| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with unresectable, KRAS, NRAS and BRAF wild-type (WT) metastatic colorectal cancer. |
| Pacientes con cáncer colorrectal metastásico irresecable con KRAS, NRAS y BRAF de tipo natural |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastastic colorectal cancer |
| Pacientes con cáncer colorrectal metastásico |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 investigate whether cetuximab alone (given until progression or cumulative toxicity) after 8 cycles of FOLFIRI + cetuximab results in a non-inferior Progression Free Survival when compared with continuous FOLFIRI + cetuximab (given until progression or cumulative toxicity).
• To assess whether an improvement in the incidence of grade 3-4 hematological and non-hematological adverse events (AEs) can be achieved in the experimental arm (cetuximab alone after 8 cycles FOLFIRI + cetuximab) as compared to the continuous chemotherapy arm (FOLFIRI plus cetuximab)
• To explore the possibility of using liquid biopsies for molecular profiling as well as monitoring treatment activity in mCRC pts receiving cetuximab-based therapy |
• Determinar si el cetuximab en monoterapia (administrado hasta la progresión o toxicidad acumulada) tras 8 ciclos de FOLFIRI + cetuximab da lugar a una supervivencia sin progresión no inferior en comparación con FOLFIRI + cetuximab continuado (administrado hasta la progresión o la toxicidad acumulada).
• Evaluar si se puede lograr una mejora en la incidencia de los acontecimientos adversos (AA) hematológicos y no hematológicos de grado 3-4 en el grupo experimental (cetuximab en monoterapia tras 8 ciclos de FOLFIRI + cetuximab) en comparación con el grupo de quimioterapia continuada (FOLFIRI + cetuximab).
• Explorar la posibilidad de usar biopsias líquidas para la elaboración de perfiles moleculares, así como controlar la actividad del tratamiento en pacientes con CCRm con un tratamiento basado en cetuximab. |
|
| E.2.2 | Secondary objectives of the trial |
• Response rate (RR)
• Early tumor shrinkage (ETS) (8 weeks)
• Overall survival (OS)
• Cetuximab-related skin toxicity
• Safety profile
• QoL
• Molecular profiles of tumor tissue and liquid biopsy
• Potential predictive factors (somatic mutations identified in tumor tissue by next generation sequencing) and surrogate markers of treatment activity (changes in molecular profile of liquid biopsies)
For definition of endpoints see Main parameters of efficacy and safety |
• Tasa de respuesta (TR)
• Reducción temprana del volumen tumoral (RTVT) (8 semanas)
• Supervivencia global (SG)
• Toxicidad cutánea relacionada con el cetuximab
• Perfil de seguridad
• CdV
• Perfiles moleculares del tejido tumoral y la biopsia líquida
• Factores predictivos potenciales (mutaciones somáticas identificadas en el tejido tumoral por secuenciación de nueva generación) y marcadores indirectos de actividad del tratamiento (cambios en el perfil molecular de las biopsias líquidas) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically proven diagnosis of colorectal adenocarcinoma
• Diagnosis of metastatic disease
• Hepatic metastases which are deemed to be amenable for surgical resection, but for which the pharmacological treatment could be considered useful before proceeding to the intervention, upon clinical judgment.
• RAS and BRAF wild-type
• Measurable disease according to RECIST criteria v1.1
• Male or female pts > 18 years of age
• ECOG Performance Status ≤ 2
• Life expectancy of at least 3 months
• Adequate bone marrow, liver and renal function assessed within 14 days before starting study treatment
• If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment
• If female and of childbearing potential, or if male, agreement to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method).
• Signed informed consent obtained at screening |
• Diagnóstico de adenocarcinoma colorrectal comprobado histológicamente
• Diagnóstico de enfermedad metastásica
• Metástasis hepáticas que se consideran aptas para la resección quirúrgica, pero en las que el tratamiento farmacológico podría considerarse útil antes de proceder a la intervención, bajo juicio clínico.
• RAS y BRAF de tipo natural
• Enfermedad mensurable de acuerdo con los criterios RECIST v. 1.1
• Hombre o mujer mayor de 18 años
• Estado funcional ECOG ≤ 2
• Esperanza de vida mínima de 3 meses
• Función medular, hepática y renal aceptables, según evaluación en los 14 días previos al inicio del tratamiento del estudio
• Si las mujeres en edad fértil tienen un resultado negativo en una prueba de embarazo un máximo de 7 días antes del inicio del tratamiento del estudio
• Si las mujeres en edad fértil y los hombres aceptan el uso de métodos anticonceptivos adecuados (p. ej., abstinencia, dispositivo intrauterino, anticonceptivos orales o método de doble barrera)
• Consentimiento informado firmado obtenido en el periodo de selección |
|
| E.4 | Principal exclusion criteria |
• Any contraindication to use cetuximab, irinotecan, 5-FU or folinic acid
• Active uncontrolled infections or active disseminated intravascular coagulation
• Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
• Pregnancy.
• Breastfeeding.
• Grade III or IV heart failure (NYHA classification)
• Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before inclusion in the study
• Cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
• Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
• Previous chemotherapy for colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study
• Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or during participation in the study
• Known or clinically suspected brain metastases
• History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea
• Severe, non-healing wounds, ulcers or bone fractures
• Uncontrolled hypertension
• Marked proteinuria (nephrotic syndrome)
• Known DPD deficiency (specific screening not required)
• Known history of alcohol or drug abuse
• A significant concomitant disease which, in the investigating physician's opinion, rules out the patient's participation in the study
• Absent or restricted legal capacity |
• Cualquier contraindicación del uso de cetuximab, irinotecán, 5-FU o ácido folínico
• Infecciones no controladas activas o coagulación intravascular diseminada activa
• Historia previa o actual de malignidades, a parte del carcinoma colorrectal, a excepción del carcinoma cutáneo basal y escamoso o del carcinoma in situ de cérvix con tratamiento curativo
• Embarazo
• Lactancia
• Insuficiencia cardíaca de grado III o IV (clasificación de la NYHA)
• Infarto de miocardio, angina de pecho inestable, angioplastia con balón con o sin implantación de stents en los últimos 12 meses antes de la inclusión en el estudio
• Arritmias cardíacas que requieran tratamiento antiarrítmico, a excepción de los betabloqueantes o la digoxina
• Disfunciones médicas o psicológicas que supongan una limitación para la capacidad de dar el consentimiento o no permitir la realización del estudio
• Quimioterapia previa para el cáncer colorrectal, con la excepción del tratamiento adyuvante, completada al menos 6 meses antes de empezar el estudio
• Participación en un estudio clínico o tratamiento con un fármaco experimental en los 30 días antes de la inclusión al estudio o durante la participación en el estudio
• Sospecha clínica o presencia de metástasis cerebrales
• Antecedentes de oclusión intestinal aguda o subaguda o enfermedad inflamatoria intestinal crónica o diarrea crónica
• Heridas tórpidas, úlceras sin cicatrizar o fracturas óseas no consolidadas graves
• Hipertensión no controlada
• Proteinuria notable (síndrome nefrótico)
• Deficiencia de DPD conocida (periodo de selección específico no requerido)
• Antecedentes conocidos de alcoholismo o drogadicción
• Una enfermedad concomitante significativa que, a criterio del investigador, impida la participación del paciente en el estudio
• Incapacidad legal o capacidad legal limitada |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Toxicity rate (grade 3-4 AEs) is defined as the percentage of patients, relative to the total of enrolled patients in each arm, experiencing a treatment related adverse events of grade 3-4, according to National Cancer Institute Common Toxicity V 4.03
The primary endpoint of this study is progression free survival (PFS) from the start of 1st line therapy. The co-primary endpoint of this study is the toxicity rate (grade 3-4 AEs)
Progression-free survival (PFS) is defined as the time from the start of therapy until the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on-study tumor assessment documenting absence of progressive disease for patients without an event. Patients who have started treatment, but having no tumor assessments after baseline will be censored on the date of treatment start. The determination of disease progression will be based on Investigator-reported measurements. Disease status will be evaluated according to RECIST 1.1 criteria. |
• Determinar si el cetuximab en monoterapia (administrado hasta la progresión o toxicidad acumulada) tras 8 ciclos de FOLFIRI + cetuximab da lugar a una supervivencia sin progresión no inferior en comparación con FOLFIRI + cetuximab continuado (administrado hasta la progresión o la toxicidad acumulada).
