E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic colorectal cancer (mCRC) |
Cáncer colorrectal metastásico (CCRm). |
|
E.1.1.1 | Medical condition in easily understood language |
colorectal cancer |
Cáncer colorrectal |
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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 | 10061451 |
E.1.2 | Term | Colorectal cancer |
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 | 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 |
Safety run-in: To confirm the recommended phase 2 dose (RP2D) of each investigational arm (NIS793 or any investigational drug(s) in combination with SOC) (SOC: either modified FOLFOX6 + bevacizumab or FOLFIRI+ bevacizumab chemotherapy regimen) Expansion part: To evaluate preliminary efficacy of each investigational arm (NIS793 or any investigational drug(s) in combination with SOC anti-cancer therapy) versus control arm(SOC anti-cancer therapy) in terms of progression-free survival (PFS) by Investigator's assessment per RECIST 1.1 |
Parte de preinclusión de seguridad (PS): Confirmar la dosis recomendada para la fase 2 (RP2D) de NIS793 o cualquier otro fármaco en investigación en combinación con el SOC (SOC: cualquiera FOLFOX6 modificado + bevacizumab o FOLFIRI + bevacizumab con pauta de quimioterapia Parte de expansión: Evaluar la eficacia preliminar de NIS793 o cualquier otro fármaco en investigación en combinación con el SOC contra el cáncer frente al brazo control (SOC contra el cáncer) en términos de supervivencia libre de progresión (PFS) por la evaluación del investigador segun RECIST 1.1 |
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E.2.2 | Secondary objectives of the trial |
Safety run-in: 1. To characterize the safety and tolerability of each investigational arm (NIS793 or any investigational drug(s) in combination with SOC) 2. Preliminary anti-tumor activity of each investigational arm 3. To characterize the pharmacokinetics (PK) of each investigational arm 4. To characterize the immunogenicity of components of each investigational arm Expansion part: 1. To evaluate and compare efficacy of each investigational arm and control arm in terms of ORR, DCR, DOR, TTR by Investigator's assessment per RECIST 1.1 2. To evaluate and compare the overall survival (OS) of each investigational arm and control arm 3. Safety and tolerability 4. To characterize the PK of each investigational arm, control arm 5. To characterize the immunogenicity of components of each investigational arm, control arm |
Preinclusión de seguridad (PS): 1. Evaluar la seguridad y la tolerabilidad de NIS793 o cualquier otro fármaco en investigación en combinación con el SOC 2. Eficacia preliminar de la actividad anti tumoral de cada grupo de investigación 3. Evaluar la farmacocinética (PK) de cada grupo en investigación 4. Investigar la inmunogenicidad de los componentes de cada grupo de investigación Parte de expansión: 1. Evaluar y comparar la eficacia en cada grupo en investigación y grupo de control en términos de ORR, DCR, DOR, TTR por la evaluación del investigador segun RECIST 1.1 2. Evaluar y comparar la supervivencia global (OS) de cada grupo de invetigación y grupo control. 3. Evaluar la seguridad y la tolerabilidad 4. Evaluar la PK de en cada grupo en investigación y grupo de control. 5. Investigar la inmunogenicidad de los componentes de cada grupo en investigación y grupo de control. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study. 2. Age 18 years (or older, if required by local regulations) at the time of informed consent. 3. Histologically or cytologically confirmed (by local laboratory and local clinical guidelines) metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery in the opinion of the investigator and progressed on or within 6 months after the last dose of one prior line of systemic anti-cancer therapy administered for metastatic disease. 4. Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 6. Adequate organ function as defined by the following laboratory values (assessed by central laboratory for eligibility except where indicated): • Absolute neutrophil count ≥ 1.5 × 109/L • Platelets count ≥ 100 × 109/L • Hemoglobin ≥ 9 g/dL • Calculated creatinine clearance ≥ 60 mL/min (e.g. by using Cockcroft-Gault equation) • Albumin ≥ 3 g/dL • PT/INR and PTT ≤ 1.5 x ULN. Participants requiring therapeutic anticoagulants are eligible if coagulation parameters are within therapeutic range. • Total bilirubin ≤ 1.5 X ULN • Aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase /serum glutamic pyruvic transaminase (ALT/SGPT) ≤ 3.0 x ULN (≤5 x ULN in presence of liver metastasis). In participants with elevated ALT or AST, the values must be stable for at least 2 weeks and with no evidence of biliary obstruction by imaging. 7. Women of child-bearing potential must have negative pregnancy tests during the screening period and before starting study treatment. 8. Able to adhere to study visit schedule and other protocol requirements. 9. Participant must have recovered from treatment related toxicities of prior anticancer therapies to grade ≤1 (CTCAE v5.0) at the time of screening, except alopecia. |
1. Se debe obtener la firma del consentimiento informado antes de la participación en el estdio 2. Participantes de 18 años de edad (o mayor, si es requerido por la regulación local) en el momento del consentimiento informado. 3. Adenocarcinoma colorrectal metastásico histológica o citológicamente confirmado (según guías analíticas y clínicas locales) que no sea susceptible de una cirugía potencialmente curativa en opinión del investigador y que haya progresado durante los 6 meses posteriores a la última dosis de una línea previa de tratamiento sistémico contra el cáncer administrado para la enfermedad metastásica. 4. Presencia de al menos una lesión medible evaluada mediante TC o RM según RECIST 1.1. 5. Estado funcional del Grupo Cooperativo Oncológico del Este (ECOG) de 0 o 1. 6. Función orgánica adecuada (evaluada en un laboratorio central para determinar su elegibilidad).
