboratory assessment, treatment delays or discontinuations, immunogenicity of cinrebafusp alfa and ramucirumab assessed by the presence and titers of anti-cinrebafusp alfa and/or antiramucirumab antibodies |
Criterios de valoración secundarios
• Supervivencia libre de progresión (PFS), tasa de control de la enfermedad (DCR, CR+PR+SD), duración de la respuesta (DOR), tiempo hasta la progresión (TTP), supervivencia general (OS)
• Perfil de seguridad general evaluado por el tipo, la frecuencia, la gravedad, el momento y la relación causal de cualquier EA, cambios en los signos vitales, ECG, química sérica u otra evaluación de laboratorio, retrasos o interrupciones del tratamiento, inmunogenicidad de cinrebafusp alfa y ramucirumab evaluados por el presencia y títulos de anticuerpos anti-cinrebafusp alfa y/o antiramucirumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Progression-free survival (PFS) will be analyzed using Kaplan-Meier methodology and is further characterized in terms of the median and survival probability at 3, 6, 9 and 12 months, along with the corresponding 2-sided 95% confidence intervals for the estimates.
•PK and PD data, as well as possible correlations between cinrebafusp alfa exposure and clinical activity, safety, including immunogenicity of cinrebafusp alfa and/or ramucirumab (Arm 1 only), and/or pharmacokinetic and drug concentration data, will be assessed descriptively. |
• La supervivencia libre de progresión (PFS) se analizará mediante la metodología de Kaplan-Meier y se caracteriza además en términos de la mediana y la probabilidad de supervivencia a los 3, 6, 9 y 12 meses, junto con los correspondientes intervalos de confianza bilaterales del 95 % para las estimaciones
•Los datos farmacocinéticos y farmacocinéticos, así como las posibles correlaciones entre la exposición a cinrebafusp alfa y la actividad clínica, la seguridad, incluida la inmunogenicidad de cinrebafusp alfa y/o ramucirumab (grupo 1 únicamente), y/o los datos de concentración farmacocinética y del fármaco, se evaluarán de forma descriptiva. |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| Immunogenicity Assessments |
|
| 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 | No |
| 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 | No |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
| Korea, Republic of |
| United States |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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