| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| KIT/PDGFR wild type GastroIntestinal Stromal Tumor (GIST) |
| Tumor del Estroma Gastrointestinal KIT/PDGFR wild type |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastrointestinal Stromal tumor with no mutations on KIT/PDGFR (wild type) |
| Tumor del estroma gastrointestinal sin mutaciones en KIT/PDGFR |
|
| 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 |
| Disease Control Rate (DCR) |
| o Tasa de control de la enfermedad (TCE) |
|
| E.2.2 | Secondary objectives of the trial |
Progression Free Survival (PFS)
Overall Survival (OS)
Responses determined by CHOI
Correlation with Translational Research
Safety (Adverse events CTCAE v4.03)
Early metabolic response by PET scan |
o Supervivencia libre de progression (SLP)
o Supervivencia global (SG)
o Respuesta evaluada por criterios CHOI
o Correlación con el estudio traslacional
o Respuesta metabólica temprana medido por PET
o Seguridad (Eventos adversos medidos por CTCAE 4.03) |
|
| 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 |
TITLE: PHASE II, SINGLE ARM, NON-RANDOMIZED AND MULTICENTER CLINICAL TRIAL OF REGORAFENIB AS A SINGLE AGENT IN THE FIRST-LINE SETTING FOR PATIENTS WITH METASTATIC AND/OR UNRESECTABLE KIT/PDGFR WILD TYPE GIST: CORRELATIVE SCIENCE STUDIES.
version and date: 1.0 19th June 2015
Objectives:
Evaluate if different subgroups of KIT/PDGFR-driven GIST genotype benefit differently from regorafenib treatment.
Identification of biomarkers of response to Regorafenib
To characterize the mechanisms involved in Regorafenib activity in GIST patients. |
TITULO: Ensayo Clínico Fase II de un solo brazo, no randomizado y multicéntrico de regorafenib como agente único para el tratamiento de primera línea de pacientes con GIST KIT/PDGFR Wild Type metastásico y/o irresecable: Estudios correlativos científicos
Versión y fecha: v 1.0 del 19 Junio 2015
Objetivos:
Evaluar si en diferentes subgrupos del genotipo de GIST KIT/PDGFR se obtienen diferentes beneficios con el tratamiento de regorafenib
Identificar los biomarcadores de respuesta a regorafenib
Caracterizar los mecanismos que están presentes en la actividad del regorafenib en los pacientes con GIST |
|
| E.3 | Principal inclusion criteria |
- Male or female subjects ?18 years of age
- Histologically confirmed GIST KIT/PDGFR wild-type, unresectable or metastatic GIST (confirmed by central laboratory). Paraffin-embedded tumor block must be provided by all subjects during screening period.
- Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18 exons of PDGFR gene
- Subjects must have at least one measurable lesion according to RECIST v1.1 criteria. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment.
- Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
Total Bilirubin ? 1.5 x the upper normal limit (UNL). Documented Gilbert Syndrome is allowed if total bilirubin is mildly elevated (?6mg/dl).
Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ? 3.0 x UNL (?5xUNL for subjects with liver involvement of GIST)
Lipase ?1.5 x UNL
Serum Creatinine ? 1.5 x UNL
Glomerular filtration rate (GFR) ? 30ml/mn/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
International Normalized Ratio (INR) ?1.5xUNL and partial thromboplastin time (PTT) or activated partial thromboplastine time (aPTT) ?1.5xUNL.
Subjects who are being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standards of care.
Platelet count ?100000mm3, hemoglobin (Hb) ? 9.0 g/dl, absolute neutrophil count (ANC) ?1500/mm3. Blood transfusions to meet the inclusion criteria will not be allowed.
Alkaline phosphatase limit ? 2.5 x UNL (? 5x UNL for subjects with disease involving the liver)
- Women of childbearing potential and men must agree to use adequate contraception from the moment of signing the Informed Consent Form until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
- Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment |
- Hombres y mujeres de ?18 años
- Confirmación histológica de GIST KIT/PDGFR wild-type, irresecable o metastático (confirmado por el laboratorio central). Todos los pacientes deben donar un bloque de tumor en parafina durante el periodo de screening.
- Revisión de mutaciones en los exons 11, 9, 13 y 17 del gen KIT y en el 12 y 18 del gen PDGFR.
- Los sujetos deben tener al menos una lesión medible por criterios RECIST v1.1. Una lesion de una zona previamente irradiada puede ser considerada medible siempre que haya evidencias objetivas de progresión de la lesión previa a la inclusión en el estudio
- Adecuada función de la médula ósea, hígado y riñón evaluada según los siguientes criterios de laboratorios y llevado a cabo entre los 7 días previos al inicio del tratamiento:
Bilirrubina total ? 1.5 x límite superior de normalidad (UNL). El Síndrome de Gilbert está permitido siempre que esté documentado y la bilirrubina total esté medio elevada (?6mg/dl).
Alanina Aminotransferasa (ALT) y aspartato aminotransferasa (AST) ? 3.0 x UNL (?5xUNL para sujetos cuyo hígado está asociado al GIST)
Lipasa ?1.5 x UNL
Creatinina sérica ? 1.5 x UNL
Tasa de filtrado glomerular (GFR) ? 30ml/mn/1.73 m2 de acuerdo con la fórmula abreviada de MDRD (Modified Diet in Renal Disease)
Tasa normalizada internacional (INR) ?1.5xUNL y tiempo parcial de tromboplastina (PTT) o tiempo de tromboplastina parcialmente activada (aPTT) ?1.5xUNL.
Los sujetos tratados con anticoagulantes como warfarina o heparina serán incluidos siempre que no hay evidencias previas de abnormalidades en estos parámetros.
Se realizarán monitorizaciones semanales hasta que el INR y PTT sean estables basadas en medidas previas a la administración de la dosis según los criterios habituales del centro.
Plaquetas ?100000mm3, hemoglobina (Hb) ? 9.0 g/dl, neutrófilos absolutos (ANC) ?1500/mm3. Las transfusiones de sangre para cumplir con los criterios de inclusión no serán permitidas.
Límite de fosfatasa alcalina ? 2.5 x UNL (? 5x UNL para sujetos con enfermedad asociada al hígado)
- Tanto mujere con potencial de embarazo como hombres deben aceptar usar métodos contraceptivos desde el momento de firmar el consentimiento informado hasta 3 meses tras el final de la medicación. El investigador o un designado debe recomendar al sujeto como alcanzar un adecuado control de la natalidad. La adecuada contracepción está definida en el estudio como cualquier método recomendado médicamente (o combinación de métodos) según la práctica habitual.
- Mujeres con potencial de embarazo debe tener un test de embarazo en sangre u orina como máximo 7 días previos al inicio del estudio y debe ser registrado un resultado negativo antes de inicio del tratamiento. |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic treatment for metastatic GIST. Patients that have received imatinib during adjuvant setting are eligible only if they have relapsed after a minimum of 6 months from the end of treatment with imatinib.
2. Cancer other than GIST within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumors (Ta (Non Invasive tumor), and Tis (Carcinoma In situ)).
3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the start of study medication.
4. Congestive Heart Failure New York Heart Association (NYHA) ? class 2.
5. Unstable angina (angina symptoms at rest, new-onset angina, ie, within the lasts 3 months prior to entering study) or myocardial infarction (MI) within the past 6 months before the start of study medication.
6. Cardiac arrhythmias requiring anti-arrhytmic therapy (beta blockers or digoxin are permitted).
7. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90mmHg despite optimal medical management).
8. Subjects with pheochromocytoma.
9. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months from start of study treatment.
10. Venous thrombotic events such as deep vein thrombosis within the 3 months before the start of study treatment.
11. Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
12. Known history of human immunodeficiency virus (HIV) infection.
13. Subjects with seizure disorder requiring medication
14. Symptomatic metastasis in brain or meningeal tumors.
15. History of organ allograft.
16. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ? NCI-CTCAE version 4.03 grade 3 or higher within 4 weeks prior to start of study treatment.
17. Non-healing wound, ulcer, or bone fracture.
18. Renal failure requiring hemo- or peritoneal dialysis.
19. Dehydration NCI-CTCAE version 4.03 grade ? 1
20. Substance abuse or medical, psychological, or social conditions that may interfere with the subject´s participation in the study or evaluation of the study results.
21. Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
22. Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study
23. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
24. Subjects unable to swallow oral medication
25. Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher (>3.5g/24hrs), measured by urine protein creatinine ratio on a random urine sample)
26. Any malabsorption condition.
27. Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution (whichever is higher).
28. Pleural effusion or ascites that causes respiratory compromise (? NCI-CTCAE version 4.03 grade 2 dyspnea) |
1. Tratamiento sistemático para el GIST metastático. Pacientes que han recibido imatinib durante la adyuvancia son elegibles solo si han recaído tras un mínimode 6 meses desde el fin de tratamiento con imatinib.
2. Otro tipo de cáncer diferente al GIST en los 5 años anteriores al reclutamiento EXCEPTO para el cáncer cervical tratado y curado, carcinoma de piel (no melanoma) y tumores superficiales de vejiga (Ta (tumores no invasivos) y Tis (Carcinoma in situ)).
3. Cirugía mayor, biopsia abierta o herida traumática significativa en los 28 días previos a inicio de la medicación.
4. Grado ? 2 en la escala de Congestive Heart Failure New York Heart Association (NYHA).
5. Angina inestable (síntmoas de angina en reposo, angina e recién diagnostic, ej. En los 3 meses previos a entrar en el studio) o infarto de miocardio (MI) en los últimos 6 meses antes del inicio de la medicación.
