E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ER positive, high proliferation breast |
Receptor estrogénico positivo, cancer de mama de alto grado de proliferación |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer |
Cancer de Mama |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10070575 |
E.1.2 | Term | Estrogen receptor positive breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective of the study is to evaluate the progression free survival (PFS) for the triplet combination of ridaforolimus, dalotuzumab and exemestane (R/D/E) compared to the combination of ridaforolimus and exemestane (R/E) in post-menopausal patients with high proliferation, estrogen receptor positive breast cancer that have progressed following treatment with a non-steroidal aromatase inhibitor. |
El objetivo principal del estudio es evaluar la supervivencia sin progresión (SSP) con la combinación triple de ridaforolimus, dalotuzumab y exemestano (R/D/E) en comparación con la de la combinación de ridaforolimus y exemestano (R/E) en pacientes posmenopáusicas con cáncer de mama muy proliferativo positivo para receptores estrogénicos que ha progresado después del tratamiento con un inhibidor de la aromatasa no esteroideo. |
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E.2.2 | Secondary objectives of the trial |
? In post-menopausal patients with high proliferation, estrogen receptor positive breast cancer who have progressed following treatment with a non-steroidal aromatase inhibitor, the secondary objectives of this trial are the following: ?To evaluate the effectiveness of the triplet combination of ridaforolimus, exemestane and dalotuzumab (R/D/E) compared to ridaforolimus and exemestane (R/E) with respect to percent (%) reduction from baseline in the sum of imaging measurements (target lesion line lengths or volumetric images) at 16 weeks. ?To evaluate the objective response rate, as measured by RECIST 1.1 of the triplet combination of R/D/E compared to the combination of R/E. ?To estimate the overall survival for the triplet combination of R/D/E compared to the combination of R/E. |
? En las pacientes posmenopáusicas con cáncer de mama muy proliferativo positivo para receptores de estrógenos que ha progresado después del tratamiento con un inhibidor de la aromatasa no esteroideos, los objetivos secundarios de este ensayo son: ? Evaluar la eficacia de la combinación triple de ridaforolimus, exemestano y dalotuzumab (R/D/E) en comparación con la de ridaforolimus y exemestano (R/E) en forma de la reducción porcentual (%) respecto al valor basal de la suma de las medidas por imagen (diámetros o volúmenes de la lesión diana) a las 16 semanas ? Evaluar la tasa de respuestas objetivas, medida por los criterios RECIST 1.1 y ?RECIST mejorados?, de la combinación triple de R/D/E en comparación con la combinación de R/E. ? Calcular la supervivencia global con la combinación triple de R/D/E comparada con la combinación de R/E. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Metastatic, ER positive, HER2 negative Breast Cancer 2. High Proliferative (as measured by a Ki67 labeling index >15%) 3. Post menopausal 4. Previous treatment with either letrozole or anastrozole 5. AT least 1 measurable lesion 6. At least 18 years of age 7. Greater than or equal to 1 on the ECOG performance status. 8. Life expectance greater than 3 months |
1. Cáncer de mama metastásico, con receptores estrogénicos positivos y receptores HER2 negativos 2. Alto grado de proliferación (medido por el índica de etiquetado Ki67 >15%) 3. Postmenopausicas 4. Tratamiento previo con letrozol o anastrozol. 5. Al menos una lesión medible. 6. Al menos 18 años de edad. 7. Estado funcional del ECOG mayor o igual a 1. 8. Esperanza de vida mayor de 3 meses. |
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E.4 | Principal exclusion criteria |
1. Patient is on other therapy for their cancer (Bisphosphonates and denosumab for the treatment of bone metastases are allowed, if they were initiated at least 28 days prior to randomization.) 2. Patient is in another study or is receiving an experimental agent. 3. Patient has previously received rapamycin or rapamycin analogs, including ridaforolimus, temsirolimus, or everolimus. 4. Patient has received prior treatment with IGF-1R inhibitors, PI3K inhibitors, or other experimental agents that target PI3K, AKT, or mTOR pathway 5. Patient who has had chemotherapy, radiotherapy, or biological therapy within 4 weeks [(6 weeks for nitrosoureas, mitomycin C, or bevacizumab and 2 weeks for hormonal therapy and kinase inhibitors)] prior to entering the study or who has not recovered from adverse events from prior treatment to at least grade 1 or baseline. 6. Patient has active brain metastasis or leptomeningeal carcinomatosis; 7. Patient has poorly controlled Type 1 or 2 diabetes, defined as a hemoglobin A1C greater than 8% or a fasting glucose of > 160 mg/dL. 8. Patient is known to be HIV positive. 9. Patient has a known history of active Hepatitis B or C. Patients who are seropositive for Hepatitis B surface antibody as their only evidence of prior hepatitis exposure are allowed. 10. Patient has a requirement for concurrent treatment with medications that are inducers or inhibitors of cytochrome P450 (CYP3A). Patients should be off these medications for at least 2 weeks prior to the first dose of ridaforolimus. Concomitant medications that are metabolized by CYP3A are allowed (e.g., simvastatin or atorvastatin). See Appendix 6.1 for examples of CYP3A inducers and inhibitors. |
1. La paciente recibe otro tratamiento para su cáncer (Se permite el uso de bisfosfonatos y denosumab para el tratamiento de las metástasis óseas, si se iniciaron al menos 28 días antes de la aleatorización.) 2. La paciente participa en otro estudio o está recibiendo un compuesto experimental 3. La paciente ha recibido anteriormente rapamicina o análogos de rapamicina, incluidos ridaforolimus, temsirolimus o everolimus. 4. La paciente ha recibido tratamiento previo con inhibidores de IGF 1R, inhibidores de PI3K u otros productos en investigación que actúan sobre las vías PI3K, AKT o mTOR. 5. La paciente ha recibido quimioterapia, radioterapia o tratamiento con productos biológicos en las 4 semanas (6 semanas para nitrosoureas, mitomicina C o bevacizumab y 2 semanas para el tratamiento hormonal y los inhibidores de cinasas) previas a la entrada en el estudio, o no se ha recuperado de los acontecimientos adversos causados por el tratamiento previo hasta un grado 1 o hasta el nivel basal como mínimo. 6. La paciente tiene metástasis cerebral activa o carcinomatosis leptomeníngea; 7. La paciente sufre diabetes de tipo 1 ó 2 mal controlada, definida por una hemoglobina A1c superior al 8 % o una glucemia en ayunas >160 mg/dl. 8. Se sabe que la paciente es seropositiva para el VIH. 9. La paciente tiene antecedentes conocidos de hepatitis B o C activa. Se permite la inclusión de las pacientes seropositivas para el anticuerpo de superficie de la hepatitis B como único indicio de exposición previa a la hepatitis. 10. La paciente necesita tratamiento simultáneo con medicamentos que son inductores o inhibidores del citocromo P450 (CYP3A). Las pacientes deben llevar al menos 2 semanas sin recibir estos medicamentos antes de la primera dosis de ridaforolimus. Se permiten los medicamentos concomitantes que son metabolizados por la CYP3A (p. ej., simvastatina o atorvastatina). Véanse en el apéndice 6.1 ejemplos de inductores e inhibidores de la CYP3A. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1.Progression Free Survival according to RECIST 1.1. |
1. Supervivencia Libre de progresión de acuerdo con los criterios RECIST 1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 8 calendar weeks while on treatment |
Cada 8 semanas de calendario durante el tratamiento |
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E.5.2 | Secondary end point(s) |
1. Percent (%) change from baseline in the sum of target lesions by linear CT analysis at 16 weeks. 2. Percent (%) change from baseline in the sum of target lesions by tumor volume analysis at 16 weeks 3. Objective response rate, as measured by RECIST 1.1. 4. Overall survival will be assessed every 3 months |
1. El cambio porcentual (%) respecto al valor basal de la suma de los diámetros de lesiones diana mediante análisis de TC lineal a las 16 semanas. 2. El cambio porcentual (%) respecto al valor basal de la suma de los volúmenes de las lesiones diana a las 16 semanas 3. La tasa de respuestas objetivas, determinada por los RECIST 1.1. 4. La supervivencia global cada 3 meses. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
:16 weeks for endpoints 1 and 2. Every 8 weeks for objective 3 every three months after disease progression. |
16 semanas para la variable 1 y 2. Cada 8 semanas para el objetivo 3 cada tres meses después de progresión de la enfermedad |
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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 | 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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
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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
| 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Brazil |
Canada |
Colombia |
Israel |
Korea, Democratic People's Republic of |
Peru |
Taiwan |
United States |
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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
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LVLS or; SPONSOR has right to terminate the study at any time. Reasons may include: quality or quantity of data recording is inaccurate or incomplete; poor adherence to protocol and regulatory requirements; the incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to patients; plans to modify or discontinue the development of the study drug; or if study drug(s) is approved for marketing and available commercially. See protocol. |
El promotor tiene derecho a dar por terminado el estudio en cualquier momento. Los motivos pueden ser: la calidad o cantidad de los datos registrados es inexacta / incompleta; incumplimiento del protocolo y de los requisitos legales; la incidencia o gravedad de la RA al medicamento que indica un riesgo potencial para la salud; planes de modificar / interrumpir el desarrollo del fármaco del estudio; o si el fármaco del estudio resulta aprobado para su comercialización. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |