| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia |
| Leucemia linfoblástica aguda de células B recidivante o refractaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL) |
| Leucemia linfoblástica aguda (LLA) recidivante o refractaria |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 the hematological remission, defined as CR (both CR and CRi), as reported by the external independent endpoint adjudication committee, in patients with relapsed/refractory ALL randomized to receive inotuzumab ozogamicin (Arm A) versus patients randomized to receive active comparator (Arm B). |
| Comparar la remisión hematológica, definida como RC (RC y RCi), notificada por un Comité independiente de adjudicación externo, en pacientes con LLA recidivante/refractaria aleatorizados para recibir ozogamicina de inotuzumab (Grupo A) frente a pacientes aleatorizados para recibir un comparador activo (Grupo B). |
|
| E.2.2 | Secondary objectives of the trial |
Safety and efficacy endpoints will be compared between the inotuzumab ozogamicin arm and the active comparator arm and will include:
Key Secondary Objective: •To compare the overall survival (OS) of patients with relapsed/refractory ALL.
Other Secondary Objectives:
•To compare the duration of response (DoR)
•To compare the progression-free survival (PFS)
•To compare the time to progression (TTP)
•To compare the rate of stem-cell transplantation in patients
•To characterize the safety and tolerability including the rate of VOD (veno-occlusive disease)/SOS (sinusoidal obstruction syndrome) following allogeneic stem cell transplant
•To assess minimal residual disease (MRD) levels and cytogenetics in patients achieving a CR/CRi
•To determine the population pharmacokinetic parameters of inotuzumab ozogamicin and confirm sources of exposure variability
•To compare patient-reported health-related quality of life (HRQOL) and patient-reported health status between treatment arms |
Los criterios de valoración de seguridad y eficacia se compararán entre grupo de ozogamicina de inotuzumab y del comparador activo. Incluirán:
Objetivo secund. princip.: Supervivencia global-SG de los pac. con LLA recidivante o refractaria
Otros objet. secund.:
•Comparar duración la respuesta-DdR
•Comparar supervivencia sin progresión-SSP
•Comparar tiempo hasta progresión-THP
•Comparar tasa de transplantes de células germinales de los pac.
•Describir seguridad y tolerabilidad, incluida tasa de enfermedad venooclusiva-EVO y síndrome de obstrucción sinusoidal-SOS después de transplante de células germinales alogénico
•Evaluar niveles de enfermedad residual mínima-ERM y citogenética en los pac. que alcancen RC/RCi
•Determinar los parámetros de farmacocinética poblacional de ozogamicina de inotuzumab y confirmar los orígenes de la variabilidad de exposición
•Comparar calidad de vida relacionada con salud-CdVRS y estado de salud notificados por los pac. entre grupos de tratam |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patient eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before patients are included in the study. Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Relapsed or refractory CD22-positive ALL (ie, ≥ 20% blasts CD22-positive) due to receive either salvage 1 or salvage 2 therapy and for which either arm of randomized study therapy offers a reasonable treatment option. Ph+ ALL patients must have failed treatment with at least 1 second generation tyrosine kinase inhibitor;
2. Patients in Salvage 1 with late relapse should be deemed poor candidates for reinduction with initial therapy;
3. Bone marrow involvement with ≥ 5% lymphoblasts;
4. Age 18 years or older;
5. ECOG performance status 0 – 2;
6. Adequate liver function, including total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome, and aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN. If organ function abnormalities are considered due to tumor, total serum bilirubin must be ≤2 x ULN;
7. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or any serum creatinine level associated with a measured or calculated creatinine clearance of ≥40 mL/min;
8. Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for a minimum of 90 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria):
• Have undergone hysterectomy or bilateral oophorectomy; or
• Have medically confirmed ovarian failure; or
• Are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause.
9. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study;
10. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
Un miembro cualificado del equipo de estudio del investigador revisará y documentará la elegibilidad del paciente antes de la inclusión del paciente en el estudio. Para poder ser incluidos en el estudio, los pacientes deberán cumplir todos los criterios de inclusión siguientes:
1. LLA CD22-positiva recidivante o refractaria (es decir, ≥20% blastos CD22-positivos) para recibir terapia de rescate 1 o rescate 2 y para quienes cualquiera de los grupos de tratamiento de estudio aleatorizado ofrezca una opción de tratamiento razonable. En los pacientes con LLA Ph+ debe haber fracasado el tratamiento con al menos 1 inhibidor tirosincinasa de segunda generación;
2. Los pacientes en 1º rescate con recidiva tardía deberán ser considerados poco candidatos para la einducción con la erapia inicial;
3. Afectación de la médula ósea con ≥ 5% de linfoblastos;
4. Edad 18 años o mayor;
5. Estado funcional ECOG 0 – 2;
6. Función hepática adecuada, con bilirrubina total sérica ≤1,5 x LSN a menos que el paciente presente un síndrome de Gilbert documentado, y aspartato y alanina aminotransferasas (AST y ALT) ≤2,5 x LSN. Se considera que las alteraciones de la función orgánica se debe al tumor, la bilirrubina total sérica debe ser ≤2 x LSN;
7. Creatinina sérica 1,5 x límite superior de la normalidad (LSN) o cualquier nivel de creatinina sérica asociado a una determinación o cálculo del aclaramiento de creatinina ≥40 ml/min.;
8. Las mujeres y hombres potencialmente fértiles deberán acordar y comprometerse a usar un método anticonceptivo fiable durante todo el estudio y como mínimo hasta 90 días después de la última dosis del tratamiento asignado. Un paciente es potencialmente fértil si, en opinión del investigador, es biológicamente capaz de engendrar un hijo y es sexualmente activo. Las pacientes mujeres no se consideran potencialmente fértiles si cumplen alguno de los criterios siguientes):
• Han sido sometidas a histerectomía u ooforectomía bilateral; o
• Presentan un fracaso ovárico confirmado médicamente; o
• Son posmenopáusicas confirmadas médicamente (cese de las menstruaciones regulares durante al menos 12 meses consecutivos sin una causa patológica o fisiológica alternativa.
9. Constancia de consentimiento informado firmado personalmente que indique que el paciente (o su representante legal) ha sido informado de todos los aspectos pertinentes del estudio;
10. Disposición y capacidad de cumplir las visitas programadas, los planes de tratamiento, las pruebas analíticas y otros procedimientos del estudio. |
|
| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the study:
1. Isolated extramedullary relapse (i.e. testicular or CNS);
2. Burkitt’s or mixed lineage leukemia;
3. Active central nervous system (CNS) leukemia, as defined by unequivocal morphologic evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment for active disease within the prior 28 days, symptomatic CNS leukemia (i.e. cranial nerve palsies or other significant neurologic dysfunction) within 28 days. Prophylactic intrathecal medication is not a reason for exclusion;
4. Prior chemotherapy within ≤ 2 weeks before randomization with the following exceptions: steroids, hydroxyurea, oral mercaptopurine, methotrexate, vincristine, thioguanine, and tyrosine kinase inhibitors are permitted within 2 weeks of randomization as maintenance or to reduce the peripheral blood blast count.
Patients must have recovered from acute non hematologic toxicity (to ≤ Grade 1) of all previous therapy prior to enrollment.
5. Prior monoclonal antibodies within 6 weeks of randomization;
6. Prior allogeneic hematopoietic stem cell transplant (HSCT) or other anti-CD22 immunotherapy ≤ 4 months before randomization. Patients must have completed immunosuppression therapy for treatment of GvHD prior to enrollment. At randomization, patients must not have > grade 2 acute GvHD, or extensive chronic GvHD;
7. Peripheral absolute lymphoblast count > 10,000 /µL (treatment with hydroxyurea and/or steroids is permitted within 2 weeks of randomization to reduce the WBC count);
8. Known systemic vasculitides (eg, Wegener’s granulomatosis, polyarteritis nodosa, systemic lupus erythematosus), primary or secondary immunodeficiency (such as HIV infection or severe inflammatory disease);
9. Current or chronic hepatitis B or C infection as evidenced by hepatitis B surface antigen and anti-hepatitis C antibody positivity, respectively, or known seropositivity for human immunodeficiency virus (HIV). HIV testing may need to be performed in accordance with local regulations or local practice;
10. Major surgery within ≤4 weeks before randomization;
11. Unstable or severe uncontrolled medical condition (eg, unstable cardiac function or unstable pulmonary condition);
12. Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer that has been definitely treated with radiation or surgery. Patients with previous malignancies are eligible provided that they have been disease free for ≥2 years;
13. Cardiac function, as measured by left ventricular ejection fraction (LVEF) that is less than 45%, or the presence of New York Heart Association (NYHA) stage III or IV congestive heart failure;
14. Patients with active heart disease (NYHA class ≥ 3 as assessed by history and physical examination);
15. QTcF > 470 msec (based on the average of 3 consecutive ECGs);
16. Myocardial infarction ≤6 months before randomization;
17. History of clinically significant ventricular arrhythmia, or unexplained syncope not believed to be vasovagal in nature, or chronic bradycardic states such as sinoatrial block or higher degrees of AV block unless a permanent pacemaker has been implanted;
18. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging drug (eg. hypokalemia, hypocalcemia, hypomagnesemia);
19. History of chronic liver disease (eg, cirrhosis) or suspected alcohol abuse;
20. History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS);
21. Administration of live vaccine ≤6 weeks before randomization;
22. Evidence of uncontrolled current serious active infection (including sepsis, bacteremia, fungemia) or patients with a recent history (within 4 months) of deep tissue infections such as fascitis or osteomyelitis;
23. Patients who have had a severe allergic reaction or anaphylactic reaction to any humanized monoclonal antibodies;
24. Pregnant females; breastfeeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for a minimum of 90 days after the last dose of investigational product;
25. Patients who are investigational site staff members or relatives of those site staff members or patients who are Pfizer employees directly involved in the conduct of the trial;
26. Participation in other investigational studies during active treatment phase;
27. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. |
No se incluirá en el ensayo pac. que presenten alguno de los criterios siguientes:
1-Recidiva extramedular aislada
2-Leucemia deBurkitt o leucemia de linaje mixto(es decir testicular o del SNC)
3-Leucemia del SNC activa definida por la prueba morfológica inequívoca de linfoblastos en el LCR, uso de tratamiento local dirigido al SNC en los 28 días anteriores, leucemia del SNC sintomática(es decir parálisis de los nervios craneales u otras disfunciones neurológicas significativas)en los 28días anteriores. La medicación intratecal profiláctica no es una razón para la exclusión
4-Quimioterapia previa en las≤2semanas antes de la aleatorización, excepciones: esteroides, hidroxiurea, mercaptopurina oral, metotrexato, vincristina, tioguanina, e inhibidores de la tirosincinasa en las 2 semanas previas a la aleatorización como mantenimiento o para reducir el recuento de blastos en sangre periférica
Los pac.se deben haber recuperado de las toxicidades agudas no hematológicas(hasta ≤Grado1) de todos los tratamientos previos antes de la inclusión
5-Anticuerpos monoclonales en las 6 semanas previas a la aleatorizac.
6-Transp. alogénico de células germinales hematopoyéticas(TCGH) previo u otros tipos de inmunoterapia anti-CD22 ≤4 meses antes de la aleatorizac. Los pac. deben haber finalizado la terapia inmunosupresora para el tto. de la EIcH antes de la inclusión. Durante la aleatoriz., los pac. no deben presentar enfermedad del injerto contra el huésped(EIcH)>grado2 o EIcH extensa crónica
7-Recuento de linfoblastos periféricos absolutos>10.000/µL(se permite el tto. con hidroxiurea y/o esteroides en las 2semanas previas a la aleatorización para reducir el recuento leucocitario)
8-Vasculitis sistémica conocida(ej.granulomatosis de Wegener, poliarteritis nodosa, lupus eritematoso sistémico), inmunodeficiencia primaria o secundaria (como infección porVIH o enferm. inflamatoria grave)
9-Infección por hepatitis B o C actual o crónica probada por la positividad del antígeno de superficie de la hepatitis B o de los anticuerpos antihepatitis C, respectivamente, o seropositividad conocida al VIH. La pruebas delVIH se podrán realizar según las normativas o la práctica local
10-Cirugía mayor en las≤4semanas anteriores a la aleatoriz.
11-Patología médica inestable o grave no controlada(ej.función cardiaca inestable o patología pulmonar inestable
12-Neoplasia maligna activa concurrente u otros cánceres cutáneos no melanomatosos, carcin. cervical in situ o cáncer de próstata localizado tratados definitivamente con radiación o cirugía. Los pac. con neoplasias malignas previas son elegibles siempre y cuando hayan estado libres de enfermedad durante≥2 años
13-Func. cardiaca, determinada por la fracción de eyecciónventricular izquierda (FEVI) inferior al45%, o presencia de insuficiencia cardiaca congestiva en estadío III oIV de la NewYorkHeart Association (NYHA)
14-Pac. con enfer. cardiaca activa(clase NYHA≥3 evaluada mediante la historia y la exploración física)
15-QTcF>470 mseg.(en base al promedio de 3ECG consecutivos)
16-Infarto de miocardio≤6 meses antes de la aleatoriz.
17-Antec.de arritmia ventricular clínicamente significativa o síncopa inexplicada no considerada de naturaleza vasovagal, o estados bradicárdicos crónicos como bloqueo sinoauricular o bloqueo AV de grado más elevado, a menos que se haya implantado un marcapasos permanente
18-Trastornos electrolíticos no controlados que puedan agravar los efectos de un fármaco que prolongue el QTc (p.ej., hipokaliemia, hipocalcemia, hipomagnesemia)
19-Antec.de enfer.hepática crónica(p.ej., cirrosis) o sospecha de abuso del alcohol
20-Antec.de enfer. venooclusiva(EVO) o síndrome de obstrucción sinusoidal(SOS)
21-Administración de vacuna de virus vivos ≤6 semanas antes de la aleatoriz.
22-Prueba de infección grave activa en curso(incluida la sepsis, bacteriemia, fungemia, o pacientes con antecedentes recientes(en los 4 meses anteriores) de infecciones de tejidos profundos como fasc itis o osteomielitis
23-Pac. que hayan presentado una reacción alérgica intensa o una reacción anafiláctica a algún anticuerpo monoclonal humanizado
24-Mujeres embarazadas; muj. en periodo de lactancia; hombres y mujeres potencialmente fértiles que no utilicen un método de contracepción efectivo o no estén de acuerdo en continuarlo durante un mínimo de 90días después de la última dosis del producto en investigación
25-Pac. miembros del personal del centro de investigación o familiares de estos miembros del personal del centro o pac. que sean empleados de Pfizer directamente involucrados en la realización del ensayo
26-Participación en otros estudios de investigación durante la fase de tto. activo
27-Cualquier otra patología médica o psiquiátrica grave, aguda o crónica o anomalía analítica que, en opinión del investigador, pueda incrementar el riesgo asociado a la particip. del pac. en el estudio o la administración del producto en investig., o pueda interferir la interpretación... |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - CR and CRi. |
| - RC y RCi. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Dependent on individual patient response |
| Depende de la respuesta individual del paciente |
|
| E.5.2 | Secondary end point(s) |
? OS (Key secondary endpoint);
? DoR;
? PFS;
- Number of Transplants;
- Adverse events and laboratory abnormalities (CTCAE v3.0 grade, timing, seriousness and relatedness);
- MRD and cytogenetics in responding patients;
- PK;
- EORTC QLQ-C30 and EQ-5D. |
- SG (principal criterio de valoración secundario);
- DdR;
- SSP;
- Número de transplantes;
- Acontecimientos adversos y alteraciones analíticas (grado CTCAE v3.0, tiempo, gravedad y relación);
- DMR y citogenética en pacientes que responden;
- FC;
- EORTC QLQ-C30 y EQ-5D |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Dependent on individual patient response |
| Dependen de la respuesta individual del paciente |
|
| 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 | 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) | 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) | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Brazil |
| Canada |
| China |
| Croatia |
| Czech Republic |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Serbia |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| End of Trial in all participating countries is defined as the Last Patient Last Visit (inclusive of long term follow-up visits, see section 6.4 of the protocol), unless stopped earlier by the external data monitory committee (E-DMC). |
| El final del ensayo en todos los países participantes se define como la última visita del último paciente (incluidas las visitas de seguimiento a largo plazo, ver apartado 6.4), a menos que sea cancelado tempranamente por el comité de supervisión de datos externo (CSD-E).) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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