E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic colorectal cancer |
Cáncer colorectal metastásico |
|
E.1.1.1 | Medical condition in easily understood language |
Colorectal cancer |
Cáncer colorectal |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 demonstrate the superiority of S 95005 in combination with bevacizumab over capecitabine in combination with bevacizumab in terms of progression-free survival (PFS) based on Investigator assessment in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy. |
Demostrar la superioridad de S 95005 en combinación con bevacizumab frente a capecitabina en combinación con bevacizumab en términos de supervivencia libre de progresión (SLP) basada en la evaluación del investigador en primera línea de tratamiento de pacientes con cáncer colorrectal metastásico que no son candidatos a terapia intensiva |
|
E.2.2 | Secondary objectives of the trial |
To confirm clinical benefit for treatment through an evaluation of Overall survival (OS), Overall response rate (ORR), Disease control rate (DCR), Duration of response (DoR), Time to treatment failure (TTF) and to compare the safety and the impact on quality of life of S 95005 in combination with bevacizumab to capecitabine in combination with bevacizumab in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy. |
Confirmar el beneficio clínico del tratamiento mediante la evaluación de supervivencia global (SG), tasa de respuesta global (TRG), tasa de control de enfermedad (TCE), duración de respuesta (DR) , tiempo hasta el fracaso del tratamiento (TFT) y comparar la seguridad y el impacto en la calidad de vida de S95005 en combinación con bevacizumab frente a capecitabina en combinación con bevacizumab en primera línea de tratamiento de pacientes con cáncer colorrectal metastásico que no son candidatos a terapia intensiva . |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female participant aged ≥18 years old at the time of ICF signature (or legal age depending on local country regulation). - Has definitive histologically confirmed adenocarcinoma of the colon or rectum. - Has at least one measurable metastatic lesion. - RAS status based on local biological assessment of tumour biopsy must be available. - Patient is not a candidate for standard full dose combination chemotherapy with irinotecan or oxaliplatin according to investigator’s judgment and decision taken during a multidisciplinary meeting (if organised in the centre). Reasons for non-eligibility to these standard treatments could be, but are not limited to, age, performance status, low tumour burden, comorbidities or non-clinical reasons. - Patient is not a candidate for curative resection of metastatic lesions according to investigator’s judgment and decision taken during a multidisciplinary meeting (if organised in the centre). - No previous systemic anticancer therapy for unresectable metastatic colorectal cancer. Previous adjuvant or neoadjuvant chemotherapy is allowed only if the patient has been disease free for at least 6 months after the completion of the chemotherapy. - Ability to swallow oral medication. - Estimated life expectancy ≥12 weeks. - ECOG (Eastern Cooperative Oncology Group) performance status ≤2. - Adequate haematological, renal, hepatic and coagulation function. - Women of childbearing potential must have been tested negative in a serum pregnancy test. Within the frame of this study, female participants of childbearing potential and male participants with partners of childbearing potential must use an highly effective method of birth control as well as their partners lasting at least 6 months after the last dose of IMP. Women using hormonal contraceptive must also use a barrier method. - Written informed consent obtained. |
-Paciente hombre o mujer de ≥ 18 años en el momento de la firma del CI (o mayoría de edad dependiendo de la legislación local de cadad país).
- Presentar un adenocarcinoma de colon o recto confirmado histológicamente -Presentar al menos una lesión metastásica medible -Se debe conocer el estado de RAS en base a la evaluación biológica local de la biopsia del tumor. -El paciente no es candidato a quimioterapia combinada estándar a dosis completa con irinotecán u oxaliplatino de acuerdo al criterio del investigador y a la decisión tomada en una reunión multidisciplinar (si se organizara en el centro). Las razones para no ser seleccionable para estos tratamientos estándar podrían ser, además de otras, edad, estado funcional, baja carga tumoral, comorbilidades o razones no clínicas. -El paciente no es candidato a una resección curativa de las lesiones metastásicas de acuerdo al criterio del investigador y a la decisión tomada en una reunión multidisciplinar (si se organizara en el centro).
-El paciente no ha recibido ninguna terapia antineoplásica sistémica previa para el cáncer colorrectal metastásico irresecable. Se permite quimioterapia previa adyuvante o neoadyuvante sólo si el paciente ha estado libre de enfermedad al menos durante 6 meses tras completar la quimioterapia.
-Capacidad para tragar medicación oral.
-Esperanza de vida estimada ≥ 12 semanas.
