| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal cancer |
| Cáncer Colorrectal metastásico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colorectal cancer |
| Cáncer colorrectal |
|
| 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 evaluate the efficacy of FOLFIRI + aflibercept in patients with or without ACE polymorphisms in terms of progression-free survival (PFS) |
Evaluar la eficacia de FOLFIRI + aflibercept en pacientes con o sin polimorfismos
de ACE en términos de supervivencia libre de progresión (SLP). |
|
| E.2.2 | Secondary objectives of the trial |
Objective response rate (ORR) (based on RECIST criteria), disease control rate (DCR), time to progression (TTP), time to treatment failure (TTF) and overall survival (OS) in patients with or without ACE polymorphisms.
ORR, DCR, PFS, TTP, TTF and OS in patients with or without polymorphisms AGTR1 and / or according to CEA levels.
Safety and tolerability of FOLFIRI + aflibercept. |
Tasa de respuesta objetiva (TRO) (basada en los criterios RECIST), tasa de control
de la enfermedad (TCE), tiempo hasta la progresión (THP), tiempo hasta el fracaso del tratamiento (TFT) y supervivencia global (SG) en pacientes con o sin
polimorfismos de ACE.
TRO, TCE, SLP, THP, TFT y SG en pacientes con o sin polimorfismos AGTR1 y/o
de acuerdo con los niveles de ACE.
Seguridad y tolerabilidad de FOLFIRI + aflibercept. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent form signed and dated, and willingness and ability to accomplish the protocol requirements.
2. Histologically confirmed Adenocarcinoma of the colon and / or rectum
3. Diagnosed metastatic disease.
4. Evidence of at least one measurable lesion using one-dimensional CT or MRI according to RECIST criteria, version 1.1.
5. Patients with metastatic colorectal cancer (MCRC) that is resistant or has progressed after treatment with oxaliplatin.
6. Age ≥ 18 years.
7. Functional status (EF) of the World Health Organization (WHO) of 0 to 2.
8. Adequate bone marrow function: neutrophils (ANC) ≥ 1.5 x 109 / l; platelets ≥ 100 x
109 / l; hemoglobin ≥ 9 g / dl.
9. Adequate renal function: serum creatinine level <1.5 times the upper limit of normal (ULN).
10. Adequate liver function: serum bilirubin ≤ 1.5 times the ULN, alkaline phosphatase (AP) <5 ULN.
11. Proteinuria <2+ (urine dipstick test) or ≤ 1 g / 24 hours.
12. Feasibility of performing regular monitoring |
1. Consentimiento informado firmado y fechado, y disposición y capacidad para
cumplir con los requisitos del protocolo.
2. Adenocarcinoma de colon y/o recto confirmado histológicamente.
3. Enfermedad metastásica diagnosticada.
4. Existencia de al menos una lesión unidimensional medible utilizando TC o RM
en función de los criterios RECIST, versión 1.1.
5. Pacientes con cáncer colorrectal metastásico (CCRM) que es resistente o ha
progresado después de un tratamiento con oxaliplatino.
6. Edad ≥ 18 años.
7. Estado funcional (EF) de la Organización Mundial de la Salud (OMS) de 0 - 2.
8. Función medular adecuada: neutrófilos (RAN) ≥ 1,5 x 109/l; plaquetas ≥ 100 x
109/l; hemoglobina ≥ 9 g/dl.
9. Función renal adecuada: nivel de creatinina sérica < 1,5 veces el límite superior
de la normalidad (LSN).
10. Función hepática adecuada: bilirrubina sérica ≤ 1,5 veces el LSN, fosfatasa
alcalina (FA) < 5 veces el LSN.
11. Proteinuria < 2+ (análisis de orina con tira reactiva) o ≤ 1 g/24 horas.
12. Viabilidad de realización de un seguimiento regular. |
|
| E.4 | Principal exclusion criteria |
1. Uncontrolled hypercalcemia.
2. Pre-existing permanent Neuropathy (NCI grade> 2).
3. Uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg and / or diastolic blood pressure> 100 mm Hg) or history of hypertensive crisis or hypertensive encephalopathy.
4. Concomitant antineoplastic treatment non-scheduled in the protocol (e.g., chemotherapy, targeted molecular therapy, immunotherapy).
5. Treatment with any other investigational product within 28 days prior to inclusion in the study.
6. Another serious and uncontrolled non-malignant disease
7. History or evidence of CNS metastases on physical examination, unless it is properly treated (e.g., non-irradiated CNS metastases, convulsion uncontrolled with standard medical treatment).
8. Diagnosis of Gilbert's syndrome.
9. Atropine sulfate or loperamide intolerance.
10. Diagnosis of dihydropyrimidine dehydrogenase deficiency.
11. Treatment with inducers of CYP3A4, unless it is suspended> 7 days before inclusion.
12. Any of the following conditions in the 3 months prior to the screening visit: gastrointestinal hemorrhage grade 3 - 4 (unless it is caused by tumor extirpation), peptic ulcer resistant to treatment, esophagitis or erosive gastritis, infectious or inflammatory bowel disease or diverticulitis.
13. Other concomitant or previous malignant neoplasia, except for: i / Carcinoma in situ of the uterine cervix properly treated, ii / spinocellular or basal skin cell carcinoma, iii / cancer in complete remission for> 5 years.
14. Any other non-malignant and uncontrolled serious disease, major surgery or traumatic injury in the last 28 days.
15. Pregnant or during breast-feeding period.
16. Patients with known allergy to any component of the study drugs.
17. History of myocardial infarction and / or stroke in the previous 6 months before inclusion, congestive heart failure NYHA class III and IV.
18. Intestinal obstruction. |
1. Hipercalcemia no controlada.
2. Neuropatía preexistente permanente (Grado NCI > 2).
3. Hipertensión no controlada (definida como presión arterial sistólica > 150 mm Hg y/o presión arterial diastólica > 100 mm Hg) o antecedentes de crisis hipertensiva o encefalopatía hipertensiva.
4. Tratamiento antineoplásico concomitante no previsto en el protocolo (p. ej.,
quimioterapia, tratamiento molecular dirigido, inmunoterapia).
5. Tratamiento con cualquier otro medicamento en investigación en los 28 días
previos a la inclusión en el estudio.
6. Otra enfermedad no maligna grave y no controlada.
7. Antecedentes o evidencia en la exploración física de metástasis en el SNC, a menos que esté debidamente tratada (p. ej., metástasis del SNC no irradiada, convulsiones no controladas con tratamiento médico estándar).
8. Diagnóstico de síndrome de Gilbert.
9. Intolerancia al sulfato de atropina o la loperamida.
10. Diagnóstico de déficit de dihidropirimidina-deshidrogenasa.
11. Tratamiento con inductores del CYP3A4, a menos que se suspendiera > 7 días antes de la inclusión.
12. Cualquiera de las siguientes afecciones en los 3 meses anteriores a la visita de inclusión: hemorragia gastrointestinal de grado 3 - 4 (a menos que sea debida a la extirpación de un tumor), úlcera péptica resistente al tratamiento, esofagitis o gastritis erosiva, enfermedad intestinal infecciosa o inflamatoria,o diverticulitis.
13. Otras neoplasias malignas concomitantes o anteriores, con excepción de: i/
carcinoma in situ de cuello uterino tratado adecuadamente, ii/ carcinoma espinocelular o basocelular cutáneo, iii/ cáncer en remisión completa durante > 5 años.
14. Cualquier otra enfermedad no maligna grave y no controlada, cirugía mayor
o lesión traumática en los últimos 28 días.
15. Mujeres embarazas o en periodo de lactancia.
16. Pacientes con alergia conocida a alguno de los componentes de los fármacos del estudio.
17. Antecedentes de infarto de miocardio y/o ictus en los 6 meses anteriores a la inclusión, insuficiencia cardíaca congestiva de clase III y IV de NYHA.
18. Obstrucción intestinal. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival |
| Supervivencia libre de progresión |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Date of the first disease progression , radiologically observed, or death (event that occurred first) , estimated period: 12 months. |
| Fecha de la primera progresión de la enfermedad, observada radiológicamente, o muerte (lo que ocurra antes), período estimado: 12 meses. |
|
| E.5.2 | Secondary end point(s) |
Objective response rate (ORR);
Disease control rate (DCR);
Time to progression (TTP):
Time to treatment failure (TFT);
Overall survival (OS). |
Tasa de respuesta objetiva (TRO);
Tasa de control de la enfermedad (TCE);
Tiempo hasta la progresión (THP);
Tiempo hasta el fracaso del tratamiento (TFT);
Supervivencia global (SG). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective response rate (ORR) during the study treatment period;
Disease control rate (DCR) during the study treatment period;
Time to progression (TTP): date of the first disease progression or date of the last assessment for patients who died before disease progression;
Time to treatment failure (TFT): date of decision to finish study treatment or date of the last disease evaluation for patient who stay on treatment at the end of study.
Overall survival (OS): date of death for any reason or last contact date with patient at the end of the study |
Tasa de respuesta objetiva (TRO): durante el período de tratamiento;
Tasa de control de la enfermedad (TCE); durante el período de tratamiento;
Tiempo hasta la progresión (THP): fecha en que
se observa por primera vez la progresión de la enfermedad o fecha de la última
evaluación de la enfermedad Para los pacientes que mueran durante el estudio y no muestren progresión de la enfermedad.
Tiempo hasta el fracaso del tratamiento (TFT): fecha en que se toma la decisión de finalizar el periodo de tratamiento.
Supervivencia global (SG). |
|
| 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 | 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 | 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 15 |
| 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 | 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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