| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ADVANCED SOLID TUMORS AND LYMPHOMA |
| Tumores sólidos y linfomas avanzados |
|
| E.1.1.1 | Medical condition in easily understood language |
| ADVANCED SOLID TUMORS AND LYMPHOMA |
| Tumores sólidos y linfomas avanzados |
|
| 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 | 10005003 |
| E.1.2 | Term | Bladder 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073071 |
| E.1.2 | Term | Hepatocellular carcinoma |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073077 |
| E.1.2 | Term | Intrahepatic cholangiocarcinoma |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10074879 |
| E.1.2 | Term | Extrahepatic cholangiocarcinoma |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017620 |
| E.1.2 | Term | Gallbladder carcinoma |
| 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 | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003899 |
| E.1.2 | Term | B-cell lymphoma |
| 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 1: dose escalation
• To determine the maximum-tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of CYC140 when administered orally once daily (QD) in 28-day cycles in adult subjects with advanced solid tumors and lymphoma
Phase 2: proof of concept
• To evaluate the preliminary efficacy of CYC140 as measured by overall response rate (ORR) in subjects with locally advanced, recurrent or metastatic, histologically confirmed advanced solid tumors or lymphoma who have failed all standard therapies or for whom standard therapy does not exist |
Fase I: escalada de dosis
• Determinar la dosis máxima tolerada (DMT) o la dosis recomendada para la fase II (DRF2) de CYC140 cuando se administra por vía oral una vez al día (1 v/d) en ciclos de 28 días en sujetos adultos con tumores sólidos avanzados y linfoma.
Fase II: prueba de concepto
• Evaluar la eficacia preliminar de CYC140 medida por la tasa de respuesta global (TRG) en sujetos con tumores sólidos localmente avanzados, recurrentes o metastásicos confirmados histológicamente o linfoma que no han respondido a ninguno de los tratamientos estándar o para los que no existe un tratamiento estándar. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
Phase 1 dose escalation
• To assess safety and tolerability of CYC140
• To investigate clinical pharmacokinetics (PK) of CYC140
• To evaluate overall response rate (ORR) in subjects receiving CYC140
Phase 2 proof of concept
• To assess the safety and tolerability of CYC140
• To evaluate the DCR, DOR, PFS, and OS in subjects receiving CYC140
Exploratory:
Phase 1- dose escalation
• To investigate the clinical pharmacodynamics of CYC140
• To investigate the clinical pharmacogenomics (PGx) of CYC140
Phase 2- proof of concept
• To investigate the clinical PGx of CYC140 |
Fase 1: escalada de dosis
• Evaluar la seguridad y tolerabilidad de CYC140.
• Investigar la farmacocinética (FC) clínica de CYC140.
• Evaluar la TRG en sujetos que reciben CYC140.
Fase 2: prueba de concepto
• Evaluar la seguridad y tolerabilidad de CYC140.
• Evaluar la tasa de lucha contra las enfermedades infecciosas (DCR), la duración de la respuesta (DdR), la supervivencia sin progresión (SSP) y la supervivencia general (SG) en sujetos que reciben CYC140.
Objetivos exploratorios:
Fase I: escalada de dosis
• Investigar la farmacodinámica clínica de CYC140.
• Investigar la farmacogenómica (FG) clínica de CYC140.
Fase II: prueba de concepto
Investigar la FG clínica de CYC140. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or females aged ≥ 18 years or per local regulatory guidance
2. Subjects with histological or cytologically-confirmed advanced cancer who have progressed on (or have not been able to tolerate) standard therapy or for whom no standard anticancer therapy is available
a. For phase 1, all tumor types may be enrolled
b. For phase 2, subjects will be enrolled as mentioned in the ‘study design’ section
c. For phase 2, subjects should also meet the following criteria:
i. Radiological progression as per RECIST (Lugano criteria for lymphoma, modified severity-weighted assessment tool [mSWAT] for CTCL) criteria on the last line of therapy before entering the trial must be documented
ii. At least one measurable lesion as defined by the RECIST criteria (version 1.1) for solid tumors iii. For subjects with lymphoma based on Lugano Criteria (Cheson et al. 2014) and CTCL subjects based on mSWAT (Olsen)
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2
4. Subjects who relapsed post-autologous or post-allogeneic transplant are eligible. Post-transplant subjects must be without active fungal disease or significant acute graft-versus-host disease.