-Estado funcional ≤ 2 según escala ECOG
-Función hematológica, renal, hepática y de coagulación adecuada
-Las mujeres en edad fértil deben haber obtenido un resultado negativo en la prueba de embarazo en suero .En el marco de este estudio, las participantes femeninas en edad fértil y los participantes varones con parejas en edad fértil deben aceptar, también sus parejas, el uso de un método anticonceptivo altamente eficaz, durante al menos 6 meses desde la última toma de medicación de estudio. Las mujeres que utilicen anticonceptivos hormonales deben emplear también un método de barrera
- Consentimiento informado por escrito obtenido |
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E.4 | Principal exclusion criteria |
- Unlikely to cooperate in the study. - Pregnancy, breastfeeding or possibility of becoming pregnant during the study. - Participation in another interventional study, major surgery, drainage for ascites, pleural effusion or pericardial fluid, previous radiotherapy, within the specified timeframes prior to the randomisation. - Patients who have not recovered from clinically relevant non-hematologic CTCAE grade ≥ 3 toxicity of previous anticancer therapy prior to the randomisation. - Symptomatic central nervous system metastases. - Has certain serious illness or serious medical condition(s) described in the protocol. - Hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. - Other malignancies excluding malignancies that are in remission for more than 5 years, cervix carcinoma-in-situ deemed cured by adequate treatment or basal cell carcinoma. - Treatment with systemic immunosuppressive therapy (except steroids given in prophylactic setting or at a chronic low dose (≤20mg/day prednisone equivalent)). - Criteria related to S 95005 administration: Has previously received S 95005. History of allergic reactions attributed to compounds of similar composition to S 95005 or any of its excipients. Any contraindication present in the SmPC of trifluridine/tipiracil, - Criteria related to bevacizumab administration: History of allergic reactions or hypersensitivity to bevacizumab or any of its excipients. History of hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies. Serious non-healing wound, non-healing ulcer or non-healing bone fracture. Deep venous thromboembolic event within 4 weeks prior to randomisation, Known coagulopathy that increases risk of bleeding, bleeding diatheses. Any other haemorrhage/bleeding event CTCAE grade ≥ 3 within 4 weeks prior to randomisation. Any contraindication present in the SmPC of bevacizumab. - Criteria related to capecitabine administration: History of allergic reactions or hypersensitivity to capecitabine or any of its excipients or fluorouracil. History of severe and unexpected reaction to fluoropyrimidine therapy. Known complete absence of dihydropyrimidine dehydrogenase (DPD) activity. Treatment with sorivudine or its chemical related analogues, such as brivudine, within 4 weeks prior to the randomisation. Any contraindication present in the SmPC of capecitabine. |
1. Improbable colaboración en el estudio. 2. Mujer embarazada, lactante o con posibilidades de quedarse embarazada durante el estudio 3. Participación en otro estudio intervencional, cirugía mayor, drenaje de ascitis, derrame pleural o líquido pericárdico , radioterapia previa, durante los tiempos especificados previos a la aleatorización. 4. Pacientes no recuperados de una toxicidad no hematológica CTCAE grado ≥3 clínicamente relevante secundaria a una terapia anticáncer previa a la aleatorización. 5. Metástasis sintomáticas en sistema nervioso central. 6. Cualquier enfermedad clínicamente significativa o condición médica significativa descrito en el protocolo. 7. Problemas hereditarios de intolerancia a la galactosa, deficiencia de lactasa de los lapones o malabsorción de glucosa-galactosa. 8. Otras neoplasias excluyendo aquellas que estén en remisión desde hace más de 5 años, carcinoma in-situ de cérvix que se considera curado por un tratamiento adecuado o carcinoma de células basales. 9. Tratamiento con terapia inmunosupresora sistémica (excepto esteroides a nivel profiláctico o a baja dosis crónica (≤ 20mg/día de quivalente de prednisona).
Criterios relacionados con la administración de S 95005 1. Haber recibido previamente S 95005. 2. Antecedentes de reacciones alérgicas atribuídas a componentes de composición similar a S 95005 o alguno de sus excipientes. 3. Cualquier contraindicación listada en la ficha técnica de trifluridina/tiriracil
Criterios relacionados con la administración de bevacizumab 1. Antecedentes de reacciones alérgicas o de hipersensibilidad a bevacizumab o a cualquiera de sus excipientes. 2. Antecedentes de hipersensibilidad a productos celulares procedentes de ovario de hámster chino o a otros anticuerpos recombinantes humanos o humanizados. 3. Heridas que no curan, úlceras que no curan o fracturas óseas que no curan, graves. 4. Evento tromboembólico venoso profundo en las 4 semanas anteriores a la aleatorización. 5. Coagulopatía conocida que incrementa el riesgo de sangrado, diátesis sangrante. Cualquier otra hemorragia/episodio de sangrado de grado ≥3 según CTCAE en las 4 semanas anteriores a la aleatorización. 6. Cualquier contraidicación presente en la ficha técnica de bevacizumab. (Apéndice 9).
Criterios relacionados con la administración de capecitabina 1. Antecedentes de reacciones alérgicas o hipersensibilidad a la capecitabina o a alguno de sus excipientes o a fluorouracilo. 2. Antecedentes de reacción severa e inesperada a la terapia con fluoropirimidinas. 3. Ausencia completa conocida de actividad de dihidropirimidina deshidrogenasa (DPD). 4. Tratamiento con sorivudina o sus análogos químicos, tales como brivudina, en las 4 semanas previas a la aleatorización. 5. Cualquier contraindicación presente en la ficha técnica de capecitabina |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) based on investigator judgement |
Supervivencia libre de progresión (SLP) en base a la evaluación del investigador |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Tumour assessments at baseline, every 8 weeks from C1D1 until radiological progression is documented and at the withdrawal visit if not done in the previous 8 weeks. |
Las evaluaciones tumorales se realizarán al inicio , cada 8 semanas (desde C1D1) hasta la progresión radiológica o el final de estudio y en la visita de retirada si no se ha realizado en las 8 semanas previas.. |
|
E.5.2 | Secondary end point(s) |
- Overall survival (OS) - Overall response rate (ORR) - Disease control rate (DCR) - Duration of response (DoR) - Time to treatment failure (TTF) - Safety and tolerability assessed by incidence of adverse events (AE), laboratory tests, physical examination and performance status (ECOG), vital signs, 12-leads ECG parameters - Quality of life (QoL) |
Supervivencia global (SG) Tasa de respuesta global (TRG) Tasa de control de la enfermedad (TCE) Duración de la respuesta (DR) Tiempo para el fracaso del tratamiento (TFT) Seguridad y tolerabilidad evaluada mediante la incidencia de acontecimientos adversos (AA), análisis de laboratorio, exploración física y estado funcional (ECOG), signos vitales, parámetros de un ECG de 12 derivaciones Calidad de vida (CdV) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR, DCR, DoR, TTF: at baseline, every 8 weeks from C1D1 until radiological progression, and at withdrawal visit if not done in the previous 8 weeks. - OS: survival status obtained at 8 week intervals until patient death or end of the study. - AE: all over the study - Laboratory tests, physical examination, ECOG, vital signs: Within 4 days prior to randomisation, At pre-dose of C1D1, At C1D15 (not for coagulation, physical examination and ECOG), Beginning with cycle 2, prior to start of study treatment in every cycle, Only for haematology and vital signs: At CxD15 (experimental arm only) prior to bevacizumab injection, Withdrawal visit. - ECG: within 28 days prior to randomisation and at withdrawal visit. - QoL: at baseline, every 6 weeks and at withdrawal visit. |
- TRG, TCE,, DR, TFT: al inicio, cada 8 semanas desde C1D1 hasta que haya progresión radiológica, y en la visita de retirada si no se ha hecho en las 8 semanas previas. - SG: status de supervivencia obtenido a intervalos de 8 semanas hasta que el paciente fallezca o el estudio se termine - AA: a lo largo de todo el estudio Análisis de laboratorio, exploraron física, ECOG, signos vitales: En las 4 semanas previas a la aleatorización En pre-dosis de C1D1 En C1D15 (no para la coagulación, exploración física ni ECOG) . |
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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 | Yes |
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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 144 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Bulgaria |
Colombia |
Czech Republic |
Denmark |
Estonia |
France |
Germany |
Hungary |
Ireland |
Italy |
Latvia |
Lithuania |
Netherlands |
Poland |
Portugal |
Romania |
Russian Federation |
Slovakia |
Spain |
Sweden |
Turkey |
Ukraine |
United Kingdom |
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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 Trial will occur 24 months after the first IMP intake of the last patient randomized and is defined as the date of the last follow-up of the last participant (including a contact phone), or the date of the last contact attempt if the last patient is declared lost to follow-up. |
La finalización del estudio será 24 meses después de la primera toma de producto en investigación por el último paciente aleatorizado y se define como la fecha del último seguimiento del último participante (incluyendo el contacto telefónico) ó la fecha del último intento de contacto si el último paciente es considerado como perdido de vista. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |