E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with recurrent Glioblastoma |
Pacientes con glioblastoma recidivante |
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E.1.1.1 | Medical condition in easily understood language |
Specific type of brain tumor called glioblastoma |
Tipo específico de tumor cerebral llamado glioblastoma |
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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 | PT |
E.1.2 | Classification code | 10018336 |
E.1.2 | Term | Glioblastoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 | 10006153 |
E.1.2 | Term | Brain tumor |
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 |
? To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by investigator-assessed progression-free survival (PFS) ? To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by investigator-assessed PFS in the subgroup of patients with Met-positive (Met+) glioblastoma |
? Evaluar la eficacia de onartuzumab + bevacizumab en comparación con placebo + bevacizumab determinada mediante la supervivencia sin progresión (SSP) evaluada por el investigador. ? Evaluar la eficacia de onartuzumab + bevacizumab en comparación con placebo + bevacizumab determinada mediante la SSP evaluada por el investigador en el subgrupo de pacientes con glioblastoma Met-positivo (Met+). |
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E.2.2 | Secondary objectives of the trial |
? To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by overall survival (OS) rate at 9 months (OS-9) and OS overall, in all patients and in those with Met+ glioblastoma ? To evaluate the efficacy of onartuzumab + bevacizumab relative to placebo + bevacizumab as measured by PFS rate at 6-months (PFS-6), objective response rate (ORR), and duration of response (DOR) in all patients and in those with Met+ tumors ? To evaluate the efficacy of onartuzumab + placebo as measured by PFS-6, PFS, ORR, and DOR in all patients and the subgroup of patients with Met+ tumors |
? Evaluar la eficacia de onartuzumab + bevacizumab en comparación con placebo + bevacizumab determinada mediante la supervivencia global (SG) a los 9 meses (SG-9) y la SG global, en todos los pacientes y en aquellos con glioblastoma Met+. ? Evaluar la eficacia de onartuzumab + bevacizumab en comparación con placebo + bevacizumab determinada mediante la SSP a los 6 meses (SSP-6), la tasa de respuesta objetiva (TRO) y la duración de la respuesta (DR) en todos los pacientes y en aquellos con tumores Met+. ? Evaluar la eficacia de onartuzumab + placebo determinada mediante la SSP-6, SSP, TRO y DR en todos los pacientes y en el subgrupo de pacientes con tumores Met+. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically confirmed glioblastoma at first recurrence after concurrent or adjuvant chemoradiotherapy A local pathology report constitutes adequate documentation of histology for study inclusion. Patients with an initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy was determined to be glioblastoma. 2. Imaging confirmation of first tumor progression or regrowth as defined by the RANO criteria A minimum of 12 weeks must have elapsed from the completion of radiotherapy to randomization to minimize the potential for magnetic resonance imaging (MRI) changes related to radiation necrosis that might be misdiagnosed as progression of disease, unless there is a new lesion outside the radiation field or unequivocal evidence of viable tumor on histopathological sampling. 3. Prior treatment with TMZ 4. No more than one prior line of chemotherapy Concurrent and adjuvant TMZ-based chemotherapy, including the combination of TMZ with an investigational agent, is considered one line of chemotherapy. 5. No prior treatment with bevacizumab or other VEGF- or VEGF-receptor-targeted agent 6. No prior exposure to experimental treatment targeting either the HGF or Met pathway 7. Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field 8. No prior treatment with prolifeprospan 20 with carmustine wafer 9. No prior intracerebral agent Recovery from the toxic effects of prior therapy, with a minimum time of: a) ? 28 days elasped from the administration of any investigational agent b) ? 28 days elapsed from the administration of any prior cytotoxic agents, except ? 14 days from vincristine, ? 21 days from procarbazine, and ? 42 days from nitrosureas c) ? 