6. Arritmias cardíacas que requieran tratamiento anti-arritmias (beta bloqueantes o digoxina están permitidos).
7. Hipertensión descontrolada (presión sistólica > 140 mmHg o presión diastólica > 90mmHg a pesar de control médico).
8. Sujetos con feocromocitoma.
9. Eventos de trombosis arterial o eventos embólicos como accidentes cerebrovasculares (incluyendo ataques isquémicos transitorios) o embolismo pulmonar en los 6 meses previos al inicio del estudio.
10. Eventos tromboembolismo venoso, como trombosis de venas profundas, en los 3 meses anteriores al inicio de estudio.
11. Infección active grado >2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) versión 4.03
12. Historia conocida de infección del virus de la inmunodeficiencia humana (HIV).
13. Sujetos con trastornos convulsivos que requieran tratamiento.
14. Metástasis sintomática en el cerebro o tumores meníngeos.
15. Historia de alotrasplantes.
16. Sujetos con evidencias o historias de predisposición a sangrado. Eventos de hemorragia o sangrado grado 3 o superior del NCI-CTCAE versión 4.03 en las 4 semanas previas al inicio del tratamiento.
17. Herida no curada, úlcera o fractura de hueso.
18. Fallo renal que requiera hemodiálisis o diálisis peritoneal.
19. Deshidratación grado ? 1 del NCI-CTCAE versión 4.03
20. Abuso de sustancias o condiciones médicas, psicológicas o sociales que puedan interferir en la participación del sujeto en el estudio o con la evaluación de los resultados.
21. Hipersensibilidad conocida a la medicación del estudio, a la clase de medicación del estudio o a los excipientes de la formulación.
22. Enfermedad o condición médica inestable que pueda poner en riesgo la seguridad del sujeto y su cumplimiento con el estudio.
23. Enfermedad intersticial pulmonar con signos y síntomas continuos en el momento de la selección.
24. Sujetos incapaces de tragar medicación oral.
25. Proteinuria persistente grado 3 o superior del NCI-CTCAE versión 4.03 (>3.5g/24hrs), medida por el cociente proteína-creatinina en orina en una muestra de orina esporádica.
26. Condición de malabsorción.
27. Fracción de eyección ventricular izquierda (LVEF) < 50% o inferior al límite inferior normal del centro (el que sea superior).
28. Grado 2 o superior de derrame pleural o ascitis que provoque compromiso respiratorio (NCI-CTCAE version 4.03, disnea) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Evaluation of Recist criteria |
| Evaluación por criterios recist |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Imaging assessment will be performed every 8 cycles during study. |
| las evaluaciones radiológicas se realizarán cada 8 semanas durante el estudio. |
|
| E.5.2 | Secondary end point(s) |
-Time that patients remains free of disease progression
-Time that patients remain alive
-Disease evaluation following Choi Criteria (measuring tumor size, lesion density and presence/absence of hypervascular intratumor nodes)
-Evaluation of metabolic response to treatment
-Assessment of adverse events following CTCAE v 4.03 |
- Tiempo que los sujetos permanecen libre de recaída
-Tiempo que los sujetos permanecen vivos
-Evaluación de la enfermedad siguiendo criterios Choi (utilizando el tamaño tumoral, densidad de la lesion y la presencia de nódulos intratumorales hipervasculares)
-Evaluación de la respuesta metabólica al tratamiento
-Evaluación de acontecimientos adversos (CTCAE v 4.03) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Tumor imaging assessment will be performed every 8 weeks
- It will be evaluated at each contact with patient (weekly for the first 8 weeks, and from cycle 3 every 4 weeks during treatment period. At follow up every 12 weeks)
-Tumor imaging assessment will be performed every 8 weeks
-A PET scan will be performed at screening and after 1 month of treatment.
-Adverse events will be evaluated weekly for the first 8 weeks (Cycles 1 and 2) and from cycle 3 they will be evaluated every 4 weeks. |
-Se realizarán evaluaciones radiológicas cada 8 semanas
- Se evaluará semanalmente durante las primeras 8 semanas, y a partir del ciclo 3 cada 4 semanas durante el periodo de tratamiento. En las visitas de seguimiento cada 12 semanas.
-Se realizarán evaluaciones radiológicas cada 8 semanas
-Se realizará un PET en basal y tras 1 mes de tratamiento
-Los acontecimientos adversos se evaluarán semanalmente durante las 8 primeras semanas (Ciclos 1 y 2) y a partir del ciclo 3 se evaluarán cada 4 semanas. |
|
| 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 | No |
| 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 | Yes |
| 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.8.3 |
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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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