E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic lymphocytic leukemia |
leucemia linfocítica crónica |
|
E.1.1.1 | Medical condition in easily understood language |
chronic lymphocytic leukemia |
leucemia linfocítica crónica |
|
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 | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To determine efficacy by investigator-assessed PFS of a combined regimen of obinutuzumab and GDC 0199 compared with GClb in previously untreated patients with CLL who have coexisting medical conditions. |
Determinar la eficacia mediante la SSP evaluada por el investigador de un régimen combinado de obinutuzumab + GDC-0199 en comparación con GClb en pacientes no tratados previamente con CLL y que presentan condiciones médicas coexistentes. |
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E.2.2 | Secondary objectives of the trial |
To determine efficacy as assessed by additional outcome measures, including Independent Review Committee [IRC]-assessed PFS, overall response and MRD response rate as measured by allele-specific oligonucleotide polymerase chain reaction [ASO-PCR] |
Determinar la eficacia, evaluada mediante criterios de valoración adicionales que incluyen la SSP evaluada por un comité de revisión independiente [CRI], la respuesta global y la tasa de respuesta de la ERM determinada mediante reacción en cadena de la polimerasa basada en la hibridación de oligonucleótidos específicos de alelo [ASO-PCR] |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Documented previously untreated CLL according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria - CLL requiring treatment according to IWCLL criteria - Total Cumulative Illness Rating Scale (CIRS score) > 6 - Adequate marrow function independent of growth factor or transfusion support within 2 weeks of screening as per protocol, unless cytopenia is due to marrow involvement of CLL - Adequate liver function - Life expectancy > 6 months - Agreement to use highly effective contraceptive methods per protocol |
-Tener CLL documentada no tratada previamente, conforme a los criterios IWCLL -CLL que requiere tratamiento conforme a los criterios IWCLL. - Puntuación CIRS total >6 - Función medular adecuada, con independencia del apoyo con factores de crecimiento o transfusiones en las 2 semanas anteriores a la selección, salvo que la citopenia se deba a afectación medular de la CLL. - Función hepática adecuada. - Esperanza de vida >6 meses. - Aceptación de utilizar métodos anticonceptivos altamente efectivos según protocolo. |
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E.4 | Principal exclusion criteria |
- Transformation of CLL to aggressive Non-Hodgkin's lymphoma (Richters transformation or pro-lymphocytic leukemia) - Known central nervous system involvement - Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML) - An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system - Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia - Inadequate renal function - History of prior malignancy, except for conditions as listed in the protocol if patients have recovered from the acute side effects incurred as a result of previous therapy - Patients with active bacterial, viral, or fungal infection requiring systemic treatment within the last two months prior to registration - History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products - Hypersensitivity to chlorambucil, obinutuzumab, or GDC-0199 or to any of the excipients - Pregnant women and nursing mothers - Positive test results for chronic HBV infection (defined as positive HBsAg serology) or positive test result for hepatitis C (hepatitis C virus [HCV] antibody serology testing) - Patients with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus-1 (HTLV-1) - Requires the use of warfarin, marcumar, or phenprocoumon - Received agents known to be strong CYP3A4 inhibitors or inducers within 7 days prior to the first dose of study drug |
- Transformación de CLL a LNH de gran malignidad (transformación de Richter o leucemia prolinfocítica). - Afectación conocida del sistema nervioso central. - Pacientes con antecedentes de leucoencefalopatía multifocal progresiva (LMP) confirmada. -Una puntuación de 4 en la afectación de aparatos, órganos o sistemas individuales evaluada mediante la definición de la escala CIRS que limita la capacidad de recibir el régimen de tratamiento de este ensayo con la excepción de ojos, oídos, nariz y garganta. -Pacientes con anemia hemolítica autoinmunitaria o trombocitopenia inmunitaria no controladas. -Función renal inadecuada. - Antecedentes de neoplasia maligna anterior, salvo las condiciones señaladas en el protocolo, si los pacientes se han recuperado de los efectos secundarios tras dosis únicas provocados por un tratamiento anterior. - Pacientes con infección bacteriana, vírica o micótica activa que requiere tratamiento sistémico en los dos meses anteriores al registro. - Antecedentes de reacciones anafilácticas o alérgicas graves a los anticuerpos monoclonales humanizados o murinos o sensibilidad o alergia conocidas a los productos murinos. - Hipersensibilidad a clorambucil, obinutuzumab, o GDC-0199 o a cualquiera de sus excipientes. - Mujeres embarazadas o en período de lactancia. - Resultados positivos en los análisis de la infección crónica por el VHB (definido como serología positiva para el HBsAg) y Resultado positivo en el análisis de la hepatitis C (análisis de serología del anticuerpo contra el virus de la hepatitis C [VHC]). - Pacientes con infección conocida por el virus de la inmunodeficiencia humana (VIH) o el virus de la leucemia de linfocitos T humana tipo I (HTLV-1). - Requiere el uso de warfarina, marcumar o fenprocumón. - Administración de los fármacos CYP3A4 en los 7 días anteriores a la primera dosis del fármaco del estudio GDC-0199. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS), defined as the time from randomization to the first occurrence of progression, relapse or death from any cause as assessed by the investigator using IWCLL criteria |
SSP, definida como el tiempo desde la aleatorización hasta la primera aparición de progresión, recidiva o muerte por cualquier causa, según la evaluación del investigador. Los investigadores evaluarán la progresión de la enfermedad por medio de los criterios IWCLL |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At baseline, day 1 of cycle 7 and 9, day 1 of cycle 4, day 28 after treatment completion or early termination, during follow up i.e. 3 months after treatment completion or early termination and then regularly until 5 years from last patient enrolled. |
En basal, día 1 del cliclo 7 y 9, día 1 del ciclo 4, día 28 despues de la terminación del tratamiento o finalización anticipada, durante el seguiento eje: 3 meses después de la terminación del tratamiento o finalización y entonces regularmente hasta 5 años desde el último paciente randomizado. |
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E.5.2 | Secondary end point(s) |
- PFS based on Institutional Review Committee (IRC)-assessments, defined as the time from randomization to the first occurrence of progression or relapse or death from any cause - Objective response rate ([ORR] defined as rate of a clinical response of complete response [CR], CR with incomplete bone marrow recovery [CRi] or partial response [PR]) as determined by the investigator, according to the IWCLL criteria - Minimal residual disease (MRD) response rate, as measured by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) - ORR at completion of combination treatment response assessment - MRD response rate, as measured by ASO-PCR at completion of combination treatment response assessment - Overall survival - Duration of objective response - Best response achieved (CR, CRi, PR, stable disease, or progressive disease) - Event-free survival - Time to next anti-leukemic treatment - Incidence of adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 - Incidence of severe adverse events - Incidence of adverse events of special interest |
- SSP basada basada en las evaluaciones del comité de revisión independiente (CRI) definida como el tiempo desde la aleatorización hasta la primera aparición de progresión, recidiva o muerte por cualquier causa, - Tasa de respuesta clínica, (TRG) definida en cuanto a RC ( respuesta completa), RCi respuesta completa con recuperación incompleta de la médula ósea o RP ( respuesta parcial), determinada por el investigador conforme a las directrices del IWCLL. - Tasa de enfermedad residual mínima ERM medida mediante reacción en cadena de la polimerasa basada en la hibridación de oligonucleótidos específicos de alelo (ASO-PCR). - Tasa de respuesta clínica (TRG) en la evaluación de la respuesta al finalizar el tratamiento combinado. - Tasa de ERM como medida mediante ( ASO-PCR) en la evaluación de la respuesta al finalizar el tratamiento combinado. - Supervivencia completa. - Duración del objetivo de respuesta. - Mejor respuesta conseguida ( RC, RCi, RP, enfermedad estable, or progresion de la enfermedad. - Supervivencia libre de Acontecimiento. - Tiempo hasta el siguiente tratamiento anti leucémico. - Incidencia de acontecimientos adversos, clasificados, según los Criterios terminológicos comunes para acontecimientos adversos del Instituto Nacional contra el Cáncer de los EE. UU. [CTCAE del NCI] version 4.0 - Incidencia de acontecimientos adversos graves - Incidencia de acontencimientos adversos de especial interés. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 5 years from last patient enrolled. |
5 años después de la aleatorización del último paciente |
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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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient reported Outcomes (PRO) |
|
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 160 |
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 |
Argentina |
Australia |
Austria |
Brazil |
Bulgaria |
Canada |
Croatia |
Czech Republic |
Denmark |
Egypt |
Estonia |
France |
Germany |
Italy |
Mexico |
New Zealand |
Romania |
Russian Federation |
Slovakia |
Spain |
Switzerland |
United Kingdom |
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
|
The end of this study is defined as 5 years from last patient enrolled (unless all patients have died). |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 8 |