Refierase al protocolo para ver resto de criterios de inclusión |
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E.4 | Principal exclusion criteria |
1. Previously administered systemic TGF-β targeted therapies. 2. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAFV600 mutation positive colorectal cancer (tests performed by local laboratory and per local guidelines). 3. Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory). 4. For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory). 5. Presence of symptomatic CNS metastases, or CNS metastases that requires directed therapy (such as focal radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study entry, and at a dose of </= 10 mg per day prednisone or equivalent for at least 2 weeks before administration of any study treatment. 6. Known history of severe allergy or hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes (e.g. monoclonal antibodies), or contraindication to any of the study drugs as outlined in the "Contraindications" or "Warnings and Precautions" sections of the SOC local prescribing information 7. Participant is currently receiving other anti-cancer therapy (medication or radiotherapy), or received other investigational product within 30 days or 5 half-lives prior to initiation of study treatment, whichever is longer. 8. Participant is currently receiving any of the prohibited medications as outlined in the protocol or in the SOC anti-cancer therapy local prescribing information, and these cannot be discontinued ≥ 7 days or 5 half-lives, whichever is longer, before the first dose of that drug. 9. Participant has not recovered from a major surgery performed prior to start of study treatment or has had a major surgery within 4 weeks days prior to start of study treatment. 10. Radiation therapy ≤ 4 weeks or brain-radiotherapy ≤ 4 weeks prior to start of study treatment 11. Impaired cardiac function or clinically significant cardio-vascular disease, such as: • Congestive heart failure requiring treatment (NYHA grade ≥2), or clinically significant arrhythmia (including uncontrolled atrial flutter/fibrillation) • Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass surgery <6 months prior to study entry • LVEF < 50% • Elevated cardiac enzymes troponin I > 2 x ULN • Cardiac valvulopathy≥ grade 2 • Uncontrolled hypertension defined by a systolic blood pressure ≥160 mg and/or diastolic blood pressure ≥100 mg Hg 12. History of positive test for human immunodeficiency virus (HIV) infection 13. Active or chronic hepatitis B virus (HBV) or hepatitis C virus infections. 14. Active untreated or uncontrolled systemic fungal, bacterial or viral infection (including COVID-19), which in the opinion of the investigator places the study participant at an unacceptable risk. 15. Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study treatment. 16. Participant has conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding. 17. Serious non-healing wounds. 18. Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment. 19. Concurrent malignancy other than the disease under investigation with exception of malignancy that was treated curatively and has not recurred within 2 years prior to the date of screening. Fully resected basal or squamous cell skin cancers and any carcinoma in situ are eligible. 20. Any significant medical condition, laboratory abnormality or psychiatric or social condition that would constitute unacceptable safety risks to the participants, contraindicate participant participation in the clinical study, limit the participant’s ability to comply with study requirements, or compromise participant’s compliance with the protocol and all requirements of the study as stated in the Informed Consent Form. 21. Women of child-bearing potential, unless they are willing to use highly effective methods of contraception during treatment with study drugs and for 90 days after stopping NIS793 whichever is latest. 22. Pregnant or breast-feeding women. |
1. Administración previa de tratamientos sistémicos dirigidos al TGF-β. 2. Cáncer colorrectal con inestabilidad de microsatélites alta (IMS-A)/deficiencia en la reparación de errores de replicación (dRER) o con mutación BRAF V600 positiva. 3. Deficiencia de la enzima dipirimidina deshidrogenasa (DPD) completa o parcial conocida (las pruebas de la deficiencia de la enzima DPD no son obligatorias a menos que así lo exija la normativa local y se puedan realizar en un laboratorio local). 4. Para participantes tratados con irinotecán: Antecedentes conocidos o evidencia clínica de actividad reducida de UGT1A1 (las pruebas del estado de UGT1A1 no son obligatorias a menos que así lo exija la normativa local y se puedan realizar en un laboratorio local). 5. Presencia de metástasis sintomáticas en el SNC o metástasis en el SNC que requieran terapia dirigida (como radioterapia focal o cirugía) o dosis crecientes de corticosteroides 2 semanas antes del ingreso al estudio. Los participantes con metástasis cerebrales sintomáticas tratadas deben estar neurológicamente estables durante 4 semanas después del tratamiento y antes del ingreso al estudio, y con una dosis de </ = 10 mg por día de prednisona o equivalente durante al menos 2 semanas antes de la administración de cualquier tratamiento del estudio.
Refierase al protocolo para ver resto de criterios de exclusión |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety run-in: Incidence of DLTs during the first treatment cycle (4 weeks) of treatment Expansion part: Progression-free survival (PFS) by Investigator’s assessment per RECIST 1.1 |
Preinclusión de seguridad (PS): incidencia de toxicidad limitante de dosis (DLT) durante el ciclo de primer tratamiento (4 semanas) de tratamiento Parte de expansión: supervivencia libre de progresión (PFS) conforme a la evaluación del investigador según RECIST 1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
safety run-in: 4 weeks of treatment expansion part: until progression of the disease |
Preinclusión de seguridad: 4 semanas de tratamiento Parte de expansión: hasta progresión de la enfermedad |
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E.5.2 | Secondary end point(s) |
Safety run-in: 1. Safety: Incidence and severity of AEs including changes in laboratory parameters, vital signs and ECG parameters 2. Tolerability: Dose interruptions, reductions and dose intensity 3. PFS, overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and time to response (TTR)by Investigator's assessment per RECIST 1.1 and Overall survival (OS) 4. Drug concentrations in serum or plasma of each investigational treatment and components of SOC therapy (bevacizumab, irinotecan, SN-38) over time and derived PK parameters (e.g. Ctrough, Cmax) 5. Incidence of antidrug antibodies (ADA), prevalence at baseline and ADA incidence during the treatment for investigational treatment(s) and bevacizumab. expansion part: 1. ORR, DCR, DOR, TTR by investigator's assessment by RECIST 1.1 2. OS 3. Incidence and severity of AEs, changes in laboratory parameters, vital signs and ECG parameters; dose interruptions, reductions and dose intensity 4. Drug concentrations in serum or plasma of each investigational treatment and components of SOC therapy (bevacizumab, irinotecan, SN-38) over time and derived PK parameters (e.g. Ctrough, Cmax) 5. Incidence of antidrug antibodies (ADA), prevalence at baseline and ADA incidence during the treatment for investigational treatment(s) and bevacizumab. |
Preinclusión de seguridad: 1. Seguridad: Incidencia y gravedad de EA, incluidos cambios en los parámetros de laboratorio, signos vitales y parámetros del ECG. 2. Tolerabilidad: Interrupciones, reducciones e intensidad de la dosis 3. PFS, tasa de respuesta global (ORR), tasa de control de la enfermedad (DCR), duración de respuesta (DOR), tiempo hasta la respuesta (TTR) conforme a la evaluación del investigador según RECIST 1.1 y supervivencia global (OS) 4. Concentraciones de fármaco en suero o plasma de cada tratamiento en investigación y componentes de la terapia SOC (bevacizumab, irinotecan, SN-38) a lo largo del tiempo y parámetros farmacocinéticos derivados (p. Ej., Ctrough, Cmax) 5. Incidencia de anticuerpos antifármacos (ADA), prevalencia al inicio del estudio e incidencia de ADA durante el tratamiento para los tratamientos en investigación y bevacizumab.. Parte de expansión: 1. Evaluar la eficacia (ORR, DCR, DOR, TTR conforme a la evaluación del investigador según RECIST 1.1 2. Supervivencia global (OS) 3. Incidencia y gravedad de EA, cambios en los parámetros de laboratorio, signos vitales y parámetros del ECG; interrupciones, reducciones e intensidad de la dosis 4. Concentraciones de fármaco en suero o plasma de cada tratamiento en investigación y componentes de la terapia SOC (bevacizumab, irinotecan, SN-38) a lo largo del tiempo y parámetros farmacocinéticos derivados (p. Ej., Ctrough, Cmax) 5. Incidencia de anticuerpos antifármacos (ADA), prevalencia al inicio del estudio e incidencia de ADA durante el tratamiento para los tratamientos en investigación y bevacizumab. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
safety run-in: 1,2 - 4 weeks of treatment 3 - end of treatment 4,5 - at protocol defined timepoints expansion part: 1, 2, 3 - at the end of treatment 4,5 - at protocol defined timepoints |
Preinclusión de seguridad: 1,2 - 4 semanas de tratamiento 3 - fin de tratamiento 4,5 - evaluaciones definidas en el protocolo Parte de expansión: 1, 2, 3 - al final del tratamiento 4,5 - evaluaciones definidas en el protocolo |
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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 | Yes |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
estudio plataforma |
platform study |
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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 |
SOC quimioterapia |
SoC chemotherapy |
|
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
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 |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
Singapore |
Taiwan |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
Czechia |
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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
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When all participants • have completed 2 years of potential survival follow-up or 80% OS events for each treatment arm have occurred • until death or lost to follow-up, or withdrawal of consent • another clinical study with NIS793 or any other new investigational drug becomes available in this participant population and all participants ongoing are eligible to be transferred to that clinical study, in the event of an early study termination decision, the date of that decision. |
Cuando todos los participantes:Hayan completado 2 años de seguimiento de supervivencia potencial u ocurran eventos de OS del 80% para cada grupo de tratamiento; hasta muerte o pérdida de seguimiento, o retirada del consentimiento; otro estudio con NIS793 o con otro fármaco nuevo en investigación disponible en población de participantes y todos participantes en curso son elegibles para transferir a ese estudio, en caso de decisión de finalización anticipada del estudio, la fecha de esa decisión. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 10 |