E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-resectable or recurrent/metastatic BTC |
BTC no resecable o recurrente / metastásico |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the biliary tract that either cannot be removed by surgery or it has come back |
Cáncer del tracto biliar que, o bien no se puede extirpar mediante cirugía, o ha regresado |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004655 |
E.1.2 | Term | Biliary carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10004593 |
E.1.2 | Term | Bile duct cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10004613 |
E.1.2 | Term | Bile duct neoplasms malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10019815 |
E.1.2 | Term | Hepatobiliary neoplasms malignant and unspecified |
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 | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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 |
The primary objective of this single-arm phase II trial is to detect an increase in progression-free survival (PFS) rate at 6 months (according to RECIST version 1.1) in patients with BTC treated with CisGem combined with pembrolizumab as compared to historical controls when treated with standard chemotherapy approach. |
El objetivo principal de este ensayo fase II de un solo grupo es detectar un aumento del 15 % en la supervivencia sin progresión (SSP) a los seis meses (de acuerdo con los criterios RECIST, versión 1.1) en pacientes con CVB tratados con CisGem en combinación con pembrolizumab en comparación con una tasa de SSP a los seis meses del 60 % observada en los controles históricos cuando recibieron tratamiento con quimioterapia estándar. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are: * Assessing both short term and long term outcome of patients receiving this combined treatment * Establishing the safety of standard chemotherapy combined with pembrolizumab in these patients.
Important exploratory objectives include: * Evaluation of pathological and clinical predictive factors for response/toxicity * Assessment of immunological responses (cytokines, lymphocyte phenotype, immunoglobulins) * Evaluation of biomarkers for prediction of response and toxicity. |
Los objetivos secundarios son: Evaluar la respuesta a corto y largo plazo de los pacientes que reciben este tratamiento combinado Establecer la seguridad de la quimioterapia estándar combinada con pembrolizumab en estos pacientes. Entre los objetivos exploratorios importantes se incluyen: Evaluación de los factores patológicos y clínicos que permiten predecir la respuesta o la toxicidad Evaluación de las respuestas inmunológicas (citocinas, fenotipo linfocitario, inmunoglobulinas) Evaluación de biomarcadores para la predicción de la respuesta y la toxicidad. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
* Histopathological diagnosis of BTC (intra- or extra-hepatic CCA) or GBC * Non-resectable or recurrent/metastatic BTC * Availability of archival FFPE (formalin-fixed, paraffin-embedded) tumor tissue for biobanking or possibility to collect tumor biopsy sample at study entry either from primary tumor or any accessible metastatic site * Possibility to collect blood samples at baseline and during treatment for translational research project * ECOG performance status 0, 1 * Age ≥ 18 with estimated life expectancy >3 months * Adequate hematological, liver, renal, cardiac, biliary function: * Adequate coagulation function * Patient is not currently participating and receiving study therapy or has not participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks prior to enrollment * Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 72 hours prior to the first dose of study treatment. * Before patient enrollment, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
* Patients with ascites grade 2 (moderate) or higher * Child Pugh B or C hepatic impairment in patients with cirrhosis * Incomplete recovery from previous surgery or unresolved biliary tract obstruction * Active infection requiring therapy. Antibiotic treatment should have been completed 5 days before treatmetn start * Patients who are candidates for curative surgery * Prior systemic chemotherapy for locally advanced or metastatic disease * Prior adjuvant chemotherapy is allowed if the last treatment was completed at least 6 months before trial entry and if neither gemcitabine nor cisplatin were given. * Also, the following treatment modalities are allowed within the rules described below (provided there has been a full recovery): - Surgery: patients may have undergone a non-curative operation (i.e. R2 resection [with macroscopic residual disease] or palliative bypass surgery only). Patients who have previously undergone curative surgery, must have evidence of non-resectable and measurable disease relapse requiring systemic chemotherapy prior to study entry. - Radiotherapy: patients may have received prior radiotherapy (with or without radiosensitising low-dose chemotherapy) for localised disease. However, there must be clear evidence of disease progression post-treatment prior to inclusion in this study. - Photodynamic therapy (PDT) for localized disease only with no evidence of metastatic disease - patients may have received prior PDT, provided the patient has fully recovered and at least 28 days have elapsed since the PDT and there is clear evidence of disease progression at the local site or disease or at a new metastatic site. - PDT for localised disease to relieve biliary obstruction in the presence of metastatic disease - Other previous localised treatments targeting intrahepatic lesions such as selective internal radiation therapy (SIRT) , transarterial chemoembolisation (TACE) and radiofrequency ablation are allowed, provided the patient has fully recovered from the treatment before participating in the study * Active autoimmune disease that has required systemic treatment in past 2 years * History of (non-infectious) pneumonitis that required steroids or current pneumonitis. No history of or current interstitial lung disease * Diagnosis of immunodeficiency, systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment * Previous allogeneic tissue/solid organ transplant * Known history of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C * Patients with hyperthyroidism or hypothyroidism unless stable on hormone replacement * History of another malignancy or a concurrent malignancy. Exceptions include patients who have been disease-free for 5 years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ. * Prior treatment with any anti-CTLA4 monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS rate at 6 months according to RECIST 1.1 |
Tasa de SSP a los seis meses de acuerdo con iRECIST |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the 6-month assessment. |
En la evaluación de 6 meses. |
|
E.5.2 | Secondary end point(s) |
* Best overall response rate (according to RECIST 1.1 and iRECIST) * Response duration and stable disease duration (according to RECIST 1.1 and iRECIST) * PFS rate at 6 months according to iRECIST * PFS according to RECIST 1.1 and iRECIST * Overall survival (OS) * Toxicity of treatment (Common Toxicity Criteria CTCAE 5.0) * Safety analysis : A safety analysis will be done when at least 10 patients have completed at least one cycle of the three- drug combination. Events of clinical interest for this safety analysis are the following: - At least Grade 2 or higher CTCAE 5.0 signs of acute renal failure - Grade 3 or 4 liver dysfunction defined as elevation of liver transaminases (AST and ALT) and alkaline phosphatase, increased bilirubin - Grade 3 or 4 gastrointestinal disorders specifically colitis, diarrhea and stomatitis - Grade 3 or 4 dyspnea, dry cough and pneumonia - Grade 3 or 4 sepsis - Grade 3 or 4 skin toxicity If 4 out of these 10 patients experience any of the above, this will trigger an IDMC review. This cut-off is based on: 1) previous ABC-02 study where 57% of patients experienced a grade 3 or 4 toxicity at 12 weeks of treatment; and 2) KEYNOTE 028 where 17% of patients experienced grade 3 or 4 toxicity. |
-Mejor tasa de respuesta global (de acuerdo con RECIST 1.1 e iRECIST) -Duración de la respuesta y duración de la enfermedad estable (de acuerdo con RECIST 1.1 e iRECIST) -Tasa de SSP a los seis meses de acuerdo con iRECIST -SSP de acuerdo con RECIST 1.1 y iRECIST posteriormente -Supervivencia global (SG) -Toxicidad de tratamiento (criterios de toxicidad comunes, CTCAE 5.0) -Análisis de la seguridad: Un análisis de la seguridad se realizará cuando un mínimo de 10 pacientes hayan completado al menos un ciclo de combinación de tres fármacos. Los acontecimientos de interés clínico para este análisis de la seguridad son los siguientes: -Signos de insuficiencia renal aguda al menos de grado 2 o superior, según CTCAE 5.0 -La disfunción hepática de grado 3 o 4 se define como una elevación de las transaminasas hepáticas (AST y ALT), fosfatasa alcalina, y aumento de la bilirrubina -Trastornos gastrointestinales de grado 3 o 4, específicamente colitis, diarrea y estomatitis -Disnea de grado 3 o 4, tos seca y neumonía -Septicemia de grado 3 o 4 -Toxicidad cutánea de grado 3 o 4 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the 6-month assessment: * PFS rate at 6 months according to iRECIST
During treatment and until progression (2 years maximum after start of study treatment): * Best overall response rate (according to RECIST 1.1 and iRECIST): * Response duration and stable disease duration (according to RECIST 1.1 and iRECIST)
2 years after start of study treatment:
* PFS according to RECIST 1.1 and iRECIST * Overall survival (OS)
from study treatment start up to 90 days of treatment discontinuation * Toxicity of treatment (Common Toxicity Criteria CTCAE 5.0)
One cycle is 21 days: * Safety analysis : A safety analysis will be done when at least 10 patients have completed at least one cycle of the three- drug combination |
En la evaluación de 6 meses: Tarifa PFS a los 6 meses según iRECIST. Durante el tratamiento y hasta la progresión (2 años máximo después del inicio del tratamiento de estudio): La mejor tasa de respuesta global (según RECIST 1.1 e iRECIST): Duración de la respuesta y duración estable de la enfermedad (según RECIST 1.1 y iRECIST) 2 años después del inicio del tratamiento de estudio: PFS según RECIST 1.1 e iRECIST Supervivencia global (OS) desde el inicio del tratamiento del estudio hasta 90 días de interrupción del tratamiento Toxicidad del tratamiento (Criterios de toxicidad comunes CTCAE 5.0) Un ciclo es de 21 días:Análisis de seguridad: se realizará un análisis de seguridad cuando al menos 10 pacientes hayan completado al menos un ciclo de la combinación de tres medicamentos |
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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 | 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 | 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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 | 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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End of study occurs when all of the following criteria have been satisfied: 1. 90 days after all patients have stopped protocol treatment 2. The trial is mature for the analysis of the primary endpoint as defined in the protocol 3. The database has been fully cleaned and frozen for this analysis |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |