| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with high-risk, operable colon cancer |
| Pacientes con cáncer de colon operable de alto riesgo |
|
| E.1.1.1 | Medical condition in easily understood language |
| Operable bowel cancer |
| Cáncer de intestino operable |
|
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009955 |
| E.1.2 | Term | Colon cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009956 |
| E.1.2 | Term | Colon cancer stage IV |
| 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 determine if neoadjuvant chemotherapy followed by deferred surgery then completion of chemotherapy post-operatively reduces 2-year recurrence compared to standard surgery and postoperative chemotherapy
- To assess the prognostic and predictive value of tumour biomarkers. |
- Determinar si la quimioterapia neoadyuvante seguida de cirugía diferida y quimioterapia postoperatoria reduce la recurrencia a 2 años en comparación con el tratamiento combinado estándar de cirugía y quimioterapia postoperatoria
- Evaluar el valor pronóstico y predictivo de biomarcadores tumorales |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the accuracy of pre-treatment CT scan staging
- To assess the tolerability of the neoadjuvant therapies
- To assess the nature and frequency of surgical complications
- To measure the impact of the treatments on patient's quality of life and resource usage
- To assess the prognostic and predictive value of tumour biomarkers
- To assess the influence of resectional quality on outcome |
- Evaluar la exactitud de la estadificación por escáner TC pretratamiento
- Evaluar la tolerabilidad de la terapia neoadyuvante
- Evaluar la naturaleza y la frecuencia de las complicaciones quirúrgicas
- Medir el impacto de los tratamientos sobre la calidad de vida de los pacientes
- Evaluar el valor pronóstico y predictivo de biomarcadores tumorales
- Evaluar la influencia de la calidad de la resección quirúrgica |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Histologically proven adenocarcinoma of the colon or high grade dysplasia on histology plus unequivocal radiological evidence of invasive cancer
- A candidate for adjuvant oxaliplatin/ fluoropyrimidine chemotherapy based on:
Either radiological high risk (rT4 or rT3 tumour with extramural extension ? 5mm)
Or radiological intermediate risk (rT3 tumour with <5mm extramural extension) and younger age/good general health
- Patients presenting with acute colonic obstruction may enter the trial only after obstruction is relieved by a successful defunctioning stoma, and when recovered to a fitness level consistent with the other eligibility criteria
- Adequate full blood count: WBC >3.0 x109/l; Plts >100 x109/l. Anaemia (Hb < 10.0 g/dl) is not an exclusion, but should be corrected by transfusion prior to surgery and chemotherapy
- Adequate renal biochemistry: GFR >50 ml/min calculated by the Wright or Cockroft formula or EDTA clearance >70 ml/min
- Adequate hepatobiliary function: bilirubin < 25 ?mol/l
- Aged 18 or over
- WHO performance status of 0, 1 or 2
- If female and of childbearing potential, must:
Have a negative pregnancy test ?72hours prior to initiating study treatment
Agree to avoid pregnancy during and for 6 months after study treatment
- If male with a partner of childbearing potential, must:
Agree to use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment
- Patient able and willing to provide written informed consent for the study |
- Adenocarcinoma de colon con histología o displasia de alto grado con histología más evidencia radiológica de cáncer invasivo.
- Candidato a quimioterapia adyuvante con oxaliplatino y fluoropirimidinas según los siguientes criterios:
Alto riesgo radiológico (tumor rT4 o rT3 con extensión extramural ? 5mm)
O riesgo radiológico intermedio (tumor rT3 con extensión extramural de 5mm)
y persona joven con buen estado de salud.
- Los pacientes que presenten una obstrucción aguda de colon podrán entrar en el estudio después de haber resuelto la obstrucción de manera exitosa mediante colostomía de descarga y se hayan recuperado.
- Leucocitos > 3.0 x109l; plaquetas >100 x109l. Anemia (Hb< 10.0 g/dl) no es un criterio de exclusión, pero debe realizarse una transfusión antes de la cirugía y la quimioterapia.
- FGR > 50 ml/min calculado con la fórmula Wright o Cockroft o aclaramiento EDTA > 70 ml/min.
- Bilirrubina < 25 ?mol/l.
- 18 años o mayor.
- Índice de performance status de la OMS de 0, 1 ó 2.
- Si es mujer en edad fértil debe presentar una test de embarazo negativo ? 72horas antes de iniciar el tratamiento del estudio y evitar el embarazo durante el desarrollo del estudio y hasta los siguientes 6 meses tras finalizar el tratamiento del estudio.
- Si es hombre con pareja en edad fértil, debe utilizar métodos anticonceptivos adecuados durante el desarrollo del estudio y hasta los siguientes 90 días tras la última dosis del tratamiento del estudio.
- Paciente capaz y dispuesto a otorgar su consentimiento informado escrito. |
|
| E.4 | Principal exclusion criteria |
- Any patient for whom radiotherapy is advised by the MDT
- Strong evidence of distant metastases or peritoneal nodules (M1)
- Peritonitis (secondary to perforated tumour)
- Colonic obstruction that has not been defunctioned
- Serious medical comorbidity, eg uncontrolled inflammatory bowel disease, uncontrolled angina or recent (<6 months) MI
- Another serious medical condition judged to compromise ability to tolerate neoadjuvant therapy and/or surgery
- Any other malignant disease within the preceding 5 years with the exception of non-melanomatous skin cancer, carcinoma in situ and early stage disease with a recurrence risk <5% |
- Cualquier paciente al que se le recomiende tratamiento con radioterapia.
- Evidencia de metástasis a distancia o nódulos peritoneales (M1).
- Peritonitis (secundaria a tumor perforado).
- Obstrucción colónica que no ha sido solucionada por colostomía de desacarga.
- Comorbilidad médica grave, por ejemplo enfermedad intestinal inflamatoria no controlada, angina no controlada o reciente (<6 meses) de infarto de miocardio.
- Cualquier otra condición médica seria según criterio médico que pueda comprometer la capacidad para tolerar la terapia adyuvante y/o la cirugía
- Cualquier otra enfermedad maligna dentro de los últimos 5 años con la excepción de cáncer de piel no-melanoma, carcinoma ?in situ? y enfermedad en estadio temprano con un riesgo de recurrencia <5%. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure for the comparison of pre- plus post-operative versus post-operative chemotherapy alone will be freedom from recurrence (or persistent disease) two years following randomisation.
The rationale for choosing two-year recurrence as primary outcome is to maximise statistical power as almost all of the effect of chemotherapy on recurrence is concentrated in this period. For example, in the QUASAR study adjuvant fluorouracil/ folinic acid chemotherapy reduced the risk of recurrence by 36% (99% CI 16%-51%) in the first two years following surgery with no further benefit or loss of benefit subsequently.
The primary outcome measure for the comparison of preoperative chemotherapy with and without panitumumab will be pathological down-staging following chemotherapy as measured by depth of extramural spread. |
| Proporción de pacientes que presentan supervivencia libre de enfermedad a los dos años tras la inclusión en el estudio para cada una de las ramas del estudio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome of the trial will be measured at 2 years post-op. |
| 2 años |
|
| E.5.2 | Secondary end point(s) |
Secondary outcome measures are:
? Death from colon cancer
? Overall survival
? Freedom from recurrence or persistent disease at 2 years (panitumumab comparison)
? Pathological assessment of downstaging (involvement of lymph nodes; serosa; resection margin)
? Quality of resection specimen and distance to high-tie
? Radiological assessment of response to neoadjuvant treatment
? Quality of life (EORTC QLQ C-30, EuroQol EQ-5D)
? Health Service costs
? Surgical morbidity/mortality
? Chemotherapy toxicity
? Adverse events |
1- Muerte por cáncer de colon a los dos años tras la inclusión en el estudio.
2- Supervivencia general a los dos años tras la inclusión en el estudio.
3- Evaluación patológica (afectación de ganglios linfáticos, serosa; margen de resección, grado de regresión) tras cirugía.
4- Calidad de la muestra resecada y distancia al margen tras cirugía.
5- Calidad de vida (EORTC QLQ C-30, EQ EuroQol - 5D) antes de la cirugía, antes del primer ciclo de quimioterapia, 1 año tras la inclusión en el estudio.
6- Duración de estancia en el hospital evaluada durante los 30 días tras la cirugía.
7- Morbi/mortalidad de la cirugía evaluada durante los 30 días tras la cirugía.
8- Toxicidad quimioterapia a las 6 semanas cada 15 días.
9- Acontecimientos adversos durante todo el desarrollo del estudio y hasta 60 días tras haber finalizado el estudio. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
? Overall survival & death from colon cancer
On patient death
? Freedom from recurrence or persistent disease at 2 yrs (panitumumab comparison)
Measured at 2 yrs
? Pathological assessment of downstaging
Measured after surgery
? Quality of resection specimen & distance to high-tie
Measured after surgery by histopath assessment
? Radiological assessment of response to neoadjuvant treatment
Measured after neoadjuvant therapy
? Quality of life
3 timepoints: immediately prior to surgery; prior to the first course of chemo & 1 year post-randomisation
? Health Service costs
? Surgical morbidity/mortality
At 30-days post-surgery
? Chemotherapy toxicity
After every 6 weeks of chemo
? Adverse events
Monitored throughout study, SAEs reported until 60 days after last trial treatment |
1.- 2 años
2.- 2 años
3.- tras cirugía
4.- tras cirugía
5.- antes de la cirugía, antes del primer ciclo de quimioterapia, 1 año tras la inclusión en el estudio
6.- a los 30 dias tras la cirugía
7.- a los 30 dias tras la cirugía
8.- cada 15 días
9.- durante todo el estudio y hasta 60 días tras haber finalizado el estudio |
|
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| terapia estandar |
| standar therapy |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | Information not present in EudraCT |
| 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
|
| The end of the trial is defined as the time when the last patient recruited has their 24-month follow-up (24 month as the primary outcome is disease free recurrence at 2 years). |
| última visita del último paciente |
|
| 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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