| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with platinum refractory/resistant ovarian, fallopian tube or peritoneal carcinoma. |
| Pacientes con carcinoma de ovario, de trompa de Falopio o peritoneal refractario/resistente al platino. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with platinum refractory/resistant ovarian, fallopian tube or peritoneal carcinoma. |
| Pacientes con carcinoma de ovario, de trompa de Falopio o peritoneal refractario/resistente al platino. |
|
| 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 | 15.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase Ib:
-establish the optimum dose for Pazopanib in combination with paclitaxel and carboplatin given weekly in a group of patients with platinum-refractory or -resistant ovarian, fallopian tube or peritoneal carcinoma. In order to achieve this, the study will
determine the maximum tolerated dose (MTD) based on the documentation of the dose limiting toxicity (DLT).
Phase II:
- determine the progression free survival (PFS) according to the RECIST 1.1 of the combination of Pazopanib with weekly paclitaxel and carboplatin in platinumrefractory
or -resistant ovarian, fallopian tube or peritoneal carcinoma. |
Fase Ib:
- establecer la dosis máxima tolerada para pazopanib en combinación con administraciones semanales de paclitaxel y carboplatino en un grupo de pacientes con carcinoma de ovario, de trompa de falopio o peritoneal refractario o resistente al platino. Para ello, se determinará la dosis máxima tolerada en función de la toxicidad limitante de dosis.
Fase II:
- determinar la supervivencia libre de progresión (SLP) en 1 año con arreglo a los criterios RECIST 1.1 de la combinación de pazopanib y la administración semanal de paclitaxel y carboplatino en carcinoma de ovario, de trompa de Falopio o peritoneal refractario o resistente al platino. |
|
| E.2.2 | Secondary objectives of the trial |
Phase Ib:
- evaluate safety and adverse event profiles.
- characterize the Pharmacokinetics (PK) of Pazopanib and chemotherapies using intensive sampling.
- determine if there is PK interaction (and if so, what kind of PK interaction) between Carboplatin and Paclitaxel as well as Pazopanib.
- evaluate the response rate (RR)
- determine and evaluate predictive biomarkers
Phase II:
- evaluate the response rate (RR) and overall survival (OS).
- determine and evaluate predictive biomarkers.
- evaluate safety and adverse event profiles. |
Fase Ib:
- evaluar el perfil de seguridad de la combinación
- determinar los perfiles farmacocinéticos
- determinar la posible interacción en el perfil farmacocinético entre pazopanib y carboplatino y pazopanib y paclitaxel
- evaluar la tase de respuesta
- determinar y evaluar marcadores predictivos
Fase II:
- evaluar tasa de respuesta y supervivencia global
- determinar y evaluar marcadores predictivos
- evaluar el perfil de seguridad de la combinación |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for both phase Ib and II:
- Female subjects more than 18 years of age
- Histologically confirmed diagnosis of ovarian, fallopian tube, or peritoneal carcinoma with recurrent disease.
- All patients with at least one earlier platinum treatment can be included but should be platinum refractory (progression during platinum therapy) or resistant(progression within 6 months after last platinum dose). There is no restriction on the number of prior lines. Non-platinum treatment after proven platinum-resistance/refractory disease is allowed.
- Evaluable (measurable or non-measurable) disease by RECIST version 1.1
- Patient must be able to receive the infusions (paclitaxel, carboplatin) and swallow the tablets (pazopanib)
- WHO Performance status must be <= 2
- LVEF assessed by ultrasound or MUGA scan of the heart > 50%, if clinically indicated.
- Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
- Adequate organ function
- Patients with childbearing potential should have a negative serum pregnancy test and use effective contraceptive methods for the whole duration of the study
- Patients who are lactating should discontinue nursing prior to the first dose.
- Patients must be able and willing to discontinue use of prohibited medications for at least 14 days (28 days for drugs with a longer half-life) of a drug prior to the first dose of study drug and for the duration of the study
- Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations |
- Mujeres mayores de 18 años de edad.
- Diagnóstico histológicamente confirmado de carcinoma de ovario, de trompa de Falopio o peritoneal con recurrencia de la enfermedad.
