| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with previously undiagnosed peripheral T-cell lymphoma who have achieved an objective response following initial treatment with CHOP-based chemotherapy |
| Pacientes con linfoma de células T periférico sin diagnóstico previo, que han alcanzado una respuesta objetiva tras el tratamiento inicial con quimioterapia con CHOP |
|
| E.1.1.1 | Medical condition in easily understood language |
| Peripheral T-cell lymphoma |
| Linfoma de células T periférico |
|
| 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 | 10034623 |
| E.1.2 | Term | Peripheral T-cell lymphoma unspecified |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Determine the efficacy of pralatrexate compared to observation when administered to patients with previously undiagnosed peripheral T-cell lymphoma (PTCL) who have achieved an objective response after completing at least 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based treatment. |
| Determinar la eficacia del pralatrexato comparado con la observación al ser administrado a pacientes con linfoma de células T periférico (LCTP) sin diagnóstico previo, que han alcanzado una respuesta objetiva tras completar como mínimo 6 ciclos de tratamiento con ciclofosfamida, doxorrubicina, vincristina y prednisona (CHOP). |
|
| E.2.2 | Secondary objectives of the trial |
| Determine the safety of pralatrexate when administered following a course of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based treatment to patients with previously undiagnosed peripheral T-cell lymphoma (PTCL). |
| Determinar la seguridad del pralatrexato al ser administrado tras un curso de tratamiento con CHOP a pacientes con LCTP sin diagnóstico previo. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient?s peripheral T-cell lymphoma(PTCL) histology has been confirmed as one of the following by a independent pathology reviewer, using the Revised European American Lymphoma (REAL) World Health Organization (WHO) disease classification:
a. T/natural killer (NK)-cell leukemia/lymphoma
b. Adult T-cell lymphoma/leukemia (human T-cell leukemia virus [HTLV] 1+)
c. Angioimmunoblastic T-cell lymphoma
d. Anaplastic large cell lymphoma (ALCL), primary systemic type, excluding anaplastic lymphoma kinase positive (ALK+) with International Prognostic Index (IPI) score < 2 at initial diagnosis and complete response after completion of CHOP-based therapy
e. PTCL-unspecified
f. Enteropathy-type intestinal lymphoma
g. Hepatosplenic T-cell lymphoma
h. Subcutaneous panniculitis T-cell lymphoma
i. Transformed mycosis fungoides
j. Extranodal T/NK-cell lymphoma nasal or nasal type
k. Primary cutaneous gamma-delta T-cell lymphoma
l. Primary cutaneous CD8+ aggressive epidermic cytotoxic T-cell lymphoma
2. Documentation that the patient has completed at least 6 cycles of CHOP-based therapy, including:
a. CHOP 21
b. CHOP 14
c. CHOEP
d. Other CHOP variants: includes all 4 components of CHOP represented, with substitution allowed for any 1 component with a drug of the same mechanism of action (eg, variant anthracyclines). Additional components to CHOP are allowed,with the exception of alemtuzumab; rituximab may be combined with CHOP provided that it is not given within 3 cycles of randomization.
3. Patient has achieved a CR or PR per investigator?s assessment following completion of CHOP-based therapy and has had a radiological assessment within 21 days prior to randomization.
4. ? 18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status ? 2.
6. Adequate hematological, hepatic, and renal function as defined by:
a. Absolute neutrophil count (ANC) ? 1000/?L
b. Platelet count ? 100,000/?L
c. Total bilirubin ? 1.5 mg/dL
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 x upper limit of normal (ULN), (AST/ALT < 5 x ULN if documented hepatic involvement with lymphoma). All patients with hepatitis B virus (HBV)-positive serology must have liver function tests within the above parameters.
e. Creatinine ? 1.5 mg/dL (if the patient?s creatinine is > 1.5 mg/dL, then the calculated creatinine clearance must be ? 50 mL/min).
7. Women of childbearing potential (ie, excluding patients who are postmenopausal for at least 1 year [> 12 months since last menses] or are surgically sterilized) must:
a. Have a negative serum pregnancy test within 14 days prior to randomization and
b. Agree to practice a medically acceptable contraceptive regimen from study treatment initiation until at least 30 days after the last administration of pralatrexate.
8. Males who are sexually active, including those with a pregnant partner, must agree to practice a medically acceptable barrier method contraceptive regimen (eg. condoms) while receiving pralatrexate and for 90 days after the last administration of pralatrexate.
9. Patient has given written informed consent (IC). |
1.Un revisor independiente de la patología ha confirmado que la histología del LCTP del paciente es una de las siguientes, utilizando la clasificación REAL (Revised European American Lymphoma) de la Organización Mundial de la Salud (OMS) para la enfermedad:
a.Linfoma/leucemia de células T/?natural killer? (NK)
b.Leucemia/linfoma de células T del adulto (virus linfotrópico humano de células T [HTLV] 1+)
c.Linfoma de células T angioinmunoblástico
d.Linfoma anaplásico de células grandes (LACG), tipo sistémico primario, con exclusión de los positivos a cinasa del linfoma anaplásico (ALK+), con puntuación en el Índice de Pronóstico Internacional (IPI) < 2 en el diagnóstico inicial y RC tras la finalización de la terapia con CHOP
e.LCTP inespecífico
f.Linfoma intestinal de tipo enteropático
g.Linfoma de células T hepatoesplénico
h.Linfoma de células T tipo paniculitis subcutánea
i.Micosis fungoide transformada
j.Linfoma de células T/NK extraganglionar nasal o tipo nasal
k.Linfoma de células T gamma-delta cutáneo primario
l.Linfoma de células T citotóxico CD8+ epidermotrópico agresivo cutáneo primario
2.Documentación de que el paciente ha completado como mínimo 6 ciclos de terapia con CHOP, lo que incluye:
a.CHOP 21
b.CHOP 14
c.CHOEP
d.Otras variantes de CHOP: incluye los 4 componentes de CHOP representados donde se permite la sustitución de cualquier componente individual con un fármaco con el mismo mecanismo de acción (por ej., variantes de antraciclinas). Se permiten componentes adicionales a CHOP, con excepción de alemtuzumab; se puede combinar rituximab con CHOP, a condición de que no se administre dentro de 3 ciclos de la aleatorización.
3.Según la valoración del investigador, el paciente ha alcanzado una RC o una RP tras la finalización de la terapia con CHOP y ha tenido una evaluación radiológica dentro de los 21 días anteriores a la aleatorización.
4.? 18 años de edad.
5.Estado funcional según escala del Eastern Cooperative Oncology Group (ECOG) ? 2.
6.Función hematológica, hepática y renal adecuada, definida por:
a.Recuento absoluto de neutrófilos (RAN) ? 1000/µl
b.Recuento de plaquetas ? 100.000/µl
c.Bilirrubina total ? 1,5 mg/dl
d.Aspartato aminotransferasa (AST) y alanino aminotransferasa (ALT) ? 2.5 x límite superior de la normalidad (LSN), (AST/ALT < 5 x LSN en caso de compromiso hepático documentado con linfoma). Todos los pacientes con serología positiva para el virus de la hepatitis B (VHB) deben tener los valores de la función hepática dentro de los parámetros anteriores.
e.Creatinina ? 1,5 mg/dl (si el valor de creatinina del paciente es > 1,5 mg/dl, el aclaramiento calculado de creatinina debe ser ? 50 ml/min).
7.Las mujeres con capacidad fértil (es decir, excluidas las pacientes postmenopáusicas durante un mínimo de 1 año [> 12 meses desde la última menstruación] o que han sido esterilizadas quirúrgicamente) deberán:
a.Contar con una prueba de embarazo en suero con resultado negativo dentro de los 14 días previos a la aleatorización, y
b.Aceptar poner en práctica un régimen de anticoncepción médicamente aceptable desde el inicio del tratamiento del estudio hasta un mínimo de 30 días después de la última administración de pralatrexato.