• Evaluar si se puede lograr una mejora en la incidencia de los acontecimientos adversos (AA) hematológicos y no hematológicos de grado 3-4 en el grupo experimental (cetuximab en monoterapia tras 8 ciclos de FOLFIRI + cetuximab) en comparación con el grupo de quimioterapia continuada (FOLFIRI + cetuximab).
• Explorar la posibilidad de usar biopsias líquidas para la elaboración de perfiles moleculares, así como controlar la actividad del tratamiento en pacientes con CCRm con un tratamiento basado en cetuximab |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| until progression |
| hasta la progression |
|
| E.5.2 | Secondary end point(s) |
Response rate (RR) is defined as the percentage of patients, relative to the total of treated patients within each arm, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria. The determination of clinical response will be based on Investigator-reported measurements. Responses will be evaluated with a chest and abdominal computed tomography (CT) scan every 8 weeks. Patients who do not have an on-study assessment will be included in the analysis as non-responders
Early tumor shrinkage (ETS): is defined as ≥20% diameter reduction measured at 1st CT (8 weeks) after start of treatment. The determination of clinical response will be based on Investigator-reported measurement.
Overall survival (OS) is defined as the time from the start of therapy until the date of death due to any cause. For patients still alive at the time of analysis, or if lost to follow up, the OS time will be censored on the last date the patients were known to be alive.
Cetuximab-related skin toxicity will be recorded and graded according to the NCI-CTC skin toxicity criteria (V 4.03). Skin toxicities observed with cetuximab include skin rash, skin dryness (xerosis), pruritus, paronychia, hair abnormality and increased growth of the eyelashes or facial hair. Skin toxicity will be collected every two weeks until disease progression (PD) or withdrawal for any cause. A skin lesion unrelated to cetuximab, according to skin toxicity criteria, will not be included in this evaluation.
The safety profile will be evaluated comparing the toxicity rate, defined as the percentage of patients, relative to the total of enrolled patients, experiencing a specific adverse event of any grade, according to National Cancer Institute Common Toxicity V 4.03.
QoL will be assessed using the Dermatology Life Quality Index (DLQI) and EORTC QLQ C30 questionnaires. These questionnaires will be completed by patients at baseline and at week 8, 16, 24 and 32.
Molecular profiling of tumor samples: multiple gene mutation analysis of tumor samples from pts enrolled in the study will be performed with the Ion AmpliSeq™ Colon and Lung Cancer Panel (Life Technologies) using Ion Torrent semiconductor sequencing. The panel contains primer pairs to analyse over 500 known mutations and eventually novel mutations in 87 hotspot regions of the following 22 genes involved in colorectal cancer: ALK, EGFR, ERBB2, ERBB4, FGFR1, FGFR2, FGFR3, MET, DDR2, KRAS, PIK3CA, BRAF, AKT1, PTEN, NRAS, MAP2K1, STK11, NOTCH1, CTNNB1, SMAD4, FBXW7, TP53.
Molecular profiling of plasma samples: liquid biopsy will be performed at various time points and plasma samples will be analysed with two different methods: 1) the blood-based RAS Biomarker Test from Sysmex Inostics; 2) the Ion AmpliSeq™ Colon and Lung Cancer Panel.
Potential predictive factors (somatic mutations identified in tumor tissue by next generation sequencing) and surrogate markers of treatment activity (changes in molecular profile of liquid biopsies) |
• Tasa de respuesta (TR)
• Reducción temprana del volumen tumoral (RTVT) (8 semanas)
• Supervivencia global (SG)
• Toxicidad cutánea relacionada con el cetuximab
• Perfil de seguridad
• CdV
• Perfiles moleculares del tejido tumoral y la biopsia líquida
• Factores predictivos potenciales (mutaciones somáticas identificadas en el tejido tumoral por secuenciación de nueva generación) y marcadores indirectos de actividad del tratamiento (cambios en el perfil molecular de las biopsias líquidas) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| until death |
| hasta la muerte |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LAST PATIENT LAST VISIT |
| última vista del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 50 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 50 |
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