- Pueden incluirse todas las pacientes con al menos un tratamiento anterior con platino, pero con enfermedad refractaria (progresión dentro de 4 semanas tras la administración del platino) o resistente al platino (progresión dentro de 6 semanas tras la última dosis de platino). No existe ningún límite en la cantidad de líneas de tratamiento anteriores. Se permite tratamiento sin platino después de que se haya probado que la enfermedad es refractaria/resistente al platino.
- Enfermedad evaluable (medible o no medible) según la versión 1.1 de los criterios RECIST.
- Desconocimiento de metástasis cerebrales o leptomeningeas.
- El estado funcional de la OMS debe ser de <= 2
- FEVI evaluada por ultrasonido o exploración MUGA del corazón > 50%, si está clínicamente indicado.
- Función orgánica adecuada (hematológica, hepática, renal).
- Ausencia de comorbilidades significativas (para obtener detalles, consulte el protocolo de estudio).
- Las pacientes con trombosis venosa profunda tratados con anticoagulantes durante al menos 6 semanas son elegibles.
- Las pacientes en edad fértil deben tener un resultado negativo en una prueba de embarazo y utilizar métodos anticonceptivos adecuados durante todo el estudio.
- Consentimiento informado por escrito. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for both phase Ib and II:
- known metastatic disease to the brain or leptomeninges
-other prior malignancies treated primarily or for recurrence within 2 years prior to inclusion in this study, except for completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma of the skin or cervix of the uterus.
- treatment with any of the following anti-cancer therapies:
- Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of study drug.
- Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days (28 days for drugs with a longer half-life) of a drug prior to the first dose of study drug.
- ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia and >Grade 2 peripheral neuropathy.
- known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs similar or related to paclitaxel, carboplatin and pazopanib
- unstable or serious condition e.g. uncontrolled infection requiring systemic therapy
- prior major surgery or trauma within 28 days prior to the first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement and diagnostic endoscopic procedures not considered to be major)
-history of any 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 III or IV congestive heart failure, as defined by the NYHA
- inadequately controlled hypertension (systolic blood pressure (SBP) >=140 mmHg, or diastolic blood pressure (DBP) >=90 mmHg). Initiation or adjustment of blood pressure medication is permitted prior to the study entry.
- prolonged corrected QT interval (QTc) defined as >480 msecs using Bazett?s formula
- history of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
- evidence of active bleeding or bleeding diathesis
- clinically significant gastro-intestinal tract abnormalities that may increase the risk for GI 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, Crohn?s disease), history of bowel obstruction (excluding postoperative (i.e. within 4 weeks post surgery)), or other GI condition with
increased risk of perforation
-clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome, major resection of stomach or small bowel.
- known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
- hemoptysis in excess of 2.5mL (one half tea spoon) within 8 weeks prior to first dose of study drug.
- any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Exclusion criteria for phase II only:
-evidence of progression (refractory disease) on paclitaxel and carboplatin weekly regimen. |
Criterios de exclusión para la fase Ib y II
- Metástasis cerebrales o leptomeningeas
- Historia de neoplasia en los dos años previos a la entrada en el estudio excepto carcinoma de piel completamente resecado (no melanoma) o carcinoma tratado con éxito de piel, cérvix o útero.
- tratamiento con cualquiera de los siguientes tratamientos anticancerosos:
- radiación, cirugía o embolización tumoral en los 14 días previos a la primera dosis del tratamiento del estudio
- quimioterapia, inmunoterapia, terapias biológicas, terapias en investigación o terapia hormonal en los 14 días previos a la primera dosis del tratamiento del estudio
- toxicidad no recuperada de tratamientos previos para el cáncer (> grado 1) o que aumenta en severidad excepto alopecia y neuropatía periférica.
- hipersensibilidad conocida a paclitaxel, carboplatino o pazopanib
- enfermedad no controlada o infección que requiera terapia sistémica
- cirugía mayor en los 28 días previos al inicio del tratamiento
- Historia de las enfermedades cardiovasculares siguientes en los últimos seis meses: angioplastia y colocación de stents, infarto de miocardio, angina inestable, cirugía de revascularización arterial coronaria, enfermedad vascular periférica sintomática, insuficiencia cardiaca congestiva de clase III o IV, según lo define la NYHA.
- Hipertensión no controlada (PAS >= 140 mmHg, or PAD >= 90 mmHg).
- Intervalo QT prolongado (>480 msegs)
- Historia de accidente cerebrovascular incluido accidente isquémico transitorio, embolismo pulmonar o trombosis venosa profunda no tratada en los últimos 6 meses
- Anormalidades del tracto gastrointestinal que puedan incrementar el riesgo de sangrado intestinal o que puedan afectar a la absorción del producto en investigación.
- Lesiones endobronquiales o que infiltren a los vasos pulmonares principales.
- Hemoptisis
- Cualquier condición familiar psicológica, sociológica o geográfica que pueda impedir el cumplimiento del protocolo y el seguimiento del paciente.
Criterios de exclusión para la fase II:
- evidencia de progresión a un régimen semanal de carboplatino y paclitaxel. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib part (dose escalation):
- document the dose limiting toxicity (DLT) within the first 6 weeks (at the end of week 3 and week 6) to identify the MTD for pazopanib and weekly paclitaxel/carboplatin.
Phase II part:
- PFS defined by RECIST 1.1 at 1 year. |
Fase Ib:
- determinar toxicidad limitante de dosis durante las 6 primeras semanas de tratamiento y dosis máxima tolerada de la combinacion
Fase II:
- Supervivencia libre de progresión a 1 año |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: end of week 3 and end of week 6
Phase II: 1 year |
Fase Ib: fin de las semanas 3 y 6
Fase II: 1 año |
|
| E.5.2 | Secondary end point(s) |
Phase Ib part
- PK data of paclitaxel, carboplatin and pazopanib
- Safety and tolerability of the combination, according to CTCAE 4.0
- Response Rate
- Predictive biomarkers
Phase II
- Response Rate
- Overall Survival/ Progression Free Survival
- Safety and tolerability of the combination, according to CTCAE 4.0
- Predictive biomarkers
- Age related subanalysis for toxicity and efficacy (cut-off 65 years) |
Fase Ib:
- datos farmacocinéticos de paclitaxel, carboplatino y pazopanib
- seguridad y tolerabilidad de la combinación (CTCAE 4.0)
- tasa de respuesta
- marcadores predictivos
Fase II:
- tasa de respuesta
- supervivencia global / supervivencia libre de progresión
- seguridad y tolerabilidad de la combinación (CTCAE 4.0)
- marcadores predictivos
- subanálisis de toxicidad y eficacia por grupos de edad (corte: 65 años) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib
PK: day 1 and 22
Safety: weekly during trt; 3 monthly during yrs 1-2 and 6 monthly during years 3-5.
RR: within 3 wks before rando; within 2 wks before tmt course 10; every 3 mths until progr during yrs 1-2 and every 6 mths until progr during years 3-5.
Biomarkers: within 2 weeks before rando
Phase II
RR: see Ib.
OS - within 3 wks before rando; within 2 wks before trt course 10; every 3 mths until progr during yrs 1-2 and every 6 mths until progr during yrs 3-5.
PFS - within 3 wks before rando; within 2 wks before trt course 10; every 3 mths until progr during yrs 1-2 and every 6 mths until progr during years 3-5.
Safety: see Ib. |
Phase Ib:
FC: días 1 y 22
Seguridad: semanal; cada 3 m (años 1 y 2) y cada 6 m (años 3 a 5).
Tasa de respuesta: cada 3 semanas antes de la randomización, en las 2 semanas previas al ciclo 10, cada 3 m hasta progresión.
Marcadores: 2 semanas previas a randomización.
Fase II:
Tasa de respuesta: cada 3 semanas antes de la randomización, cada dos m hasta el ciclo 10, cada 3 m hasta progresión.
SG: cada 3 semanas antes de la randomización, en las 2 semanas previas al ciclo 10, cada 3 m hasta progresión.
SLP: cada 3 semanas antes de la randomización, en las 2 semanas previas al ciclo 10, cada 3 m hasta progresión.
Seguridad: semanal; cada 3 meses (1 y 2) y cada 6 m (años 3 a 5).
Marcadores: en las 2 semanas previas a la randomización. |
|
| 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 | 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) | 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 |
|
| 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 | No |
| 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
| 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 | 3 |
| 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
|
End of trial occurs when all of the following criteria have been satisfied:
1. Thirty 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 |
El final del ensayo ocurre cuando se cumplen los siguientes criterios:
1. 30 días después de que todos los pacientes han terminado el tratamiento del estudio
2. El estudio está maduro para el análisis de objetivo primario
3. La base de datos está limpia y cerrada para el análisis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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