8.Los hombres sexualmente activos, incluidos aquellos con la pareja embarazada, deberán aceptar poner en práctica un régimen de anticoncepción con método de barrera médicamente aceptable (por ejemplo, preservativos) mientras reciben pralatrexato y durante 90 días después de la última administración de pralatrexato.
9.El paciente ha otorgado su consentimiento informado (CI) por escrito. |
|
| E.4 | Principal exclusion criteria |
1. Patient has:
a. Precursor T/NK neoplasms
b. Anaplastic large cell lymphoma (anaplastic lymphoma kinase positive) with International Prognostic Index score < 2 at initial diagnosis and complete response after completion of CHOP-based therapy
c. T-cell prolymphocytic leukemia (T-PLL)
d. T-cell large granular lymphocytic leukemia
e. Mycosis fungoides, other than transformed mycosis fungoides
f. Sézary syndrome
g. Primary cutaneous CD30+ disorders: Anaplastic large cell lymphoma and lymphomatoid papulosis
2. If there is a history of prior malignancies other than those exceptions listed below, the patient must be disease-free for ? 5 years. Patients with the following prior malignancies less than 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease.
a. Non-melanoma skin cancer
b. Carcinoma in situ of the cervix
c. Localized prostate cancer
d. Localized thyroid cancer
3. Patient has received prior treatment (chemotherapy or radiation) for peripheral T-cell lymphoma (PTCL), other than a single allowed CHOP regimen, with the exception of:
a. Patients with nasal NK lymphoma are permitted to have received local radiation therapy no less than 4 weeks prior to randomization.
b. Patients with transformed mycosis fungoides are permitted to have received 1 systemic single-agent chemotherapy (other than methotrexate) prior to transformation of their disease.
4. Prior exposure to pralatrexate.
5. Receipt of systemic corticosteroids within 3 weeks of study treatment, unless patient has been taking a continuous dose of ? 10 mg/day of oral prednisone or equivalent for at least 4 weeks or as part of a CHOP prednisone taper.
6. Planned use of any treatment for PTCL during the course of the study.
7. Patient has:
a. Human immunodeficiency virus (HIV)-positive diagnosis with a CD4 count of < 100 mm3 or detectable viral load within past 3 months and is receiving anti-retroviral therapy.
b. HBV-positive serology and is receiving interferon therapy or has liver function test results outside the parameters of study inclusion criteria. Patients are permitted to receive other antiviral therapies if the therapy has been administered at a stable dose for ? 4 weeks.
c. Hepatitis C virus (HCV) with detectable viral load or immunological evidence of chronic active disease or receiving/requiring antiviral therapy.
d. Symptomatic central nervous system (CNS) metastases or lesions for which treatment is required.
e. Uncontrolled hypertension or congestive heart failure Class III/IV according to the New York Heart Association?s Heart Failure Guidelines (see http://www.americanheart.org/presenter.jhtml?identifier=3065080).
f. Active uncontrolled infection, underlying medical condition including unstable cardiac disease, or other serious illness that would impair the ability of the patient to receive protocol treatment.
8. Patient has had major surgery within 2 weeks prior to study entry; other than for line placement or biopsy procedure. |
1.El paciente tiene:
a.Neoplasias precursoras de células T/NK
b.LACG (ALK+) con puntuación IPI < 2 al diagnóstico inicial y RC tras la finalización de la terapia con CHOP
c.Leucemia prolinfocítica de células T (LPL-T)
d.Leucemia linfocítica granular de células T grandes
e.Micosis fungoides, distintas de micosis fungoides transformadas
f.Síndrome de Sézary
g.Trastornos CD30+ cutáneos primarios: LACG y papulosis linfomatoide
2.Si hay antecedentes de procesos malignos diferentes de las excepciones que se enumeran a continuación, el paciente deberá haber estado libre de la enfermedad por ? 5 años. Se podrá incluir a los pacientes con antecedentes de los siguientes procesos malignos a menos de 5 años antes de la incorporación al estudio, si han recibido un tratamiento que haya dado lugar a la completa resolución del cáncer, y en la actualidad no presentan ninguna evidencia clínica, radiológica ni de laboratorio de enfermedad activa o recurrente.
a.Cáncer de piel no melanoma
b.Carcinoma cervical in situ
c.Cáncer de próstata localizado
d.Cáncer de tiroides localizado
3.El paciente ha recibido un tratamiento anterior (quimioterapia o radiación) para el LCTP, diferente de un único régimen de CHOP permitido, con las siguientes excepciones:
a.A los pacientes con linfoma NK nasal se les permite haber recibido radioterapia localizada no menos de 4 semanas antes de la aleatorización.
b.A los pacientes con micosis fungoides transformadas se les permite haber recibido 1 quimioterapia sistémica con agente único (que no sea metotrexato) antes de la transformación de su enfermedad.
4.Exposición previa al pralatrexato.
5.Recepción de corticosteroides sistémicos dentro de las 3 semanas del tratamiento del estudio, salvo que el paciente haya estado tomando una dosis continua de ? 10 mg/día de prednisona oral o equivalente durante un mínimo de 4 semanas o como parte de CHOP con reducción gradual de prednisona.
6.Se ha planificado el uso de cualquier tratamiento para el LCTP durante el curso del estudio.
7.El paciente tiene:
a.Un diagnóstico positivo para el virus de inmunodeficiencia humana (VIH) con un recuento de CD4 de < 100 mm3 o carga viral detectable dentro de los 3 meses anteriores, y está recibiendo tratamiento con antirretrovirales.
b.Serología positiva para el VHB y está recibiendo tratamiento con interferón o los resultados de las pruebas de la función hepática están fuera de los parámetros de los criterios de inclusión del estudio. Se permite que los pacientes reciban otra terapia antiviral si la dosis administrada es estable durante ? 4 semanas.
c.Virus de la hepatitis C (VHC) con carga viral detectable o evidencia inmunológica de enfermedad crónica activa, o recibe/requiere terapia antiviral.
d.Metástasis o lesiones sintomáticas del sistema nervioso central (SNC) para las cuales se requiere tratamiento.
e.Hipertensión no controlada o insuficiencia cardiaca congestiva de clase III/IV según las Directrices sobre insuficiencia cardiaca de la New York Heart Association (véase http://www.americanheart.org/presenter.jhtml?identifier=3065080).
f.Infección activa no controlada, afección médica subyacente incluida cardiopatía inestable, u otra enfermedad grave que podría afectar la capacidad del paciente para recibir el tratamiento del protocolo.
8.El paciente ha sido sometido a una cirugía mayor dentro de las 2 semanas previas a la incorporación al estudio; diferente de la colocación de una vía o un procedimiento de biopsia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival and overall survival. |
| Supervivencia sin progresión y supervivencia general |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival and overall survival - assessed throughout the period of the study. |
| Supervivencia sin progresión y supervivencia general - evaluadas durante el periodo del estudio |
|
| E.5.2 | Secondary end point(s) |
| Objective response (complete response [CR] or partial response [PR]) to pralatrexate versus observation |
| Respuesta objetiva (respuesta completa [RC] o respuesta parcial [RP]) al pralatrexato frente a la observación |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Objective response (complete response [CR] or partial response [PR]) to pralatrexate versus observation - response assessment to occur at 8 weeks, then every 12 weeks (± 1 week) through 3 years post-randomization, then every 24 weeks through 7 years post-randomization. |
| Respuesta objetiva (respuesta completa [RC] o respuesta parcial [RP]) al pralatrexato frente a la observación - evaluación de la respuesta que se produzca a las 8 semanas, entonces cada 12 semanas (± 1 semana) hasta los 3 años después de la aleatorización, entonces cada 24 semana hasta 7 años después de la aleatorización. |
|
| 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 | 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 | 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) | 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 | 1 |
| 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 | 70 |
| 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 |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Taiwan |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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 | 30 |
Print
