| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Localised Colon Cancer (stage II-III) |
| Cáncer Colorrectal Localizado (estadio II-III) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colon Cancer (stage II-III) |
| Cáncer Colorrectal (estadio II-III) |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10009954 |
| E.1.2 | Term | Colon cancer stage II |
| 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 | 21.0 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase IIa: To analyse the potential effect of FOLFOXIRI as an intensive adjuvant treatment for ctDNA clearance as a surrogate biomarker of treatment efficacy.
Phase IIb: To study differences on the conversion rate between an intensive adjuvant treatment (FOLFOXIRI) versus conventional adjuvant therapy (CAPOX). |
Fase IIa: analizar el efecto potencial de FOLFOXIRI como tratamiento adyuvante intensivo para el aclaramiento del ctDNA como biomarcador subrogado de la eficacia del tratamiento.
Fase IIb: Estudiar las diferencias en la tasa de conversión entre un tratamiento adyuvante intensivo (FOLFOXIRI) frente a la terapia adyuvante convencional (CAPOX). |
|
| E.2.2 | Secondary objectives of the trial |
Phase IIb:
a) To evaluate the impact of intensive chemotherapy treatment on disease-free survival in patients with positive ctDNA at 24 months after end of treatment
b) To evaluate the disease-free survival at 12 months after end of treatment, according to the seroconversion rate (ctDNA positive that becomes ctDNA negative) in each treatment arm.
c) To assess the toxicity of triplet combination chemotherapy of FOLFOXIRI compared with conventional adjuvant treatment (CAPOX) for patients with localized colon cancer.
d) To evaluate the impact of FOLFOXIRI compared with CAPOX on quality of life in patients with localized colon cancer. |
Fase IIb:
a) Evaluar el impacto del tratamiento de quimioterapia intensiva en la supervivencia libre de enfermedad en pacientes con ADNct positivo a los 24 meses de finalizar el tratamiento.
b) Evaluar la supervivencia libre de enfermedad a los 12 meses después del final del tratamiento, de acuerdo con la tasa de seroconversión (ctDNA positivo que se vuelve ctDNA negativo) en cada brazo de tratamiento.
c) Evaluar la toxicidad de la quimioterapia de combinación triple de FOLFOXIRI en comparación con el tratamiento adyuvante convencional (CAPOX) para pacientes con cáncer de colon localizado.
d) Evaluar el impacto de FOLFOXIRI en comparación con CAPOX en la calidad de vida en pacientes con cáncer de colon localizado. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. CIRCULATE-SPAIN-01 trial written informed consent.
2. Age ≥ 18 years and ≤ 75 years.
3. Histologically confirmed diagnosis of operable stage II or stage III Colon Cancer.
4. Postoperative, ctDNA positive
5. ECOG performance status 0-1.
6. Normal organ functions |
1. Consentimiento informado por escrito del ensayo CIRCULATE-SPAIN-01.
2. Edad ≥ 18 años y ≤ 75 años.
3. Diagnóstico histológicamente confirmado de cáncer de colon operable en estadio II o estadio III.
4. ctDNA positivo post-operatorio.
5. Estado funcional ECOG 0-1.
6. Funciones normales de los órganos. |
|
| E.4 | Principal exclusion criteria |
1. Patients having an MSI-H/MMRd tumor are excluded from the study (done according to standard clinical practice).
2. History of another neoplastic disease, unless in remission for ≥ 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
3. Had an incomplete diagnostic colonoscopy and/or polyps’ removal for patients in whom the remaining colon was not removed or explored. Note: Patients with intraoperative complete colonoscopy or early perioperative complete colonoscopy.
4. Macroscopic or microscopic evidence of residual tumor (R1 or R2 resections). Patients should never have had any evidence of metastatic disease (including presence of tumor cells in the peritoneal lavage).
5. Current treatment with another investigational drug or participation in another investigational study.
6. Patient unable to comply with the study protocol owing to psychological, social or geographical reasons.
7. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
8. Inadequate contraception (male or female patients) if of childbearing or procreational potential.
9. Current clinically unconcluded cardiovascular disease.
10. Acute or subacute intestinal occlusion or history of inflammatory bowel disease.
11. Pre-existing neuropathy > grade 1. Known grade 3 or 4 allergic reaction to any of the components of the treatment.
12. Has a known DPD (DihydroPyrimidine Dehydrogenase) deficiency.
13. Has a known Gilbert Syndrome or UGT1A1 homozygous *28/*28 germline variant.
14. Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required.
15. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus infection. Note: no testing for Hepatitis B and Hepatitis C is required.
16. Has a known history of active TB (Bacillus Tuberculosis). |
1. Los pacientes que tienen un tumor MSI-H / MMRd se excluyen del estudio (realizado de acuerdo con la práctica clínica estándar).
2. Historia de otra enfermedad neoplásica, a menos que esté en remisión durante ≥ 5 años. No se excluyen las participantes con carcinoma de células basales de piel, carcinoma de células escamosas de piel o carcinoma in situ (p. Ej., Carcinoma de mama, cáncer de cuello uterino in situ) que se hayan sometido a una terapia potencialmente curativa.
3. Colonoscopia de diagnóstico incompleta y / o extirpación de pólipos en pacientes en quienes no se extirpó o exploró el colon restante. Nota: Pacientes con colonoscopia completa intraoperatoria o colonoscopia completa perioperatoria temprana.
4. Evidencia macroscópica o microscópica de tumor residual (resecciones R1 o R2). Los pacientes nunca deberían haber tenido evidencia de enfermedad metastásica (incluida la presencia de células tumorales en el lavado peritoneal).
5. Tratamiento actual con otro fármaco en investigación o participación en otro estudio de investigación.
6. Paciente incapaz de cumplir con el protocolo del estudio por motivos psicológicos, sociales o geográficos.
7. Está embarazada o amamantando, o espera concebir o engendrar hijos dentro de la duración proyectada del estudio.
8. Anticoncepción inadecuada (pacientes masculinos o femeninos) si está en edad fértil o procreacional.
9. Enfermedad cardiovascular actual clínicamente no concluida.
10. Oclusión intestinal aguda o subaguda o antecedentes de enfermedad inflamatoria intestinal.
11. Neuropatía preexistente> grado 1. Reacción alérgica conocida de grado 3 o 4 a cualquiera de los componentes del tratamiento.
12. Tiene una deficiencia conocida de DPD (dihidropirimidina deshidrogenasa).
13. Tiene un síndrome de Gilbert conocido o una variante de línea germinal homocigótica UGT1A1 * 28 / * 28.
14. Tiene antecedentes conocidos del virus de la inmunodeficiencia humana (VIH). Nota: No se requiere una prueba de VIH.
15. Tiene antecedentes conocidos de hepatitis B (definida como reactiva al antígeno de superficie de la hepatitis B [HBsAg]) o infección activa conocida por el virus de la hepatitis C. Nota: no se requieren pruebas para la hepatitis B y la hepatitis C.
16. Tiene antecedentes conocidos de TB activa (Bacillus Tuberculosis). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase IIa: Proportion of patients who negativize ctDNA after treatment.
Phase IIb: Proportion of patients who negativize ctDNA after treatment in intensive group versus standard of care. |
Fase IIa: Proporción de pacientes que negativizan el ctDNA tras tratamiento.
Fase IIb: Proporción de pacientes que negativizan el ctDNA tras tratamiento intensivo vs tratamiento habitual. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of treatment and Follow up visits (month 10, month 14, month 18, month 22, month 26, month 30). |
| Final del tratamiento y Visitas de Seguimiento después del tratamiento (mes 10, mes 14, mes 18, mes 22, mes 26, mes 30). |
|
| E.5.2 | Secondary end point(s) |
Phase IIb:
- Disease-free survival comparison between both treatment groups 24 months after treatment.
- Disease-free survival comparison between both treatment groups 12 months after treatment.
- Proportion of patients treated with triplet combination chemotherapy of FOLFOXIRI presenting adverse events in comparison to conventional adjuvant treatment (CAPOX).
- QLQ-C30 Quality of Life of Cancer Patients and QLQ – CR29, comparation scores between groups at baseline, 3 months and end of treatment. |
Fase IIb:
- Comparación de supervivencia libre de enfermedad entre ambos grupos de tratamiento 24 meses después del tratamiento.
- Comparación de supervivencia libre de enfermedad entre ambos grupos de tratamiento 12 meses después del tratamiento
- Proporción de pacientes tratados con quimioterapia de combinación triple de FOLFOXIRI que presentaron eventos adversos en comparación con el tratamiento adyuvante convencional (CAPOX).
- QLQ-C30 Calidad de vida de los pacientes con cáncer y QLQ - CR29, comparación de puntuaciones entre los grupos al inicio, a los 3 meses y al final del tratamiento |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Screening, Treatment Visits, End of tratment, Follow up visits (month 10, month 14, month 18, month 22, month 26, month 30). |
| Selección, visitas de tratamiento, finalización del tratamiento, visitas de seguimiento (mes 10, mes 14, mes 18, mes 22, mes 26, mes 30). |
|
| 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) | 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 | 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 | 7 |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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