5. Subjects must have the following laboratory values:
a. Absolute neutrophil count ≥ 1.5 × 109/L
b. Hemoglobin ≥ 8.0 g/dL
c. Platelet count ≥ 75 × 109/L
d. Albumin ≥ 3 g/dL
e. Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within institutional normal limits. (Subjects with correctable lab abnormalities deemed not clinically significant by the investigator may be enrolled after discussion with the Sponsor)
f. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum glutamic-pyruvic transaminase ≤ 3 × upper limit of normal (ULN) or ≤ 5.0 × ULN if liver metastases is present
g. Total serum bilirubin ≤ 1.5 × ULN
h. 24-hour or calculated creatinine clearance (CrCl) ≥ 50 mL/min (according to Cockcroft-Gault formula)*. For subjects with urothelial cancer, a creatinine clearance of ≥ 40 mL/min is acceptable. *For CrCl value, the eligibility should be determined using the Cockcroft-Gault formula:
▪ Male CrCl (mL/min) = body weight (kg) × (140 – age)/[72 × serum creatinine (mg/dL)]
▪ Female CrCl (mL/min) = male CrCl × 0.85
6. WOCBP must have a negative pregnancy test (urine/serum) within 7 days prior initiating the study drug. Both males and females must agree to use effective birth control during the study (prior receiving first dose and for 6 months after the last dose) if conception is possible during this interval. Female subjects are considered to not be of childbearing potential if they have a history of hysterectomy or are postmenopausal (no menses for 12 months without an alternative medical cause). For both males and females, see Section 5.5 for the definitions of contraceptive methods considered effective for this protocol
7. Subjects must be able to swallow and retain orally administered medication, and not have any clinically significant GI abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels
8. Ability to agree to and sign the informed consent form, and comply with the protocol |
1. Male or females aged ≥ 18 years or per local regulatory guidance
2. Subjects with histological or cytologically-confirmed advanced cancer who have progressed on (or have not been able to tolerate) standard therapy or for whom no standard anticancer therapy is available
a. For phase 1, all tumor types may be enrolled
b. For phase 2, subjects will be enrolled as mentioned in the ‘study design’ section
c. For phase 2, subjects should also meet the following criteria:
i. Radiological progression as per RECIST (Lugano criteria for lymphoma, modified severity-weighted assessment tool [mSWAT] for CTCL) criteria on the last line of therapy before entering the trial must be documented
ii. At least one measurable lesion as defined by the RECIST criteria (version 1.1) for solid tumors
iii. For subjects with lymphoma based on Lugano Criteria (Cheson et al. 2014) and CTCL subjects based on mSWAT (Olsen)
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 2
4. Subjects who relapsed post-autologous or post-allogeneic transplant are eligible. Post-transplant subjects must be without active fungal disease or significant acute graft-versus-host disease.
5. Subjects must have the following laboratory values:
a. Absolute neutrophil count ≥ 1.5 × 109/L
b. Hemoglobin ≥ 8.0 g/dL
c. Platelet count ≥ 75 × 109/L
d. Albumin ≥ 3 g/dL
e. Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within institutional normal limits. (Subjects with correctable lab abnormalities deemed not clinically significant by the investigator may be enrolled after discussion with the Sponsor)
f. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase and alanine aminotransferase/serum glutamic-pyruvic transaminase ≤ 3 × upper limit of normal (ULN) or ≤ 5.0 × ULN if liver metastases is present
g. Total serum bilirubin ≤ 1.5 × ULN
h. 24-hour or calculated creatinine clearance (CrCl) ≥ 50 mL/min (according to Cockcroft-Gault formula)*. For subjects with urothelial cancer, a creatinine clearance of ≥ 40 mL/min is acceptable. *For CrCl value, the eligibility should be determined using the Cockcroft-Gault formula:
▪ Male CrCl (mL/min) = body weight (kg) × (140 – age)/[72 × serum creatinine (mg/dL)]
▪ Female CrCl (mL/min) = male CrCl × 0.85
6. WOCBP must have a negative pregnancy test (urine/serum) within 7 days prior initiating the study drug. Both males and females must agree to use effective birth control during the study (prior receiving first dose and for 6 months after the last dose) if conception is possible during this interval. Female subjects are considered to not be of childbearing potential if they have a history of hysterectomy or are postmenopausal (no menses for 12 months without an alternative medical cause). For both males and females, see Section 5.5 for the definitions of contraceptive methods considered effective for this protocol
7. Subjects must be able to swallow and retain orally administered medication, and not have any clinically significant GI abnormalities that may alter absorption, such as malabsorption syndrome or major resection of the stomach or bowels
8. Ability to agree to and sign the informed consent form, and comply with the protocol
1. Hombres o mujeres de ≥18 años de edad o según las directrices normativas del país.
2. Sujetos con cáncer avanzado confirmado histológica o citológicamente que han progresado con el tratamiento estándar (o no han podido tolerarlo) o para quienes no se dispone de tratamiento antineoplásico estándar.
a. Para la fase I, pueden inscribirse todos los tipos de tumores.
b. Para la fase II, los sujetos se inscribirán según lo mencionado en la sección “diseño del estudio”.
c. Para la fase II, los sujetos también deben cumplir los siguientes criterios:
i. Debe documentarse la progresión radiológica según los criterios de evaluación de la respuesta al tratamiento en tumores sólidos (RECIST) (criterios de Lugano para el linfoma, herramienta de evaluación ponderada por gravedad modificada [mSWAT] para el LCLT) en la última línea de tratamiento antes de entrar en el ensayo.
ii. Debe tener, al menos, una lesión medible según los criterios RECIST (versión 1.1) para tumores sólidos.
iii. Para sujetos con linfoma basado en los criterios de Lugano (Cheson et al. 2014) y sujetos con LCLT basados en mSWAT (Olsen).
3. Estado funcional según el Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0-2.
4. Los sujetos con recaída después de un autotrasplante o trasplante alogénico son aptos. Los sujetos que se han sometido a un trasplante no deben presentar enfermedad fúngica activa ni enfermedad de injerto contra huésped aguda significativa.
5. Los sujetos deben tener los siguientes valores analíticos:
a. RAN ≥1,5 × 109/l.
b. Hemoglobin ≥ 8.0 g/dL
c. Platelet count ≥ 75 × 109/L
d. Albumin ≥ 3 g/d
(Referirse a la sinopsis del protocolo) |
|
| E.4 | Principal exclusion criteria |
Disease exclusions
1. Subjects with a history of brain metastases or with signs/symptoms attributable to brain metastases and those who have not been assessed with radiologic imaging to rule out the presence of brain metastases. Subjects with treated brain metastases that are asymptomatic and have been clinically stable for at least 4 weeks will be eligible
2. Subjects who have not received vaccines for SARS-COV-2 and have suspected signs and symptoms of the novel coronavirus infection (COVID-19) or have confirmed COVID-19
Exclusions owing to medical conditions
3. Subjects with a history of another primary malignancy other than:
a. In situ carcinomas (e.g., breast, cervix and prostate)
b. Locally excised non-melanoma skin cancer
c. No evidence of the disease from another primary cancer for 2 or more years and has not taken any anti-cancer treatment in 2 years. Exceptions are gonadotropin-releasing hormone (GnRH) therapy for prostate cancer and hormonal maintenance therapy for breast cancer
4. Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase risk associated with study drug administration or may interfere with the interpretation of study results such as but not limited to:
a. Uncontrolled diabetes mellitus
b. Liver disease such as decompensated liver disease
c. Life-threatening autoimmune disease
5. Diseases that significantly affect GI absorption of CYC140
6. Subjects with impaired cardiac function or clinically significant cardiac disease, including any of the following:
a. Baseline-corrected QT level using Fridericia formula (QTcF) > 470 ms or congenital QT syndrome. For subjects with known bundle-branch blocks (BBB), use the QTcR equation
b. History or presence of serious uncontrolled ventricular arrhythmias
c. Severe/unstable angina, New York Heart Association (NYHA) classification 4 congestive heart failure (CHF) (Appendix 1)
d. Echocardiogram or multiple grated acquisitions under 30% ejection fraction
e. Any history of ventricular fibrillation or Torsades de Pointes
7. Presence of active chronic inflammatory bowel disease (ulcerative colitis or Crohn’s disease) or GI perforation within 6 months of enrollment
8. Presence of an active infection requiring IV antibiotics
9. Presence of a known history of human immunodeficiency virus-1/2 with uncontrolled viral load and on medications that might interfere with metabolism
10. Presence of active hepatitis B virus (HBV) or hepatitis C virus (HCV). In subjects with a history of HBV, hepatitis B core antibody (HBcAb) testing is required and if positive, HBV DNA testing will be performed and if positive, the subject will be excluded. For subjects with HCV Ab positive, HCV viral load must be below the limit of quantification
Prior therapy exclusions
11. Chemotherapy, biological therapy, targeted therapy, immunotherapy, extended-field radiotherapy or investigational agents within 5 half-lives or 3 weeks (whichever is shorter), prior administering the first dose of study drug on Day 1 or in those who have not recovered from the side-effects of such therapy
12. Subjects who are taking drugs with a strong risk of causing QT/QTc prolongation unless medically necessary (after discussion with medical monitor) (See Appendix 4 for the list of drugs)
13. Major surgery/surgical therapy for any cause within 4 weeks of the first dose |
Exclusión de enfermedades
1. Sujetos con antecedentes de metástasis cerebrales o con signos/síntomas atribuibles a las metástasis cerebrales y aquellos a los que no se ha evaluado mediante exploraciones radiológicas para descartar la presencia de metástasis cerebrales. Los sujetos con metástasis cerebrales tratadas que sean asintomáticas y hayan estado clínicamente estables durante al menos 4 semanas serán aptos
2. Sujetos que no han recibido vacunas contra el coronavirus asociado al síndrome respiratorio agudo grave de tipo 2 (SARS-COV-2) y que tienen sospecha de signos y síntomas de la nueva infección por coronavirus (COVID-19) o tienen infección por COVID-19 confirmada.
Exclusiones debidas a afecciones médicas
3. Sujetos con antecedentes de otra neoplasia maligna primaria distinta de
a. Carcinoma in situ (p. ej., mama, cuello uterino y próstata).
b. Cáncer de piel no melanoma extirpado localmente.
c. Ausencia de evidencia de enfermedad de otro cáncer primario durante 2 o más años y que no se haya tomado ningún tratamiento antineoplásico en 2 años. Las excepciones son el tratamiento con hormona liberadora de gonadotropina (GnRH) para el cáncer de próstata y el tratamiento de mantenimiento hormonal para el cáncer de mama.
4. Cualquier otra afección médica o psiquiátrica aguda o crónica de importancia clínica o cualquier anomalía de laboratorio que pueda aumentar el riesgo asociado a la administración del fármaco del estudio o interferir con la interpretación de los resultados del estudio, como, entre otros:
a. Diabetes mellitus mal controlada.
b. Enfermedad hepática como enfermedad hepática descompensada.
c. Enfermedad autoinmunitaria potencialmente mortal.
5. Enfermedades que afectan significativamente a la absorción GI de CYC140.
6. Insuficiencia cardiovascular o enfermedad cardiovascular de importancia clínica, incluidas cualquiera de las siguientes:
a. Nivel de QT corregido al inicio mediante la fórmula de Fridericia (QTcF) >470 ms o síndrome de QT congénito. Para sujetos con bloqueos de rama (BBB) conocidos, utilice la ecuación QTcR.
b. Antecedentes o presencia de arritmias ventriculares graves no controladas.
c. Angina grave o inestable, insuficiencia cardiaca congestiva (ICC) de grado 4 según la clasificación de la Asociación de cardiología de Nueva York (NYHA) (Anexo 1).
d. Ecocardiograma o ventriculografía isotópica por debajo del 30 % de la fracción de expulsión.
e. Cualquier antecedente de fibrilación ventricular de taquicardia ventricular helicoidal.
7. Presencia de enfermedad intestinal inflamatoria crónica activa (colitis ulcerosa o enfermedad de Crohn) o perforación GI en los 6 meses anteriores a la inscripción.
8. Presencia de infección activa que requiere antibióticos por vía intravenosa (i.v.).
9. Presencia de antecedentes conocidos de virus de la inmunodeficiencia humana-1/2 con carga vírica no controlada y toma de medicamentos que podrían interferir con el metabolismo.
10. Presencia de virus de la hepatitis B (VHB) o virus de la hepatitis C (VHC) activo. En los sujetos con antecedentes de VHB, se requiere la prueba de anticuerpos contra el núcleo de la hepatitis B (HBcAb) y, si es positiva, se realizará la prueba de ADN del VHB y, si es positiva, se excluirá al sujeto. Para los sujetos con Ab contra el VHC positivo, la carga vírica del VHC debe estar por debajo del límite de cuantificación.
Exclusión por tratamientos anteriores
11. Quimioterapia, tratamiento biológico, tratamiento dirigido, inmunoterapia, radioterapia de campo extendido o fármacos en investigación dentro de las 5 semividas o 3 semanas (lo que sea más corto) antes de administrar la primera dosis del fármaco del estudio el día 1 o a aquellos que no se hayan recuperado de los efectos secundarios de dicho tratamiento.
12. Sujetos que estén tomando fármacos con un fuerte riesgo de causar prolongación del intervalo QT/QTc, a menos que sea médicamente necesario (tras comentarlo con el supervisor médico).
13. Cirugía mayor o tratamiento quirúrgico por cualquier causa en las 4 semanas anteriores a la primera dosis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1: dose escalation
• The incidence rate of dose-limiting toxicities (first cycle only) at each dose level
Phase 2: proof of concept
• ORR according to Response Evaluation Criteria in Solid Tumors: RECIST guidelines (version 1.1, 2009) (Lugano Criteria for lymphoma, mSWAT for CTCL) for each tumor type. The overall response rate is defined as proportion of subjects who had the best overall response (BOR) of complete response (CR) or partial response (PR) |
Fase 1: escalada de dosis
• La tasa de incidencia de la toxicidad limitante de la dosis (primer ciclo solo) en cada nivel de dosis
Fase 2: prueba de concepto
• Tasa de respuesta global de acuerdo a los criterios de evaluación de la respuesta al tratamiento en tumores sólidos: RECIST (versión 1.1, 2009) (criterios de Lugano para el linfoma, herramienta de evaluación ponderada por gravedad modificada [mSWAT] para el LCLT) para cada tipo de tumor. La tasa de respuesta global se define como la proporción de sujetos que tuvieron la mejor respuesta global (MRG) de respuesta completa (RC) o respuesta parcial (RP) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At predetermined time points described in the protocol. |
| En distintos momentos predeterminados descritos en el protocolo |
|
| E.5.2 | Secondary end point(s) |
Secondary:
Phase 1 dose escalation, Phase 2 proof of concept
• Safety: Type, frequency and severity of adverse drug reactions according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0)
• Disease control rate (DCR) is defined as the proportion of subjects who achieve a response of CR, PR and stable disease according to RECIST
• Response rate as per Lugano Criteria for lymphoma, mSWAT for CTCL
• Progression-free survival (PFS) is defined as the time from the first dose date to objectively documented disease progression or death
• Duration of response, computed for subjects with a BOR of CR or PR, is defined as the time between the date of first response and the subsequent date of objectively documented disease progression or death
• Overall survival is defined as the time between the first dosing date and the date of death
PK (Phase 1 dose escalation only): CYC140 plasma concentrations and basic PK parameters, including but not limited to, area under the plasma concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0t), area under the plasma concentration-time curve from time 0 to time infinity (AUCinf), area under the plasma concentration-time curve from the time 0 to the time 24 h (AUC0-24), maximum observed plasma concentration (Cmax), time to reach maximum observed plasma concentration (Tmax), oral clearance, apparent distribution volume, observed accumulation ratio, terminal elimination half-life (t½), mean residence time and other PK parameters if deemed appropriate (Phase 1)
Exploratory:
Phase 1 dose escalation, Phase 2 proof of concept
• Pharmacodynamics: PLK1 and BRD4 inhibition assessed by differential expression of target genes (such as MYC, PLK1, CDKN1A, HEXIM1) relative to baseline (Phase 1 only)
• PGx: Plasma cell-free DNA mutation and copy number variation profile determined by NGS |
Secundarios:
Fase 1: escalada de dosis, Fase 2: prueba de concepto
• Seguridad: tipo, frecuencia y gravedad de las reacciones adversas a la medicación según los Criterios terminológicos comunes para acontecimientos adversos (CTCAE) (versión 5.0) del Instituto Nacional del Cáncer .
• La tasa de lucha contra las enfermedades infecciosas (DCR) se define como la proporción de sujetos que alcanzan una respuesta RC, RP y enfermedad estable de acuerdo con el RECIST
• Tasa de respuesta según los criterios de Lugano para linfoma, mSWAT para el LCLT
• La supervivencia sin progresión (SSP) se define el tiempo desde la fecha de la primera dosis a la progresión de la enfermedad objetivamente documentada o muerte
• Duración de la respuesta, calculada para sujetos con MRG de RC or RP, se define como el tiempo entre la fecha de la primera respuesta y la fecha posterior de progresión de la enfermedad objetivamente documentada o muerte
• La supervivencia global se define como el tiempo entre la fecha de la primera dosis y la fecha de la muerte
FC (Fase 1 de escalada de dosis solo): concentraciones de CTC140 en plasma y parámetros básicos de FC, incluido pero no solo, el área bajo la curva de concentración de plasma-tiempo desde el momento 0 a las 24 horas (AUC0-24), concentración de plasma máxima observada (Cmax), momento en que se alcanza la concentración de plasma máxima observada (Tmax), distancia oral, distribución de volumen aparente, proporción acumulada observada, semivida de eliminación terminal (t1/2), tiempo medio de permanencia y otros parámetros FC si se consideran apropiados (Fase 1)
Exploratorios:
Fase 1: escalada de dosis, Fase 2: prueba de concepto
• Farmacodinámica: inhibición de PLK1 y BRD4 evaluada por manifestación diferencial de genes diana (tales como MYC, PLK1, CDKN1A, HEXIM1) respecto al basal (Fase 1 solo).
• FG: plasma libre de mutaciones de ADN y perfil de la variación del número de copias determinado por NGS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At predetermined time points described in the protocol. |
| En distintos momentos predeterminados descritos en el protocolo |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and biomarkers assessment |
| Tolerabilidad y evaluación de biomarcadores |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose-escalation, proof of concept |
| Escalada de dosis, prueba de concepto |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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 |
| Korea, Republic of |
| Spain |
| United States |
|
| 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
|
| LVLS |
| Última Visita del Último Sujeto |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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