7 days elapsed from administration of any non-cytotoxic agent (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid) 11. Patients who have undergone recent surgery for recurrent or progressive tumor are eligible provided that: a) Surgery must have confirmed the recurrence. b) A minimum of 28 days must have elapsed from the day of surgery to randomization. For core or needle biopsy, a minimum of 7 days must have elapsed prior to randomization. c) Craniotomy or intracranial biopsy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization. 12. No evidence of recent hemorrhage on baseline MRI of the brain However, patients with clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes related to surgery, or presence of punctuate hemorrhage in the tumor are eligible. 13. No need for urgent palliative intervention for primary disease (e.g., impending herniation) 14. Availability of formalin-fixed paraffin-embedded tumor tissue representative of glioblastoma 15. Willingness and ability to provide written informed consent and to comply with the study protocol as judged by the investigator 16. Age ? 18 years 17. Karnofsky performance status ? 70% 18. Stable or decreasing dose of corticosteroids within 5 days prior to randomization 19. For women who are not postmenopausal (i.e., < 2 years after last menstruation) or surgically sterile (absence of ovaries and/or uterus) and who are sexually active: agreement to use an adequate method of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly) during the treatment period and for at least 6 months after the last dose of study drug 20. For male patients who are partners of premenopausal women: agreement to use a barrier method of contraception during the treatment period and for at least 6 months after the last dose of study drug |
1. Glioblastoma confirmado histológicamente en primera recidiva tras haber administrado quimio-radioterapia simultánea o adyuvante. 2. Confirmación por imagen de primera progresión del tumor o recrecimiento según se define en los criterios RANO. 3. Tratamiento previo con TMZ. 4. No más de una línea previa de quimioterapia. 5. Ausencia de tratamiento previo con bevacizumab u otro fármaco dirigido contra el VEGF o el receptor del VEGF. 6. Ausencia de exposición previa a un tratamiento experimental dirigido contra la vía de HGF o Met. 7. Se permitirá el tratamiento previo con bisturí de rayos gamma u otra radioterapia focal en dosis altas, pero el paciente deberá contar con una confirmación histológica posterior de la recidiva, a menos que se trate de una lesión nueva localizada fuera del campo irradiado. 8. Ausencia de tratamiento previo con obleas de prolifeprospan 20 con carmustina. 9. Ausencia de tratamiento intracerebral previo. 10. Recuperación de los efectos tóxicos del tratamiento previo, con un tiempo mínimo de: a) ? 28 días transcurridos desde la administración de cualquier fármaco en investigación. b) ? 28 días transcurridos desde la administración de cualquier fármaco citotóxico previo, con las excepciones siguientes: ? 14 días con vincristina, ? 21 días con procarbacina y ? 42 días con nitrosoureas. c) ? 7 días transcurridos desde la administración de cualquier fármaco no citotóxico (por ejemplo, interferón, tamoxifeno, talidomida o ácido cisretinoico). 11. Los pacientes que se hayan sometido a cirugía reciente en relación con el tumor recidivante o progresivo podrán participar siempre que: a) La cirugía haya confirmado la recidiva. b) Haya transcurrido un mínimo de 28 días entre el día de la intervención y la aleatorización. En caso de biopsia con trócar o aguja, tendrá que haber transcurrido un mínimo de 7 días antes de la aleatorización. c) Que el lugar de la craneotomía o biopsia intracraneal haya cicatrizado de manera adecuada, esté exento de secreción o celulitis y la craneoplastia subyacente parezca intacta en el momento de la aleatorización. 12. Ausencia de signos de hemorragia reciente en la RM basal del cerebro. 13. Ausencia de necesidad de una intervención paliativa urgente relacionada con la enfermedad primaria (por ejemplo, hernia inminente). 14. Disponibilidad de tejido tumoral fijado con formol e incluido en parafina representativo de glioblastoma. 15. Disposición y capacidad para otorgar el consentimiento informado por escrito y de cumplir el protocolo del estudio según el criterio del investigador. 16. Edad ? 18 años. 17. Estado funcional de Karnofsky ? 70 %. 18. Dosis estable o decreciente de esteroides en los 5 días anteriores a la aleatorización. 19. En las mujeres que no sean posmenopáusicas (es decir, < 2 años después de la última menstruación) o no hayan sido esterilizadas por métodos quirúrgicos (ausencia de los ovarios o el útero) y que sean sexualmente activas: compromiso de utilizar un método anticonceptivo adecuado (anticonceptivos orales, dispositivo intrauterino, método de barrera junto con gel espermicida) durante el período de tratamiento y durante al menos 6 meses después de la última dosis del fármaco del estudio. 20. En los pacientes varones que sean parejas de mujeres premenopáusicas: compromiso de utilizar un método anticonceptivo de barrera durante el período de tratamiento y durante al menos 6 meses después de la última dosis del fármaco del estudio. |
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E.4 | Principal exclusion criteria |
1. Patients unable to undergo brain MRI scans with IV gadolinium 2. Pregnancy or lactation 3. Absolute neutrophil count (ANC) < 1.5 × 109/L; platelet count < 100 × 109/L; or hemoglobin (Hb) < 9.0 g/dL within 7 days prior to enrollment Note: The use of transfusion or other intervention to achieve Hb ? 9 g/dL is acceptable. 4. Total bilirubin ? 1.5 × ULN (except in patients diagnosed with Gilbert?s disease) 5. AST (SGOT), ALT (SGPT), or alkaline phosphatase (ALP) ? 2.5 ×ULN 6. Serum creatinine > 1.5 × ULN or calculated creatinine clearance (CrCl) < 60 mL/min (Cockcroft and Gault) 7. Urine dipstick test for proteinuria ? 2+ Patients found to have ? 2+ proteinuria should undergo a 24-hour urine collection and must demonstrate ? 1.0 g of protein in 24 hours) 8. International normalized ratio (INR), protohrombin time (PT), or activated partial thromboplastin time (APTT) as follows: In the absence of therapeutic intent to anticoagulate the patient: INR > 1.5 or PT > 1.5 × ULN or aPTT > 1.5 ×ULN OR In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution) or patient has not been on a stable dose of anticoagulants for at least 2 weeks before randomization. (Note: Per ASCO guidelines, low-molecular-weight heparin [LMWH] should be the preferred approach.) 9. Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg while on antihypertensive medication) 10. Uncontrolled diabetes, as evidenced by fasting serum glucose level > 200 mg/dL 11. Prior history of hypertensive crisis or hypertensive encephalopathy 12. New York Heart Association (NYHA) Grade II or greater congestive cardiac failure 13. History of myocardial infarction (within 12 months) or unstable angina (within 6 months) prior to randomization 14. History of stroke or transient ischemic attacks within 6 months prior to randomization 15. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization 16. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) 17. History of abdominal fistula or gastrointestinal perforation within 6 months prior to randomization 18. History of intracranial abscess within 6 months prior to randomization 19. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization 20. Anticipation of need for major surgical procedure during the course of the trial 21. Serious non-healing wound, active ulcer, or untreated bone fracture 22. History of another malignancy in the previous 3 years, with a disease-free interval of < 3 years Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. 23. Evidence of any active infection requiring hospitalization or IV antibiotics within 2 weeks prior to randomization 24. Known hypersensitivity to any excipients of onartuzumab or bevacizumab 25. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibody |
1. Pacientes que no puedan someterse a RM cerebrales con gadolinio IV. 2. Embarazo o lactancia 3. Recuento absoluto de neutrófilos (RAN) < 1,5 x 109/l, recuento de plaquetas < 100 x 109/l o hemoglobina (Hb) < 9,0 g/dl en los 7 días anteriores al reclutamiento. 4. Bilirrubina total ? 1,5 veces el LSN (salvo en los pacientes diagnosticados de enfermedad de Gilbert). 5. AST (SGOT), ALT (SGPT) o fosfatasa alcalina (FA) ? 2,5 veces el LSN. 6. Creatinina sérica > 1,5 veces el LSN o aclaramiento de creatinina calculado (CrCl) < 60 ml/min (Cockcroft y Gault). 7. Proteinuria ? 2+ en un análisis de orina con tira reactiva. 8. Cociente internacional normalizado (INR), tiempo de protrombina (TP) o tiempo de tromboplastina parcial activado (TTPa) como se indica a continuación: En ausencia de intención terapéutica de anticoagular al paciente: INR > 1,5 ó TP > 1,5 veces el LSN o TTPa > 1,5 veces el LSN. O En presencia de intención terapéutica de anticoagular al paciente: el INR o el TP y el TTPa no se encuentran dentro de los límites terapéuticos (según la referencia médica en el centro) o el paciente no ha recibido una dosis estable de anticoagulantes durante al menos 2 semanas antes de la aleatorización. (Nota: conforme a las directrices de la ASCO, una heparina de bajo peso molecular [HBPM] ha de ser el fármaco de elección.) 9. Hipertensión arterial controlada de manera inadecuada (definida como una presión arterial sistólica > 150 mm Hg o una presión arterial diastólica > 100 mm Hg mientras se recibe medicación antihipertensiva). 10. Diabetes no controlada, demostrada por una glucemia en ayunas > 200 mg/dl. 11. Antecedentes de crisis hipertensivas o encefalopatía hipertensiva. 12. Insuficiencia cardíaca congestiva de grado II o superior de la New York Heart Association (NYHA). 13. Antecedentes de infarto de miocardio (en los 12 meses anteriores) o angina de pecho inestable (en los 6 meses anteriores) antes de la aleatorización. 14. Antecedentes de ictus o accidente isquémico transitorio en los 6 meses anteriores a la aleatorización 15. Vasculopatía importante (por ejemplo, aneurisma aórtico con necesidad de reparación quirúrgica o trombosis arterial periférica reciente) en los 6 meses anteriores a la aleatorización 16. Signos de diátesis hemorrágica o coagulopatía (en ausencia de tratamiento anticoagulante). 17. Antecedentes de fístula abdominal o perforación digestiva en los 6 meses anteriores a la aleatorización 18. Antecedentes de absceso intracraneal en los 6 meses anteriores a la aleatorización. 19. Intervención quirúrgica mayor, biopsia abierta o lesión traumática importante en los 28 días anteriores a la aleatorización. 20. Previsión de la necesidad de practicar una intervención quirúrgica mayor durante el estudio. 21. Herida importante no cicatrizada, úlcera activa o fractura ósea no tratada. 22. Antecedentes de otra neoplasia maligna en los 3 años anteriores, con un intervalo sin enfermedad < 3 años. 23. Datos de cualquier infección activa con necesidad de hospitalización o administración de antibióticos IV en las 2 semanas anteriores a la aleatorización. 24. Hipersensibilidad conocida a cualquiera de los excipientes de onartuzumab o bevacizumab. 25. Hipersensibilidad a productos derivados de células de ovario de hámster chino o a otros anticuerpos humanizados o humanos recombinantes. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
? Progression-free survival (PFS) |
Supervivencia libre de progresión (SLP) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS will be evaluated when 44 investigator-assessed PFS events in patients with Met diagnostic-positive tumors and 88 PFS events in the ITT population have occurred. |
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E.5.2 | Secondary end point(s) |
Overall Survival (OS) OS-9 PFS-6 Objective Response Rate (ORR) Duration of Objective Response (DOR) |
Supervivencia global (SG) SG-9 SLP-6 Tasa de respuesta objetiva (TRO) Duración de la respuesta objetiva (DRO) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Follow-up for survival will continue until all patients have either died, or are lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability, QoL, Serum levels and incidence of anti-therapeutic antibodies (ATAs) against MetMAb |
Tolerabilidad, calidad de vida, niveles séricos e incidencia de anticuerpos antiterapeuticos (ATT) contra MetMab. |
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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 | 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) | No |
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 | 3 |
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 | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Canada |
France |
Germany |
Italy |
Spain |
Switzerland |
United Kingdom |
United States |
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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 efficacy analysis will occur when 48 investigator-assessed PFS events in patients with Met diagnostic-positive tumors and 96 PFS events in the ITT population have occurred. Follow-up for survival will continue until all patients have either died, or are lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. Depending on study outcome, patients may be allowed to continue treatment if they are deriving benefit, with continued safety follow-up. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |