| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with unresectable, locally advanced or metastatic solitary fibrous tumor (SFT) or extraskeletal myxoid chondrosarcoma (EMC) |
| Pacientes con tumor fibroso solitario (TFS) o condrosarcoma mixoide extraesquelético (CME) irresecables, localmente avanzados o metastáticos |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with solitary fibrous tumor (SFT) or extraskeletal myxoid chondrosarcoma (EMC) that cannot be removed with surgery, locally advanced or having metastasis |
| Pacientes con tumor fibroso solitario (TFS) o condrosarcoma mixoide extraesquelético (CME) que no se pueden extirpar con cirugía, localmente avanzados o que tienen metástasis |
|
| 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 |
| To determine the objective response rate (ORR) (confirmed complete response [CR] and partial response [PR]) in patients with unresectable, locally advanced or metastatic solitary fibrous tumor and extraskeletal myxoid chondrosarcoma, using Choi and RECIST 1.1 criteria respectively. |
| Determinar la tasa de respuesta objetiva (TRO) (respuesta completa [RC] y respuesta parcial [RP] confirmadas) en pacientes con tumor fibroso solitario y condrosarcoma mixoide extraesquelético irresecables, localmente avanzados o metastáticos, usando criterios Choi y RECIST 1.1 respectivamente. |
|
| E.2.2 | Secondary objectives of the trial |
To estimate the efficacy of pazopanib as measured by the progression-free survival (PFS) rate assessed by median time in patients with unresectable, locally advanced or metastatic solitary fibrous tumor and extraskeletal myxoid chondrosarcoma.
To evaluate overall survival (OS).
To evaluate clinical benefit rate (CBR).
To evaluate long term safety profile according to CTCAE 4.0. |
Estimar la eficacia de pazopanib medida como la tasa de supervivencia libre de progresión (SLP) evaluada como tiempo medio en pacientes con tumor fibroso solitario y condrosarcoma mixoide extraesquelético irresecables, localmente avanzados o metastáticos.
Evaluar la supervivencia global (SG).
Evaluar la tasa de beneficio clínico (TBC).
Evaluar el perfil de seguridad a largo plazo según CTCAE 4.0. |
|
| 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 sub-study
SFT cohort:
To perform a central pathologic review (diagnosis confirmation) of paraffin-embedded tumor blocks for each recruited patient with SFT, including (exploratory) STAT6 immunohistochemistry.
To evaluate the serum profile of serum cytokine markers as indicator of response to pazopanib. The Luminex technology will be employed for the analysis of 12 cytokines [VEGF-A, PlGF-1, SDF-1 alpha (CXCL12), TNF alpha, IL-8, IL-6, PDGF?beta, HGF, E-Selectine, ICAM1, MMP-9 and FGFb].
To evaluate the profile of angiogenic markers in the primary tumor. Microvessel density (MVD) and VEGF/PDGF pathways will be evaluated by IHQ expression as well as their correlation with prognosis and their role as predictive factors to treatment with pazopanib (response, PFS and OS).
To evaluate pharmacodynamic markers (MVD, VEGF/PDGF) only in patients with paired samples (in the biopsies taken after treatment).
EMC cohort:
To perform a central pathologic review (diagnosis confirmation) of paraffin-embedded tumor blocks for each recruited patient with EMC, including FISH analysis and/or RT-PCR NR4A3 and its partners (EWSR1, TAF15).
To evaluate the expression and activation profile of angiogenic targets (VEGFR, PDGFR, RET, MCSR1) in the primary tumor by immunohistochemistry, pRTK array and IP/WB respectively. |
Subestudio traslacional
Cohorte TFS:
Realizar una revisión patológica central (confirmación de diagnóstico) de bloques de tumor en parafina para cada paciente incluido con TFS, incluyendo inmunohistoquímica STAT6 exploratoria.
Evaluar el perfil de suero de marcadores de citoquinas en suero como indicador de respuesta de pazopanib. Se usará tecnología Luminex para el análisis de 12 citoquinas [VEGF-A, PlGF-1, SDF-1 alpha (CXCL12), TNF alpha, IL-8, IL-6, PDGF?beta, HGF, E-Selectine, ICAM1, MMP-9 and FGFb].
Evaluar el perfil de marcadores angiogénicos en el tumor primario. Se evaluará densidad de microvasos (MVD) y vías VEGF/PDGF mediante expresión IHC además de su correlación con prognosis y su papel como factores predictivos al tratamiento con pazopanib (respuesta, SLP y SG).
Evaluar marcadores farmacodinámicos (MVD, VEGF/PDGF) solo en pacientes con muestras pareadas (en las biopsias tomadas después del tratamiento).
Cohorte CME:
Realizar una revisión patológica central (confirmación de diagnóstico) de bloques de tumor en parafina para cada paciente incluido con CME, incluyendo análisis FISH y/o RT-PCR NR4A3 y sus partners (EWSR1, TAF15).
Evaluar el perfil de expresión y activación de dianas angiogénicas (VEGFR, PDGFR, RET, MCSR1) en el tumor primario por inmunohistoquímica, array pRTK e IP/WB respectivamente. |
|
| E.3 | Principal inclusion criteria |
1. Patients must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient?s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
2. Age ? 18 years or legal age of consent if greater than 18 years.
3. Histologic diagnosis of solitary fibrous tumor (stratum 1) or extraskeletal myxoid chondrosarcoma (stratum 2) (unresectable, locally advanced or metastatic disease) confirmed by central pathology review. Paraffin-embedded tumor tissue must be provided for all subjects for biomarker analysis before and (when feasible) after treatment with investigational product.
4. Patients with metastatic tumor suitable for complete resection can be recruited. In absence of progressive disease these patients should be treated with the study drug for at least 6 months.
5. For patients who have received previous anticancer treatments, progressive disease must be demonstrated within 6 months prior to enrollment.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Measurable disease according to Choi (SFT) and RECIST 1.1 (EMC) criteria. Patients must have at least one measurable lesion (not in a previously irradiated area). If the only measurable disease is in a previously irradiated area, documented progression should exist after radiotherapy within the 6 months prior to enrollment.
8. Patients could have received a maximum of 4 lines of chemotherapy for metastatic disease prior to trial enrollment.
9. Patients must be able to swallow and retain the study drug. |
1. Los pacientes deben proporcionar consentimiento informado escrito antes de realizar cualquier procedimiento o evaluación específica del estudio y deben estar dispuestos a cumplir el tratamiento y el seguimiento. El consentimiento informado debe obtenerse antes de iniciar el proceso de selección. Los procedimientos efectuados como parte de la rutina clínica del paciente (ej: análisis de sangre, pruebas de imagen, etc.) y obtenidos antes de la firma del consentimiento informado pueden usarse para fines de selección o de la etapa basal siempre y cuando estos procedimientos se hayan hecho como se especifica en el protocolo.
2. Edad ? 18 años o edad legal de consentimiento si es mayor a 18 años.
3. Diagnóstico histológico de tumor fibroso solitario (cohorte 1) o condrosarcoma mixoide extraesquelético (cohorte 2) (enfermedad irresecable, localmente avanzada o metastática) confirmado por revisión patológica central. Todos los pacientes deben proporcionar tejido de tumor en parafina para el análisis de biomarcadores antes y (cuando se pueda) después del tratamiento con el producto en investigación.
4. Los pacientes con tumor metastático adecuado para resección completa pueden ser reclutados. En ausencia de enfermedad en progresión estos pacientes deberían ser tratados con el medicamento del estudio por al menos 6 meses.
5. Para pacientes que han recibido tratamientos antineoplásicos previos, la enfermedad en progresión debe ser demostrada en un plazo de 6 meses antes del reclutamiento.
6. Estado Eastern Cooperative Oncology Group (ECOG) de 0-2.
7. Enfermedad medible según criterios Choi (TFS) y RECIST 1.1 (CME). Los pacientes deben tener al menos una lesión medible (no en un área que hay sido previamente irradiada). Si la única enfermedad medible está en un área irradiada previamente, debería existir una progresión documentada después de la radioterapia en los 6 meses previos al reclutamiento.
8. Los pacientes podrían haber recibido un máximo de 4 líneas de quimioterapia para enfermedad metastática antes de ser reclutados en el ensayo.
9. Los pacientes deben ser capaces de tragar y retener la medicación del estudio. |
|
| E.4 | Principal exclusion criteria |
1. Prior malignancy, except patients who have had another malignancy and have been disease-free for 10 years, or those with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma.
2. Central nervous system metastases at baseline, with the exception of patients who have previously-treated central nervous system metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants in prior 6-month time interval.
3. Patients who have received previous antiangiogenic agents.
4. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
? Active peptic ulcer disease
? Known intraluminal metastatic lesion(s) with risk of bleeding
? Inflammatory bowel disease (e.g. ulcerative colitis, Chrohn?s disease), or other gastrointestinal conditions with increased risk of perforation
? History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment
5. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
? Malabsorption syndrome
? Major resection of the stomach or small bowel
6. Corrected QT interval (QTc) > 480 msecs.
7. History of any one or more of the following cardiovascular conditions within the past 6 months:
? Cardiac angioplasty or stenting
? Myocardial infarction
? Unstable angina
? Coronary artery bypass graft surgery
? Symptomatic peripheral vascular disease
? Class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) |
1. Neoplasia maligna previa, excepto pacientes que hayan tenido otra malignidad y hayan estado libres de enfermedad por 10 años, o aquellos que presentan historia de tumor cutáneo no melanomatoso completamente extirpado o de carcinoma in situ correctamente tratado.
2. Metástasis a nivel de sistema nervioso central en el screening, excepto aquellos pacientes que han tenido metástasis a nivel de sistema nervioso central tratada previamente (cirugía ± radioterapia, radiocirugía, o gamma knife) y que cumplen estos dos criterios: a) se encuentran asintomáticos y b) no han requerido tratamiento con corticoides o anticomiciales en los 6 meses previos.
3. Pacientes que hayan recibido agentes antiangiogénicos previos.
4. Alteraciones gastrointenstinales clínicamente significativas que pueden aumentar el riesgo de sangrado digestivo incluyendo, aunque no limitado a:
? Enfermedad ulcerosa péptica activa.
? Lesiones metastáticas intraluminales con riesgo de sangrado.
? Enfermedad inflamatoria intestinal (como enfermedad de Crohn, colitis ulcerosa?) u otras patologías digestivas que aumenten el riesgo de perforación.
? Historia de fistula abdominal, perforación gastrointestinal o absceso intraabdominal durante los 28 días previos al inicio del tratamiento.
5. Alteraciones gastrointestinales que pueden afectar la absorción del fármaco incluyendo pero no limitado a:
? Síndrome malabsortivo.
? Resección amplia gástrica o de intestino delgado.
6. Intervalo QT corregido (QTc) > 480 msecs.
7. Historia de cualquiera de las siguientes enfermedades cardiovasculares en los últimos 6 meses:
? Angioplastia cardiaca o colocación de stent.
? Infarto de miocardio.
? Angina inestable.
? Cirugía de bypass coronario.
? Enfermedad vascular periférica sintomática.
? Insuficiencia cardiaca congestiva clase II, III o IV definida por la New York Heart Association (NYHA) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR) (confirmed complete response [CR] and partial response [PR]), measured using Choi and RECIST 1.1 criteria. Response criteria will be based on the baseline identification of target lesions and follow-up until tumor progression. |
| Tasa de respuesta objetiva (TRO) (respuesta completa [RC] y respuesta parcial [RP] confirmadas), medidas usando criterios Choi y RECIST 1.1. Los criterios de respuesta se basarán en la identificación basal de lesiones diana y seguimiento hasta progresión del tumor. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and until disease progression. |
| Basal y hasta progresión de enfermedad. |
|
| E.5.2 | Secondary end point(s) |
Efficacy measured by the progression-free survival (PFS) rate assessed by median time.
Overall survival (OS) measured since treatment start date until date of death, whichever the cause.
Clinical benefit rate (CBR). Patients who have reached CR, PR or SD during 6 months or more, presenting clinical improvement of symptoms, will be considered as having experienced clinical benefit.
Long term safety profile of pazopanib, 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 NCI-CTCAE 4.0. |
Eficacia medida como tasa de supervivencia libre de progresión (SLP) evaluada por tiempo medio.
Supervivencia global (SG) medida desde la fecha de inicio de tratamiento hasta la muerte, cualquiera que sea la causa.
Tasa de beneficio clínico (TBC). Los pacientes que hayan alcanzado RC, RP o EE durante 6 meses o más, presentando mejora clínica de síntomas, serán considerados como que han experimentado beneficio clínico.
Perfil de seguridad de pazopanib a largo plazo, mediante evaluación de acontecimientos adversos (tipo, incidencia, severidad, tiempo de aparición, causas relacionadas) además de exploraciones físicas y pruebas de laboratorio. La toxicidad se clasificará en grados y será tabulada usando NCI-CTCAE 4.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival (PFS) rate assessed by median time.
Overall survival (OS) measured since treatment start date until date of death.
Patients who have reached CR, PR or SD during 6 months or more, presenting clinical improvement of symptoms, will be considered as having experienced clinical benefit.
Long term safety profile of pazopanib, 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 NCI-CTCAE 4.0. |
Tasa de supervivencia libre de progresión (SLP) evaluada por tiempo medio.
Supervivencia global (SG) medida desde la fecha de inicio de tratamiento hasta la muerte.
Los pacientes que hayan alcanzado RC, RP o EE durante 6 meses o más, presentando mejora clínica de síntomas, serán considerados como que han experimentado beneficio clínico.
Perfil de seguridad de pazopanib a largo plazo, mediante evaluación de acontecimientos adversos (tipo, incidencia, severidad, tiempo de aparición, causas relacionadas) además de exploraciones físicas y pruebas de laboratorio. La toxicidad se clasificará en grados y será tabulada usando NCI-CTCAE 4.0. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Translational (biomarker study) |
| Traslacional (estudio de biomarcadores) |
|
| 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 | 8 |
| 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
|
| The study will be considered closed from a normative point of view after data on primary and secondary variables are sufficiently prepared for its initial publication. |
| El estudio se considerará cerrado desde un punto de vista normativo después de que los datos relacionados con las variables principales y secundarias estén lo suficientemente preparados para publicación inicial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
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