| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Locally Advanced Chondrosarcoma |
| Condrosarcoma metastásico o localmente avanzado |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chondrosarcoma is a type of cancer that arises in the cartilage (the tissue that covers the ends of bones in joints). |
|
| 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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008734 |
| E.1.2 | Term | Chondrosarcoma |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- Compare progression-free survival (PFS) in patients with metastatic or locally advanced (unresectable) chondrosarcoma administered IPI-926 or placebo.
- Evaluate the safety of IPI-926 in patients with metastatic or locally advanced(unresectable) chondrosarcoma |
- Comparar la supervivencia sin progresión (SSP) de los pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) a quienes se administra IPI-926 o un placebo.
- Evaluar la seguridad del IPI-926 en pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) |
|
| E.2.2 | Secondary objectives of the trial |
- Compare time to progression (TTP), overall survival (OS), overall response rate (ORR), and response duration in patients with metastatic or locally advanced (unresectable) chondrosarcoma administered IPI-926 or placebo.
- Assess PFS, TTP, OS, and ORR following administration of IPI-926 in the open label portion of the study.
- Examine the pharmacokinetics of IPI 926 and its metabolite IPI-541 |
- Comparar el tiempo hasta la progresión de la enfermedad (TPE), la supervivencia global (SG), la tasa de respuesta global (TRG) y la duración de la respuesta de los pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) a quienes se administra IPI-926 o un placebo.
- Evaluar la SSP, el TPE, la SG y la TRG tras la administración de IPI-926 en la parte del estudio sin enmascaramiento.
- Explorar la farmacocinética del IPI-926 y del metabolito IPI-541. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age at the time of signing informed consent.
2. Pathologically diagnosed conventional chondrosarcoma. (Note: Patients must have tumor sample(s) available or provide tumor samples from a new biopsy for central confirmation of diagnosis. Central pathology review will be completed after randomization. The most recent tumor tissue sample will be used for diagnosis.)
3. Metastasis to at least 1 location or locally advanced disease that is deemed unresectable by a surgeon.
4. At least 1 radiologically measurable target lesion per RECIST 1.1. If the lesion has received prior radiotherapy, then progression of the lesion (defined as radiographic growth of the lesion by at least 20%) must have occurred since the completion of radiation.
5. Patients must have documented radiographic progression of disease within the 6-month period prior to screening.
6. Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1.
7. Life expectancy of at least 3 months.
8. Recovery to less than or equal to Grade 1 or baseline of any toxicities due to prior systemic treatments, excluding alopecia.
9. All women of child-bearing potential (WCBP), all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study and for 30 days after the last dose of study drug. Women of child-bearing potential (defined as being less than 1 year post-menopausal) must have a negative serum or urine beta human chorionic gonadotropin (beta hCG) pregnancy test. Adequate methods of contraception include use of oral contraceptives with an additional barrier method, double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera, partner vasectomy, and total abstinence.
10. Ability to adhere to the study visit schedule and all protocol requirements.
11. Voluntarily signed an informed consent form. |
1. Edad más o igual a 18 años en el momento de firmar el consentimiento informado.
2. Condrosarcoma típico diagnosticado mediante análisis anatomopatológico. (Nota: deben existir muestras del tumor disponibles o de lo contrario habrá que realizarle al paciente una nueva biopsia para corroborar el diagnóstico desde el servicio centralizado. El examen anatomopatológico central se realizará después de la aleatorización y se utilizará la muestra de tejido tumoral más reciente).
3. Metástasis al menos a 1 ubicación o avance local del tumor que el cirujano considere irresecable.
4. Al menos 1 lesión diana mensurable por radiología según los criterios RECIST 1.1. Si se ha administrado radioterapia a la lesión, ésta debe haber progresado (entendiéndose que ha crecido al menos un 20%) desde el final de la radioterapia.
5. Documentación radiográfica de la progresión de la enfermedad en los 6 meses anteriores a la selección. Atención: La progresión radiográfica de la enfermedad se fundamentará como mínimo en dos exploraciones (RMN o TAC), realizadas en los 6 meses anteriores al período de selección o durante el mismo, en las cuales se observe la progresión de la enfermedad con arreglo a la definición de los RECIST. La segunda exploración puede tomarse como la basal. No es necesario remitir las exploraciones (TAC o RMN) a revisión centralizada para seleccionar a los pacientes, aunque sí se hará
después de la aleatorización.
6. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 ó 1.
7. Esperanza de vida de al menos 3 meses.
8. Recuperación a grado menos o igual a 1 o al grado basal de todos los efectos tóxicos secundarios a los tratamientos sistémicos, sin contar la alopecia.
9. En el caso de las mujeres en edad fértil (MEF), de los varones sexualmente activos y de la pareja de todos los pacientes, compromiso de utilizar métodos anticonceptivos válidos durante todo el estudio y hasta transcurridos 30 días de la última dosis del fármaco del estudio. Las mujeres en edad fértil (definidas como aquéllas que hayan alcanzado la madurez sexual y no se hayan sometido a esterilización quirúrgica ni lleven al menos 24 meses consecutivos desde la menopausia si tienen 55 años o 12 meses consecutivos si tienen > 55) deben dar negativo a la prueba del embarazo por gonadotropina coriónica humana beta; (beta hCG) en suero o en orina. Se aceptarán como válidos los anticonceptivos orales junto con un método de barrera adicional, los métodos de doble barrera (diafragma con gel espermicida o preservativo con espuma anticonceptiva), Depo-Progevera®, la vasectomía de la pareja y la abstinencia sexual absoluta.
10. Capacidad de cumplir el calendario de visitas del estudio y todos los requisitos del protocolo.
11. Firma voluntaria del documento de consentimiento informado. |
|
| E.4 | Principal exclusion criteria |
1. Other invasive malignancies diagnose within the last 5 years, except non melanoma skin cancer and localized cured prostate and cervical cancer.
2. Systemic anti-cancer therapy within 21 days prior to the first dose of study drug, or radiotherapy within 14 days prior to the first dose of study drug.
3. Prior treatment with a Hedgehog pathway inhibitor.
4. Medically significant surgical procedures or significant traumatic injury within 28 days before Day 1.
5. Inadequate hematologic function defined by:
? Absolute neutrophil count (ANC) <1,000 cells/mm3 (1.0 x 109/L).
- Hemoglobin <8.0 g/dL (80 g/L) (may be increased to this level with transfusion as long as there is no evidence of active bleeding).
6. Inadequate hepatic function defined by:
- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN).
- Total bilirubin >1.5 x ULN (with the exception of patients with Gilbert's disease).
- Cirrhotic liver disease, ongoing alcohol abuse, or known chronic active or acute hepatitis.
7. Inadequate renal function defined by serum creatinine >1.5 x ULN.
8. Patients with a history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the last 6 months.
9. Presence of active infection or systemic use of antibiotics within 72 hours of treatment.
10. Significant co-morbid condition or disease, which in the judgment of the Investigator, would place the patient at undue risk or interfere with the study. Examples include, but are not limited to sepsis and recent significant traumatic injury.
11. Known human immunodeficiency virus (HIV) positivity.
12. Known hypersensitivity to IPI-926, or any of the excipients in IPI-926 or placebo capsules.
13. Pregnant or lactating women. |
1. Antecedentes de otra neoplasia invasora diagnosticada en los últimos 5 años, a excepción del cáncer de piel distinto del melanoma y el cáncer localizado y curado de próstata o de cuello uterino.
2. Tratamiento antineoplásico sistémico en los 21 días antes de la primera dosis del fármaco del estudio o radioterapia en los 14 días antes de la primera dosis del fármaco del estudio.
3. Tratamiento anterior con un inhibidor de la vía de hedgehog.
4. Intervención quirúrgica de relevancia médica o traumatismo
importante en los 28 días antes del día 1.
5. Insuficiencia hematológica, definida como:
- Cifra absoluta de neutrófilos (CAN) < 1.000 células /mm3 (1,0 × 109/l).
- Hemoglobina < 8,0 g/dl (80 g/l) (puede administrarse transfusión para que la concentración suba a dicho nivel si no se observa hemorragia activa).
6. Insuficiencia hepática, definida como:
- Aspartato-aminotransferasa (AST) y/o alanina-aminotransferasa (ALT) > 2,5 × límite superior de la normalidad (LSN).
- Bilirrubina total > 1,5 × LSN (salvo en pacientes con enfermedad de Gilbert).
- Cirrosis hepática, alcoholismo actual o hepatitis crónica activa o aguda.
7. Insuficiencia renal, definida como una creatinina sérica > 1,5 × LSN.
8. Antecedentes de ictus, angina inestable, infarto de miocardio o arritmia ventricular que hayan requerido medicación o control mecánico en los últimos 6 meses.
9. Infección activa actual o antibioticoterapia sistémica en las 72 horas antes del tratamiento.
10. Cualquier comorbilidad significativa que, a juicio del investigador, comporte para el paciente un riesgo indebido o vaya a interferir con el estudio. Como ejemplos se citan a título meramente indicativo la septicemia y los traumatismos importantes recientes.
11. Infección por el virus de la inmunodeficiencia humana (VIH).
12. Hipersensibilidad al IPI-926 o a cualquiera de los excipientes de las cápsulas de IPI-926 o del placebo.
13. Embarazo o lactancia materna en el caso de las mujeres. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- PFS, defined as time from randomizationto disease progression or death, following administration of IPI-926 or placebo in patients with metastatic or locally advanced (unresectable) chondrosarcoma.
- Incidence of reported adverse events and abnormal laboratory test results. |
- SSP, definida como el tiempo transcurrido desde la aleatorización hasta la progresión de la enfermedad o la muerte, tras la administración de IPI-926 o placebo a pacientes con condrosarcomas
metastásicos o localmente avanzados (irresecables)
- Incidencia de acontecimientos adversos referidos y alteraciones analíticas. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor imaging is conducted every 4 weeks for 8 weeks, then every 8 weeks for 12 weeks, then every 12 weeks until tumor progression. Survival is evaluated continuously throughout the study. |
|
| E.5.2 | Secondary end point(s) |
- TTP, defined as time from randomization to disease progression, in patients with metastatic or locally advanced (unresectable) chondrosarcoma administered IPI-926 or placebo.
- OS, defined as time from randomization to death, in patients with metastatic or locally advanced (unresectable) chondrosarcoma administered IPI-926 or placebo.
- ORR, defined as an overall response of either partial response (PR) or complete response (CR) occurring at any point post-treatment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, in patients with metastatic or locally advanced (unresectable) chondrosarcoma administered IPI 926 or placebo.
- PFS, TTP, OS, and ORR following administration of IPI-926 in the open label portion of the study.
- Plasma concentrations of IPI 926 and its metabolite IPI 541. |
- TPE, definido como el tiempo transcurrido desde la aleatorización hasta la progresión de la enfermedad, en pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) a quienes se administra IPI-926 o un placebo.
- SG, definida como el tiempo transcurrido desde la aleatorización hasta la muerte, en pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) a quienes se administra IPI-926 o un placebo.
- TRG, definida como una respuesta global de respuesta parcial (RP) o de respuesta completa (RC) en cualquier momento posterior al tratamiento según la versión 1.1 de los «Criterios de evaluación de la respuesta de tumores sólidos» (RECIST) en pacientes con condrosarcomas metastásicos o localmente avanzados (irresecables) a quienes se administra IPI-926 o un placebo.
- SSP, TPE, SG y TRG tras la administración de IPI-926 en la parte del estudio sin enmascaramiento.
- Concentraciones plasmáticas del IPI-926 y del metabolito IPI-541. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Tumor imaging related 2ry endpoints (time to progression (TTP), overall response rate (ORR), and response duration) will be evaluated every 4 weeks for 8 weeks, then every 8 weeks for 12 weeks, then every 12 weeks until tumor progression. Overall survival is evaluated continuously (after study discontinuation then approximately every 3 months for up to 2 years followed by contact at 3 years to collect survival data). Pharmacokinetics are evaluated pre-dose on Day 1 of Cycles 1, 2, and 3, and on Day 1 of every third cycle thereafter. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Australia |
| Canada |
| 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
|
| Last visit of the last subject |
| Ultima visita del ultimo sujeto |
|
| 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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