| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally recurrent and/or metastatic triple negative breast cancer |
| Cáncer de mama localizado triple negativo que sea recidivante, metastásico o ambos |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer |
| Cáncer de mama |
|
| 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 | 10006193 |
| E.1.2 | Term | Breast cancer NOS recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To compare progression free survival (PFS) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs subjects treated with placebo in combination with paclitaxel. |
| Comparar la supervivencia libre de progresión (SLP) de los sujetos tratados con tivozanib clorhidrato en combinación con paclitaxel, frente a placebo en combinación con paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
? To assess ORR (objective response rate) and duration of response (DoR) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
? To assess overall survival (OS) of subjects treated with tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
? To evaluate safety and tolerability of tivozanib hydrochloride in combination with paclitaxel vs placebo in combination with paclitaxel.
? To assess the pharmacokinetics (PK) of tivozanib hydrochloride and paclitaxel when administered in combination.
? To evaluate the hypoxia signature as a predictive biomarker of tivozanib hydrochloride response and establish the optimal cut-off to identify biomarker positive and negative subgroups.
? To evaluate Quality of Life (QoL). |
?Evaluar la tasa de respuesta objetiva (TRO) y la duración de la respuesta (DR) de los sujetos tratados con tivozanib clorhidrato en combinación con paclitaxel, frente a placebo en combinación con paclitaxel.
?Evaluar la supervivencia global (SG) de los sujetos tratados con tivozanib clorhidrato en combinación con paclitaxel, frente a placebo en combinación con paclitaxel.
?Evaluar la seguridad y tolerabilidad de tivozanib clorhidrato en combinación con paclitaxel frente a placebo en combinación con paclitaxel.
?Evaluar la farmacocinética (FC) de tivozanib clorhidrato y paclitaxel cuando se administran en combinación.
?Evaluar el motivo distintivo de los genes inducibles por hipoxia como biomarcador pronóstico de la respuesta a tivozanib clorhidrato, y establecer el valor de corte óptimo para identificar subgrupos con positividad y con negatividad al marcador.
?Evaluar la calidad de vida (CdV). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ? 18 year old females
2. Subjects with unresectable locally recurrent or metastatic triple-negative breast cancer (TNBC)
3. Histologically or cytologically confirmed TNBC; Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epithelial Receptor-2 (HER2) negative by IHC. For ER and PR, a score of <1% positive nuclei will be considered negative. A HER2 IHC score of 0 or 1+ is considered negative. A HER2 IHC score of 2+ will be considered negative only if verified by FISH. Local laboratory analysis will be used for eligibility; central laboratory confirmation will be performed retrospectively.
4. Measurable disease per Response Evaluation Criteria in Solid Tumors [RECIST], Version 1.1.
5. ECOG performance status of 0 or 1.
6. A female is eligible to participate if she is of non-childbearing potential or has documentation of a negative pregnancy test within 7 days prior to the start of the study treatment. Sexually active pre-menopausal female subjects must agree to use adequate, highly effective contraceptive measures, while on study and for 30 days after the last dose of last study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable or injectible contraceptive plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm).
7. Confirmed available archival tumor tissue. If more than one biopsy is available, the most recent is preferred.
8. Ability to give written informed consent and comply with protocol requirements, including drug treatments and follow-up procedures. |
| 1.Mujeres ? 18 años.2.CMTN no resecable, localmente recurrente o metastásico.3.CMTN confirmado histológica o citológicamente; negatividad para receptor estrogénico, receptor de la progesterona y receptor 2 del factor de crecimiento epidérmico humano según análisis inmunohistoquímico. 4.Enfermedad mensurable según los criterios de evaluación de la respuesta en tumores sólidos5.Estado funcional de 0 o 1 según la escala del ECOG 6.Una mujer será apta para participar si no tiene posibilidad de quedarse embarazada o se confirma un resultado negativo en un análisis para la detección del embarazo en los 7 días previos al inicio del tratamiento del estudio. Las mujeres premenopáusicas sexualmente activas deben aceptar el uso de métodos anticonceptivos adecuados y altamente eficaces, durante el estudio y en los 30 días posteriores a la última dosis del último fármaco en estudio. 7.Disponibilidad confirmada de tejido tumoral archivado. Si se dispone de tejido procedente de más de una biopsia, se preferirá el más reciente.8.Capacidad para otorgar el consentimiento informado por escrito y cumplir los requisitos del protocolo, incluidos los tratamientos farmacológicos y los procedimientos de seguimiento. |
|
| E.4 | Principal exclusion criteria |
1. Any prior systemic therapy (including chemotherapy, signal transduction inhibitors and monoclonal antibodies, immunotherapy, bevacizumab, any investigational or licensed drug that targets VEGF or VEGF receptors/pathway or are mammalian target of rapamycin [mTOR] inhibitors) for treatment of advanced or mBC.
2. Major surgical procedure within 4 weeks prior to administration of first dose of study drug; radiotherapy or minor surgical procedure within 2 weeks prior to administration of first dose of study drug; inadequate recovery from prior therapy or surgical procedure;
3. Untreated central nervous system metastases
Note: Subjects with previously treated (radiotherapy or surgery) brain metastasis that have been stable off steroids or enzyme-inducing anti-epileptic drugs for at least 3 months following prior treatment may be enrolled.
4. Any of the following hematologic and coagulation abnormalities:
? Hemoglobin < 9.0 g/dL;
? Absolute neutrophil count (ANC) < 1500 per mm3;
? Platelet count < 100,000 per mm3;
5. Any of the following serum chemistry and urinalysis abnormalities:
? Total bilirubin > 1.5 × ULN;
? Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis);
? Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis);
? Creatinine > 2.0 × ULN;
? Proteinuria > 2+ by urinalysis or urine dipstick.
6. Significant cardiovascular disease, including:
? Symptomatic Left Ventricular Dysfunction or Baseline left ventricular ejection fraction (LVEF) by multigated acquisition scan (MUGA) or echocardiogram (ECHO) of <50%;
? Uncontrolled hypertension: systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg documented on 2 consecutive measurements taken at least 24 hours apart;
? Myocardial infarction, or unstable angina within 6 months prior to administration of first dose of study drug;
? History of Class III or IV congestive heart failure, as defined by the New York Heart Association;
? History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation);
? Cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication; and/or
? Coronary or peripheral artery bypass graft within 6 months of screening.
7. Severe peripheral neuropathy, defined as ? Grade 2 (per CTCAE Version 4.0)
8. Non-healing wound, bone fracture, or skin ulcer
9. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug.
10. Serious/active infection or infection requiring parenteral antibiotics
11. Significant arterial or venous thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
? Deep vein thrombosis;
? Pulmonary embolism
? Cerebrovascular accident (CVA) or transient ischemic attack (TIA);
? Peripheral ischemia > Grade 2 (per CTCAE Version 4.0).
12. Significant bleeding disorders within 6 months prior to administration of first dose of study drug, including but not limited to:
? Hematemesis, hematochezia, melena or other gastrointestinal bleeding ? Grade 2 (per CTCAE Version 4.0);
- Hemoptysis or other pulmonary bleeding ? Grade 2 (per CTCAE Version 4.0);
- Hematuria or other genitourinary bleeding ? Grade 2 (per CTCAE Version 4.0).
13. Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers and in situ cervical cancer. Subjects are considered to have a currently active malignancy if they have completed anti-cancer therapy and have not been disease free for > 2 years.
14. Pregnant or lactating females.
15. History of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV); subjects on immune suppressive therapy for organ transplant. Previously known chronic hepatitis B or hepatitis C infection.
16. Life-threatening illness or organ system dysfunction compromising safety evaluation.
17. Inability to swallow pills, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure. Subjects with gastric band (eg LAP-BAND®) will be allowed.
18. Known hypersensitivity to drugs chemically related to paclitaxel or its excipients (eg Cremophor®EL).
19. Psychiatric disorder or altered mental status precluding informed consent or protocol-related testing. |
1.Cualquier tratamiento sistémico previo para tratar el cáncer de mama metastásico (CMm) o recurrente.2.Cirugía mayor en las 4 semanas previas a la administración de la primera dosis del fármaco en estudio, o radioterapia o cirugía menor en las 2 semanas previas; recuperación insuficiente del tratamiento anterior o la intervención quirúrgica.3.Metástasis no tratadas en el sistema nervioso central
4.Cualquiera de las anomalías hematológicas y de coagulación siguientes:
? Hemoglobina < 9,0 g/dl;
? Recuento absoluto de neutrófilos (RAN) < 1500 por mm3;
? Cifra de plaquetas < 100 000 por mm3.
5.Cualquiera de las siguientes anomalías en bioquímica sérica y el análisis de orina:
? Bilirrubina total > 1,5 x LSN;
? Aspartato-aminotransferasa (AST) o alanina-aminotransferasa (ALT) > 2,5 x LSN (o > 5 x LSN en sujetos con metástasis hepática);
? Fosfatasa alcalina > 2,5 x LSN (o > 5 x LSN en sujetos con metástasis hepática u ósea);
? Creatinina > 2,0 x LSN;
? Proteinuria > 2+ según análisis de orina o tira reactiva.
6.Enfermedad cardiovascular significativa, incluida:
? Disfunción ventricular izquierda sintomática o fracción de eyección ventricular izquierda (FEVI) basal según ventriculografía nuclear (MUGA) o ecocardiograma (ECO) < 50 %;
? Hipertensión no controlada: presión arterial sistólica > 140 mm Hg y/o presión arterial diastólica > 90 mm Hg confirmada en 2 determinaciones consecutivas obtenidas con al menos 24 horas de diferencia;
? Infarto de miocardio o angina inestable en los 6 meses previos a la administración de la primera dosis del fármaco en estudio;
? Antecedentes de insuficiencia cardíaca congestiva de clase III o IV, definida según la clasificación de la New York Heart Association;
? Antecedentes de arritmia ventricular grave (es decir, taquicardia ventricular o fibrilación ventricular);
? Arritmias cardíacas que precisen medicamentos antiarrítmicos (salvo fibrilación auricular bien controlada con medicamentos antiarrítmicos); y/o
? Derivación aortocoronaria o vascular periférica en los 6 meses previos a la selección.
7.Neuropatía periférica grave, definida con un Grado ? 2 (según los CTCAE, versión 4.0).
8.Herida tórpida, fractura ósea o úlcera cutánea.
9.Úlcera péptica activa, enfermedad inflamatoria intestinal, colitis ulcerosa u otra afección gastrointestinal con riesgo mayor de perforación; antecedentes de fístula abdominal, perforación gastrointestinal o absceso intraabdominal en las 4 semanas previas a la administración de la primera dosis del fármaco en estudio.
10.Infección grave/activa o infección que precise antibióticos parenterales.
11.Trastornos vasculares o arteriales o venosos tromboembólicos significativos en los 6 meses previos a la administración de la primera dosis del fármaco en estudio, incluidos, entre otros:
? Trombosis venosa profunda;
? Embolia pulmonar;
? Accidente cerebrovascular (ACV) o accidente isquémico transitorio (AIT);
? Isquemia periférica de Grado > 2 (según los CTCAE, versión 4.0).
12.Trastornos hemorrágicos significativos en los 6 meses previos a la administración de la primera dosis del fármaco en estudio, incluidos, entre otros:
? Hematemesis, rectorragia, melena u otras hemorragias gastrointestinales de Grado ? 2 (según los CTCAE, versión 4.0);
? Hemoptisis u otras hemorragias pulmonares de Grado ? 2 (según los CTCAE, versión 4.0);
? Hematuria u otras hemorragias genitourinarias de Grado ? 2 (según los CTCAE, versión 4.0);
13.Segunda neoplasia maligna primaria actualmente activa, incluidas neoplasias malignas hematológicas (leucemia, linfoma, mieloma múltiple, etc.), otros tipos de cáncer de piel no melanoma y cáncer cervicouterino in situ. Se considerará que los sujetos tiene una neoplasia maligna actualmente activa si han completado tratamiento antineoplásico y no se han mantenido libres del cáncer durante > 2 años.
14.Mujeres embarazadas o lactantes.
15.Antecedentes de enfermedad con inmunodepresión genética o adquirida, como infección por el virus de la inmunodeficiencia humana (VIH); sujetos en tratamiento con inmunosupresores por trasplante de algún órgano. Infección crónica diagnosticada previamente por el virus de la hepatitis B o el virus de la hepatitis C.
16.Enfermedad o disfunción orgánica potencialmente mortal que ponga en peligro la evaluación de la seguridad.
17.Imposibilidad de tragar píldoras, síndrome de malabsorción o enfermedad gastrointestinal que afecte intensamente a la absorción de los fármacos en estudio, resección de una parte considerable del estómago o el intestino delgado, o derivación gástrica. Se permitirá la inclusión de sujetos con banda gástrica (por ejemplo, LAP-BAND®) .
18.Hipersensibilidad conocida a fármacos relacionados químicamente con el paclitaxel o sus excipientes (por ejemplo, Cremophor®EL).
19.Trastornos psiquiátricos o estado mental alterado que impida el otorgamiento del consentimiento informado o la realización de las pruebas especificadas en el protocolo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
| Supervivencia libre de progresión (SLP) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS is defined as the time from randomization to progression or death and will be evaluated throughout the duration of the study |
| PFS se define como el tiempo desde la aleatorización hasta la progresión o muerte y se evaluará durante toda la duración del estudio |
|
| E.5.2 | Secondary end point(s) |
| Objective response rate (ORR - the proportion of subjects with a best response of CR or PR) and overall survival (OS) |
| Tasa de respuesta objetiva (TRO - la proporción de sujetos con una mejor respuesta RC o RP) y la supervivencia global (SG). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the duration of the study.
Final OS analysis will take place after all subjects have been lost to follow up or have died, or when 3 years have passed after the last subject was randomized, or when the 103rd OS event has occurred, whichever occurs first. |
Durante toda la duración del estudio
El análisis final de la SG se realizará cuando todos los sujetos sean pérdidas durante el seguimiento o hayan fallecido, o cuando hayan transcurrido 3 años desde la aleatorización del último sujeto, o cuando se haya producido el acontecimiento 103 relativo a la SG, dependiendo de lo que suceda en primer lugar. |
|
| 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) | Yes |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Bahamas |
| Canada |
| Ghana |
| Italy |
| Korea, Democratic People's Republic of |
| Spain |
| Taiwan |
| Thailand |
| Ukraine |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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