| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Gastrointestinal stromal tumor (GIST) |
| Tumor del estroma gastrointestinal |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastrointestinal stromal tumor (GIST) is a rare cancer affecting the digestive tract or nearby structures within the abdomen. |
| Tumor del estroma gastrointestinal es un cancer raro que afecta el tracto digestivo y otras estructuras adyacentes en el abdomen |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary clinical study objective
1.- To determine the maximum tolerated dose (MTD) and recommended phase II doses (RP2D) of selinexor in combination with imatinib among unresectable and/or metastatic GIST patients with prior failure to at least imatinib for advanced/metastatic disease. |
| 1.Determinar la dosis máxima tolerable (DMT) y la dosis de fase II recomendada de Selinexor en combinación con Imatinib en pacientes con GIST irresecable y/o metastásico que hayan sido tratados al menos con Imatinib. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary clinical study objectives
1.- To evaluate the clinical benefit rate (CBR: CR+PR+ SD ≥ 16 wks).
2.- To evaluate progression free survival (PFS).
3.- To evaluate overall survival (OS).
4.- To evaluate the objective response rate (ORR).
5.- To evaluate the safety profile according to CTCAE 4.03.
6.- To compare PFS on selinexor and imatinib with PFS on last prior anti-cancer therapy. |
Objetivos Secundarios
1-Evaluar la tasa de beneficio clínico (TBC: RC+RP+ EE ≥ 16 semanas)
2- Evaluar la supervivencia Libre de Progresión (SLP)
3- Evaluar la Supervivencia Global (SG)
4- Evaluar la tasa de respuestas objetivas con RECIST 1.1
5- Evaluar el perfil de seguridad de acuerdo con los criterios de CTCAE 4.03
6- Comparar la SLP en Selinexor e Imatinib con la SLP al último tipo de tratamiento anti cáncer. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Translational substudy: To explore the relationship between GIST genotype and CBR with selinexor and imatinib. |
| 1. Explorar la relación entre el genotipo de GIST y la Tasa de Beneficio Clínico (TBC) con el tratamiento combinado de Selinexor e Imatinib. |
|
| E.3 | Principal inclusion criteria |
1. Age ≥18 years at the time of study entry.
2. Histologically confirmed metastatic and/or unresectable GIST. Patients must demonstrate prior failure to at least imatinib. Any number of previous therapies for GIST is allowed.
3. Failure of imatinib is defined as disease progression after ≥ 6 months of treatment with imatinib for advanced/metastatic disease. Exception to this rule is GIST patients with documented KIT or PDGFRA mutations.
4. Measurable disease per modified RECIST 1.1.
5. ECOG performance status 0 to 2.
6. Adequate hematopoietic function (within 7 days prior to enrollment):
a. Hemoglobin ≥ 9.0 g/dL (90 g/L).
b. Absolute neutrophil count ≥ 1000/mm3.
c. Platelets ≥ 100,000 /mm3.
Patients must have at least a 2-week interval from the last red blood cell (RBC) transfusion and/or growth factor support prior to the Screening hemoglobin and neutrophil assessment. However, patients may receive RBC, growth factor support, and/or platelet transfusions as clinically indicated per institutional guidelines during the study.
7. Adequate organ function (within 7 days prior to enrollment):
a. Alanine aminotransferanse (ALT) and aspartate aminotransferanse (AST)
≤2.5 x upper limit of normal (ULN), or ≤ 5.0 x ULN if liver metastases are
present.
b. Alkaline phosphatase (ALP) limit < 2.5 x ULN or ≤ 5.0 x ULN if liver
metastases are present.
c. Total serum bilirubin ≤ 2 x ULN. Patients with Gilbert’s syndrome must have a total bilirubin of < 3 × ULN.
d. Adequate renal function: estimated creatinine clearance of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault
8. Patients must be able to swallow oral medication and no malabsorption condition.
9. Willingness to use effective means of birth control throughout the duration of clinical study and for at least 3 months after completion of study drug.
10. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of study drug administration.
11. Ability to understand and the willingness to sign a written informed consent document. |
1. Edad ≥18 años en el momento de entrada en el estudio.
2. GIST metastásico y/o no resecable confirmado histológicamente. Los pacientes tienen que haber tenido un fallo previo al tratamiento a al menos Imatinib. Se admiten cualquier número de terapias anteriores para el tratamiento de GIST.
3. El fallo tras el tratamiento con Imatinib se define como progresión de la enfermedad después de ≥ 6 meses de tratamiento con Imatinib para enfermedad avanzada y o metastásica. Los pacientes con GIST y mutaciones documentadas en KIT y PDGFRA constituyen una excepción.
4. Enfermedad medible por RECIST modificado 1.1.
5. ECOG 0 a 2.
6. Función hematopoyética adecuada (hasta 7 días antes de la entrada en el estudio):
a. Hemoglobina ≥ 9.0 g/dL (90 g/L).
b. Recuento absoluto de neutrófilos ≥ 1000/mm3.
c. Plaquetas ≥ 100,000 /mm3.
Los pacientes deberán tener al menos un intervalo de 2 semanas desde la última trasfusión de sangre y/o del tratamiento con factores de crecimiento antes de la colecta de sangre para la evaluación de valores de hemoglobina y neutrófilos en el periodo de Screening del estudio. Sin embargo, los pacientes pueden recibir trasfusiones de sangre, tratamiento con factores de crecimiento y/o trasfusiones de plaquetas de acuerdo con la práctica clínica de la institución, durante el estudio.
7. Funcionamiento adecuado de los órganos (hasta 7 días antes de entrada en el estudio):
a. Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST)
≤2.5 x límite normal superior (LNS), or ≤ 5.0 x LNS si hay metástasis en el hígado
b. Alkaline phosphatase (ALP) < 2.5 x LNS or ≤ 5.0 x LNS si hay metástasis en el hígado c. Total serum bilirubin ≤ 2 x LNS. Los pacientes con syndrome de Gilbert han de tener una bilirrubina total <3x LNS.
d. Función renal adecuada: aclaramiento de creatina estimado de ≥ 30 mL/min, calculado usando la fórmula de Cockroft y Gault.
8. Los pacientes han de ser capaces de tragar la medicación oral y evitar condiciones de mal absorción.
9. Disponibilidad para usar métodos contraceptivos eficaces durante todo el estudio y hasta 3 meses después de terminar el tratamiento con la medicación de estudio (Selinexor e Imatinib)
10. Las mujeres en edad fértil tienen que tener un test de embarazo negativo hasta 7 días antes de entrar en el estudio y comenzar el tratamiento.
11. Capacidad de comprender la hoja de información al paciente y disponibilidad para firmar el consentimiento informado del estudio. |
|
| E.4 | Principal exclusion criteria |
1. Intolerance to first-line treatment imatinib 400mg daily.
2. Use of any approved tyrosine kinase inhibitors or investigational agents within 1 week or 5 half-lives of the agent, whichever is shorter, prior to receiving study drugs.
3. Participants who have had radiotherapy within 4 weeks prior to study entry.
4. Major surgery or significant traumatic injury within 4 weeks prior to study entry.
5. Presence of symptomatic or uncontrolled brain or central nervous system metastases.
6. Known or suspected allergy or hypersensitivity to the selinexor, imatinib or any of its components.
7. Patient has a history of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug (The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.)
8. Unstable cardiovascular function: • Symptomatic ischemia, or • Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or • Congestive heart failure (CHF) NYHA Class ≥ 3, or • Myocardial infarction (MI) within 3 months. • Left ventricular ejection fraction < 40 %. • Hypertension > 140 mm Hg systolic or > 90 mm Hg diastolic with or without antihypertensive therapy.
9. Ongoing infection > Grade 2.
10. Patients with any seizure disorder requiring medication.
11. HIV-positive individuals on combination antiretroviral.
12. Patients with active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
13. Serious psychiatric or medical conditions that could interfere with treatment.
14. Pregnant or lactating females.
15. Strong CYP3A4 inhibitors (e.g. clarithromycin, indinavir , itraconazole, ketoconazole , nefazodone , nelfinavir , posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort) within 28 days or 5 drug half-lives (if drug half-life in patients is known), whichever is longer, before start of study treatment. |
1. Intolerante al tratamiento de primera línea con Imatinib 400mg diarias.
2. Tratamiento con cualquier inhibidor tirosina quinasa o producto investigacional hasta 1 semana o 5 medias vidas del agente, lo que sea más corto, antes de iniciar el tratamiento para el estudio.
3. Pacientes que hayan tenido tratamiento con radioterapia en las 4 semanas previas a la entrada en el estudio.
4. Cirugía mayor o lesión traumática significativa en las 4 semanas previas de entrada en el estudio.
5. Presencia de metástasis (sintomáticas o no controladas) en el cerebro o en el sistema nerviosos central.
6. Alergia conocida o sospechosa, o hipersensibilidad a Selinexor, Imatinib o a algunos de sus componentes.
7. Paciente con historial clínico de otra enfermedad maligna que haya sido diagnosticada o tratada hasta 1 año antes de empezar la primera dosis del tratamiento en estudio. Las siguientes enfermedades no cumplen la regla de 1 año: cáncer de piel basocelular y de células escamosas completamente resecado, cáncer de próstata localizado y tratado y cualquier tipo de carcinoma in situ totalmente resecado.
8. Función cardiaca inestable: • Isquemia Sintomática, o • Anomalías de conducción clínicamente significativas no controladas (ej:, taquicardia ventricular con agentes antiarrítmicos está excluida; bloqueo aurículoventricular de primer grado o bloqueo fascicular izquierdo anterior asintomático / bloqueo de rama derecha no se excluirán o or • Insuficiencia cardiaca congestiva NYHA gado ≥ 3, o • Infarto de miocardio en los 3 meses previos • Función cardiaca (FEVI) < 40 %. • Hipertensión > 140 mm Hg sistólica o > 90 mm Hg diastólica con o sin terapia anti hipertensión
9. Infección activa > Grado 2.
10. Pacientes que sufran de convulsiones y requieran medicación.
11. Individuos positivos para VIH y en tratamiento con antirretrovirales.
12. Pacientes con hepatitis B o C activa, hepatitis B o C crónica que requieren tratamiento antiviral.
13. Trastornos psicológicos graves o cualquier condición que interfiera con el seguimiento del tratamiento.
14. Mujeres embarazadas o amamantando.
15. CYP3A4 inhibidores potentes (ej: claritromicina, indinavir, itraconazol, ketoconazol, nefazodona, nelfinavir, posaconazol, ritonavir, saquinavir, telitromicina, voriconazolo) or Inductores potentes de CYP3A4 (ej: carbamazepina, fenobarbital, fenitoína, rifampincina, hierbas de San Juan) hasta 28 días o 5 medias vidas del fármaco (si la media vida del fármaco en pacientes es conocida), lo que sea más tarde, antes de empezar el tratamiento con la medicación en estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary clinical study endpoint
1.- Maximum tolerated dose (MTD) is defined as the highest dose level with ≤1 out of 6 patients experiencing a dose limiting toxicity (DLT) during the first 28 days of treatment. Dose escalation cohort (Phase 1b) seeks to determine the frequency and characteristics of DLTs of the selinexor plus imatinib combination at each dose level during the first cycle of therapy. Toxicity will be graded by using CTCAE 4.03. Phase Ib will be carried out in standard 3+3 format, based on the toxicities found during the first cycle of therapy. Failure to prior therapies involves progression to imatinib and progression or intolerance to any given TKI after imatinib failure. |
1.- La dosis máxima tolerable (DMT) se define como la dosis más alta con la cual ≤1 de los 6 pacientes experiencia toxicidad limitante de dosis en los primeros 28 días de tratamiento. La cohorte de escalada de dosis (Fase 1b) procura determinar la frecuencia y las características de la toxicidad limitante de dosis de la combinación de Selinexor con Imatinib en cada nivel de dosis durante el primerio ciclo de tratamiento.
La toxicidad será clasificada de acuerdo con los CTCAE 4.03. La determinación de la dosis recomendada para el Fase II será llevada a cabo en un formato clásico 3+3, basado en las toxicidades encontradas durante el primer ciclo de tratamiento.
Fallo en terapias anteriores pueden ser: progresión tras el tratamiento con Imatinib y progresión o intolerancia a cualquier tratamiento con inhibidores tirosina quinasa tras haber fallado en el tratamiento con Imatinib. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the first 28 days of treatment |
| Durante los primeros 28 días de tratamiento |
|
| E.5.2 | Secondary end point(s) |
Secondary clinical study endpoints
1.- Clinical benefit rate (CBR): Number of patients with CBR ≥30% lasting ≥16 weeks treated in the phase II portion of the study. CBR is defined as the rate of complete response (CR) or partial response (PR) or stable disease (SD) (according to RECIST 1.1 criteria)
2.- Progression free survival (PFS): Efficacy measured by PFS assessed by median time. PFS is defined as the time between the date of first experimental treatment dose and the date of disease progression (according to RECIST 1.1 criteria).
3.- Overall survival (OS): Efficacy measured by OS. OS is defined as the time between the date of first experimental treatment dose and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive, or when the last enrolled patiens are followed up to for 12 months, whichever is early.
4.- Objective response rate (ORR): Efficacy measured by ORR. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 and Choi criteria).
5.- Safety profile according to CTCAE 4.03: Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.03. |
Secondary clinical study endpoints
1.- Clinical benefit rate (CBR): Number of patients with CBR ≥30% lasting ≥16 weeks treated in the phase II portion of the study. CBR is defined as the rate of complete response (CR) or partial response (PR) or stable disease (SD) (according to RECIST 1.1 criteria)
2.- Progression free survival (PFS): Efficacy measured by PFS assessed by median time. PFS is defined as the time between the date of first experimental treatment dose and the date of disease progression (according to RECIST 1.1 criteria).
3.- Overall survival (OS): Efficacy measured by OS. OS is defined as the time between the date of first experimental treatment dose and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive, or when the last enrolled patiens are followed up to for 12 months, whichever is early.
4.- Objective response rate (ORR): Efficacy measured by ORR. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 and Choi criteria).
5.- Safety profile according to CTCAE 4.03: Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.03. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary clinical study endpoints
1.- CBR: Number of patients with CBR ≥30% lasting ≥16 weeks
2.- Progression free survival (PFS): defined as the time between the date of first experimental treatment dose and the date of disease progression
3.- Overall survival (OS): defined as the time between the date of first experimental treatment dose and the date of death due to any cause.
4.- Objective response rate (ORR): defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects
5.- Safety profile according to CTCAE 4.03: Safety profile during the treatment. |
CBR: Número de pacientes con CBR ≥30% con una duración ≥16 semanas
2.- Supervivencia libre de progresión (SLP): definida como el tiempo transcurrido entre la fecha de la primera dosis de tratamiento experimental y la fecha de progresión de la enfermedad
3.- Supervivencia global (OS): definida como el tiempo transcurrido entre la fecha de la primera dosis de tratamiento experimental y la fecha de fallecimiento por cualquier causa.
4.- Tasa de respuesta objetiva (ORR): definida como el número de sujetos con una mejor respuesta global (BOR) de respuesta completa (CR) o respuesta parcial (PR) dividida por el número de sujetos evaluables de respuesta
5.- Perfil de seguridad según CTCAE 4.03: perfil de seguridad durante el tratamiento. |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 |
| evaluate the synergistic effect of treatment with selinexor and imatinib in GIST patients |
| evaluar el efecto sinergico del tratamiento con selinexor e imatinib en pacientes GIST |
|
| 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 | 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) | Yes |
| 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 | 6 |
| 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
|
| LVLS |
| ultima 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 | 3 |
| 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 | 3 |
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