| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
leucemia linfocítica crónica/linfoma linfocítico pequeño recidivante o resistente a tratamiento.
relapsed or refractory CLL/SLL. |
|
| E.1.1.1 | Medical condition in easily understood language |
leucemia linfocítica crónica/linfoma linfocítico pequeño recidivante o resistente a tratamiento.
relapsed or refractory CLL/SLL |
|
| 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 | 10060671 |
| E.1.2 | Term | B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma refractory |
| 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 |
Evaluar la eficacia de ibrutinib en comparación con ofatumumab basándose en la opinion del comité revisor independiente (CRI) en pacientes con LLC/LLP recidivante o resistente a tratamiento
Evaluar la eficacia de ibrutinib en comparación con ofatumumab basándose en la opinion del comité revisor independiente (CRI) de la supervivencia libre de progresión (SLP) en pacientes con LLC/LLP recidivante o resistente a tratamiento
To evaluate the efficacy of ibrutinib compared to ofatumumab based on the independent review committee (IRC) of PFS in patients with relapsed or refractory CLL/SLL |
|
| E.2.2 | Secondary objectives of the trial |
To compare between the two treatment groups in terms of:
Efficacy
? To evaluate Investigator-assessed PFS per IWCLL 2008 criteria
? To determine IRC-assessed ORR per IWCLL2008 criteria
? To evaluate Investigator-assessed ORR per IWCLL 2008 criteria
? To evaluate OS
? To evaluate hematological improvement
? To evaluate improvement and/or resolution of disease-related symptoms
Safety
? To evaluate the safety and tolerability of ibrutinib compared to of Ofatumumab |
Comparar la eficacia entre los dos grupos de tratamiento en lo que respecta a:
?Evaluar la tasa de SLP evaluada por el investigador según los criterios IWCLL de 2008
?Determinar la tasa de respuesta global (TRG) evaluada por el CRI según los criterios IWCLL de 2008
?Determinar la tasa de TRG evaluada por el investigador según los criterios IWCLL de 2008
?Evaluar la supervivencia global (SG)
?Evaluar la mejoría hematológica
?Evaluar la mejoría y/o resolución de los síntomas relacionados con la enfermedad.
Seguridad
?Evaluar la seguridad y tolerabilidad de ibrutinib en comparación con ofatumumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Men and women ? 18 years of age
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
3. Life expectancy of > 4 months from the 1st dose of study medication
4. Diagnosis of CLL/SLL that meets published diagnostic criteria (Hallek 2008): a) Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co expressing at least one B-cell marker (CD19, CD20, or CD23) and CD5, b) The diagnosis of CLL requires a history of lymphocytosis with a B-lymphocyte count ?5,000/µl while SLL patients are characterized by the same criteria with a circulating B lymphocyte count <5,000/µl. Prolymphocytes may comprise no more than 55% of blood lymphocytes
5. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring treatment: a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (Hgb < 11 g/dL) and/or thrombocytopenia (platelets < 100,000/L), b) Massive, progressive, or symptomatic splenomegaly, c) Massive nodes, progressive, or symptomatic lymphadenopathy, d) Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of < 30 X 109/L (30,000/?L), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL should be excluded, e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, f) Constitutional symptoms, defined as one or more of the following disease-related symptoms or signs, i) Unintentional weight loss > 10% within the previous 6 months prior to Screening
ii) Significant fatigue; iii) Fevers higher than 100.5° F or 38 .0° C for 2 or more weeks prior to Screening without evidence of infection or iv) Night sweats for more than 1 month prior to Screening without evidence of infection
6. Must have received at least one prior therapy for CLL/SLL and not be appropriate for treatment or retreatment with purine analog based therapy, defined by at least one of the following criteria: a) Failure to respond (stable disease [SD] or disease progression on treatment), or a progression-free interval of less than 3 years from treatment with a purine analog based therapy and anti-CD20 containing chemoimmunotherapy regimen after at least two cycles, b) Age ? 70 years, or age ? 65 and the presence of co-morbidities (Cumulative Illness Rating Scale [CIRS] ? 6 or CrCl < 70 mL/min) that might place the patient at an unacceptable risk for treatment-related toxicity with purine analog based therapy, provided they have received >1 prior treatment including at least two cycles of an alkylating-agent based (or purine analog based) anti-CD20 antibody containing chemoimmunotherapy regimen. CIRS score can be determined utilizing a web-based tool.
c) History of purine analog-associated autoimmune anemia or autoimmune thrombocytopenia, d) FISH showing 17p del in ? 20% of cells (either at diagnosis or any time before study entry) either alone or in combination with other cytogenetic abnormalities, provided they have received at least one prior therapy
7. Measurable nodal disease by CT.
8. Meet the following laboratory parameters: a) Absolute neutrophil count (ANC) ? 750 cells/?L (0.75 x 109/L), independent of growth factor support within 7 days of the first dose with study drug, b) Platelet count ? 30,000 cells/?L (30 x 109/L) without transfusion support within 7 days of the first dose with study drug. Patients with transfusion-dependent thrombocytopenia are excluded, c) Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 2.5 x upper limit of normal (ULN), d) Total bilirubin ? 1.5 x ULN (unless due to Gilbert?s syndrome or disease infiltration of the liver), e) Creatinine ? 2 x ULN and estimated Glomerular Filtration Rate (GFR [Cockcroft-Gault]) ? 30 mL/min
9. Able to provide written informed consent and can understand and comply with the study
10. Able to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study
11. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 3 days of the first dose of study drug and for 1 month following the last dose. Post menopausal females (>45 years old and without menses for >1 year) and surgically sterilized females are exempt from this criterion.
12. Male patients must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential. |
-Hombres y mujeres ? 18 años.
-Estado funcional 0 - 1 según el Eastern Cooperative Oncology Group (ECOG).
-Esperanza de vida superior a 4 meses.
-Diagnóstico de LLC o LLP que cumple los criterios IWCLL de 2008.
-Enfermedad activa que cumpla al menos uno de los criterios IWCLL de 2008 para que requiera tratamiento.
-Haber recibido al menos un tratamiento previo para la LLC/LLP.
-No ser aptos para tratamiento o retratamiento con terapia a base de análogos de purinas.
-Afectación ganglionar medible mediante TAC.
-Presentar los siguientes parámetros de laboratorio para cumplir los criterios de inclusión:
?Recuento absoluto de neutrófilos (RAN) ? 750 células/?l (0,75 x 109/l), independientemente del tratamiento con factores de crecimiento.
?Cifra de plaquetas ? 30 000 células/?l (30 x 109/l) sin tratamiento con transfusiones.
?Aspartato transaminasa (AST/SGOT) o alanina transaminasa (ALT/SGPT) séricas < 2,5 veces el límite superior de la normalidad (LSN).
?Bilirrubina total ? 1,5 x LSN.
?Creatinina ? 2 x LSN y tasa de filtración glomerular estimada (TFG [fórmula de Cockcroft-Gault]) ? 30 ml/min.
?Los pacientes deberán estar en condiciones de recibir el tratamiento ambulatorio y monitorización analítica en el centro que administra el fármaco del estudio durante todo el estudio. |
|
| E.4 | Principal exclusion criteria |
Patients will be ineligible for this study if they meet any of the following criteria:
1. Known central nervous system (CNS) lymphoma or leukemia
2. Any history of Richter?s transformation or prolymphocytic leukemia
3. No documentation of cytogenetic and/or FISH results reflecting 17p del status in records prior to first dose of study drug
4. Uncontrolled Autoimmune Hemolytic Anemia (AIHA) or ideopathic thrombocytopenia purpura (ITP), such as those patients with a declining hemoglobin (Hgb) level or platelet count secondary to autoimmune destruction within the 4 weeks prior to first dose of study drug or the need for daily corticosteroids >20 mg daily
5. Prior exposure to ofatumumab or to ibrutinib
6. Previous randomization in a PCI-32765/ibrutinib study
7. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days prior to first dose of study drug
8. Corticosteroid use within 1 week prior to first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. Patients requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count lowering are excluded
9. Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose of study drug
10. Prior autologous transplant within 6 months prior to first dose of study drug
11. Prior allogeneic stem cell transplant within 6 months prior to first dose of study drug
12. Major surgery within 4 weeks prior to first dose of study drug
13. History of prior malignancy, with the exception of the following:
a) Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician
b) Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
c) Adequately treated cervical carcinoma in situ without current evidence of disease
14. Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug
15. Unable to swallow capsules or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine
16. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
17. Known history of infection with human immunodeficiency virus (HIV)
18. Serologic status reflecting active hepatitis B or C infection. Patients with hepatitis B core antibody positive who are antigen negative will need to have a negative polymerase chain reaction (PCR) result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive will be excluded
19. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
20. Pregnant or lactating women
21. Current life-threatening illness, medical condition, or organ system dysfunction
22. Requires anticoagulation with warfarin
23. Requires treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor |
-Linfoma del SNC conocido o leucemia.
-Antecedentes de transformación de Richter o leucemia prolinfocítica.
-Ausencia de resultados citogenéticos y/o FISH que reflejen el estado 17p del en la historia clínica del paciente antes de la primera dosis del fármaco del estudio.
-Anemia hemolítica autoinmunitaria (AHAI) no controlada o púrpura trombocitopénica idiopática (PTI).
-Exposición previa a ofatumumab o ibrutinib.
-Haber recibido cualquier quimioterapia, radioterapia de haz externo, anticuerpos contra el cáncer o fármaco en investigación en los 30 días anteriores a la primera dosis del fármaco del estudio.
-Uso de corticosteroides > 20 mg en la semana previa a la primera dosis del fármaco del estudio.
-Tratamiento con anticuerpos conjugados con toxinas o radioterapia en las 10 semanas previas a la primera dosis del fármaco del estudio.
-Trasplante autólogo previo en los 6 meses previos a la primera dosis del fármaco del estudio.
-Trasplante alogénico de células madre en los 6 meses previos a la primera dosis del fármaco del estudio.
-Antecedentes de cirugía mayor en las 4 semanas previas a la primera dosis del fármaco del estudio.
-Antecedentes de neoplasia maligna previa, con la excepción de ciertas neoplasias malignas de piel y otro tipo tratadas con intención curativa y sin signos de enfermedad activa durante más de 3 años.
-Enfermedad cardiovascular clínicamente significativa activa actualmente o antecedentes de infarto de miocardio en los 6 meses previos a la primera dosis del fármaco del estudio.
-Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH).
-Estado serológico que refleje infección activa por hepatitis B o C.
-Imposibilidad de tragar cápsulas o enfermedad que afecte significativamente a la función gastrointestinal.
-Infección sistémica activa no controlada, fúngica, bacteriana, viral o de otro tipo.
-Antecedentes de ictus o hemorragia intracraneal en los 6 meses previos a la primera dosis del fármaco del estudio.
-Necesidad de anticoagulación con warfarina.
-Necesidad de tratamiento con un inhibidor potente de CYP 3A4/5 y/o CYP2D6. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
El criterio principal de valoración de este estudio es la SLP, evaluada por el CRI según los criterios IWCLL de 2008.
The primary endpoint of the study is PFS, as assessed by IRC review per IWCLL 2008 criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are :
Efficacy
To compare between the two treatment groups in terms of:
? Investigator-assessed PFS per IWCLL 2008 criteria.
? Overall response rate (ORR) is defined as the proportion of patients who achieve complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR) per IWCLL 2008 criteria over the course of the study as evaluated by an IRC
? Investigator-assessed ORR per IWCLL 2008 criteria
? OS
? Hematological improvement in the subset of patients with cytopenia(s) at baseline assessed by time to improvement and percentage of patients with improvement
? Improvement of disease-related symptoms (fatigue, night sweats, and splenomegaly)
Safety
? To compare the safety and tolerability between the two treatment groups |
Criterios secundarios de valoración:
Eficacia
Comparar la eficacia entre los dos grupos de tratamiento en lo que respecta a:
?SLP evaluada por el investigador según los criterios IWCLL de 2008.
?La TRG se define como el porcentaje de pacientes que consiguen una respuesta (evaluada por el CRI según los criterios IWCLL de 2008).
?TRG evaluada por el investigador según los criterios IWCLL de 2008.
?SG.
?Mejoría hematológica en el subgrupo de pacientes con citopenia(s) en el periodo basal evaluada por tiempo y porcentaje de pacientes con mejoría en el hemograma.
?Mejoría de los síntomas relacionados con la enfermedad (cansancio, sudoración nocturna y esplenomegalia).
Seguridad
?Comparar la seguridad y tolerabilidad entre los dos grupos de tratamiento. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Tolerabilidad.
Tolerability |
|
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Austria |
| France |
| Ireland |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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