| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Follicular Lymphoma |
| Linfoma folicular avanzado |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016910 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016909 |
| E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage III |
| 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 |
To demonstrate that CT-P10 is:
- equivalent to Rituxan in terms of pharmacokinetics as determined by area under the serum concentration-time curve at steady state (AUCtau) and maximum serum concentration at steady state (CmaxSS) at Cycle 4.
- noninferior to Rituxan in terms of efficacy as determined by overall response rate (complete response [CR] + unconfirmed complete response [CRu] + partial response [PR]) over Cycle 8 (Core Study Period) according to the 1999 International Working Group (IWG criteria in previously untreated patients with advanced (stage III-IV) CD20+ FL. |
Demostrar que CT-P10:
- es equivalente a Rituxán en cuanto a farmacocinética, según lo determinado mediante el área bajo la curva de concentración sérica-tiempo en estado de equilibrio (AUCtau) y la concentración sérica máxima en estado de equilibrio (CmaxSS) en el ciclo 4.
- no es inferior a Rituxán en cuanto a eficacia, según lo determinado mediante la tasa de respuesta global (respuesta completa [RC] + respuesta completa no confirmada [RCnc] + respuesta parcial [RP]) durante 8 ciclos (período principal del estudio) conforme a los criterios del International Working Group (IWG) de 1999 en pacientes con LF CD20+ avanzado (estadio III-IV) sin tratamiento previo. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate additional pharmacokinetics, efficacy parameters, pharmacodynamics, overall safety, and biomarkers of CT-P10 in comparison with Rituxan during the Core Study Period, Maintenance Study Period, and Follow-up Period. |
| Evaluar otros parámetros farmacocinéticos, de eficacia, farmacodinamia, seguridad global y biomarcadores de CT-P10 en comparación con Rituxán durante el período principal del estudio, el periodo de mantenimiento y el periodo de seguimiento. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Patient is male or female older than 18 years.
2. Patient has histologically confirmed FL according to the World Health Organization 2008 classification (Jaffe 2009); grades 1 to 3a based on local laboratory review.
3. Patient has at least 1 measurable tumour mass that has not previously been irradiated, and the mass must be:
- greater than 1.5 cm in the longest dimension or
- between 1.1 and 1.5 cm in the longest dimension and greater than 1.0 cm in the shortest axis
4. Patient has confirmed CD20+ lymphoma, as assessed by local laboratory review. (Tissue obtained within 6 months before Day 1 of Cycle 1 will be reviewed by a central independent reviewer to detect pathological type.)
5. Patient has Ann Arbor stage III or IV disease.
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Oken 1982).
7. For both male and female patients and their partners of childbearing potential, patient agrees to practice total abstinence or to use one of the following medically acceptable methods of contraception during the course of the study and for 12 months following discontinuation of study treatment (excluding women who are not of childbearing potential and men who have been sterilised):
- Barrier contraceptives (male condom, female condom or diaphragm with a spermicidal gel)
- Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings)
- Intrauterine devices
Male or female patients and their partners who have been surgically sterilised for less than 6 months prior to study entry must agree to use 1 medically acceptable method of contraception or practice total abstinence. Menopausal females must have experienced their last period more than 12 months prior to study entry (ie, when the informed consent form [ICF] is signed) to be classified as not of childbearing potential.
8. For both premenopausal women and women who are less than or equal to 12 months after the onset of menopause, patient has a negative serum pregnancy test during the Screening Period.
9. Patient has adequate bone marrow, hepatic, and renal function reserve as evidenced by:
- Haemoglobin level of >= 8 g/dL
- Absolute neutrophil count (ANC) of >= 1500/mm3
- Platelet count of >= 75 000/mm3
- Total bilirubin level of <= 2.0 mg/dL
- Aspartate aminotransferase and alanine aminotransferase levels of <= 3 times the upper limit of normal (ULN) for the reference laboratory (<= 5 × ULN for the reference laboratory with known hepatic involvement by lymphoma)
- A serum creatinine level of <= 1.5 × ULN for the reference laboratory, or a calculated creatinine clearance by the Cockcroft-Gault equation (Rostoker et al 2007) of >= 50 mL/min
10. Patient is able to understand verbal and written instructions and can comply with all study requirements.
11. Patient is informed, given ample time and opportunity to read and understand about participation in the study, and has signed and dated the written ICF. |
Todos los pacientes deberán cumplir todos los criterios siguientes para poder participar en este estudio:
1. Paciente de uno u otro sexo, mayor de 18 años.
2. Presencia de un LF confirmado histológicamente conforme a la clasificación de la Organización Mundial de la Salud de 2008 (Jaffe 2009); grado 1 a 3a según la valoración del laboratorio local.
3. Presencia de al menos una masa tumoral mensurable que no haya sido irradiada previamente y que ha de ser:
- mayor de 1,5 cm en su dimensión mayor o
- entre 1,1 y 1,5 cm en su dimensión mayor y mayor de 1,0 cm en su eje menor.
4. Presencia de un linfoma CD20+ confirmado, conforme a la valoración del laboratorio local. (Un evaluador central independiente examinará tejido obtenido en los 6 meses previos al día 1 del ciclo 1 para identificar el tipo anatomopatológico.)
5. Enfermedad en estadio III o IV de Ann Arbor.
6. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 a 2 (Oken 1982).
7. El paciente, sea varón o mujer, y su pareja en edad fértil se comprometen a practicar abstinencia total o a utilizar uno de los siguientes métodos anticonceptivos médicamente aceptables durante el estudio y hasta 12 meses después de suspender el tratamiento del estudio (exceptuando las mujeres que no estén en edad fértil y los varones esterilizados):
- Anticonceptivos de barrera (preservativo masculino, preservativo femenino o diafragma con gel espermicida).
- Anticonceptivos hormonales (implantes, inyectables, anticonceptivos orales combinados, parches transdérmicos o anillos anticonceptivos).
- Dispositivos intrauterinos.
Los pacientes, sean varones o mujeres, y sus parejas que se hayan sometido a una esterilización por métodos quirúrgicos menos de 6 meses antes de su entrada en el estudio deberán comprometerse a utilizar un método anticonceptivo médicamente aceptable o a practicar abstinencia total.
Se considerará que no están en edad fértil las mujeres posmenopáusicas que hayan tenido su última menstruación más de 12 meses antes de la entrada en el estudio (es decir, cuando se haya firmado el documento de consentimiento informado [DCI]).
8. En las mujeres premenopáusicas y en las que no hayan transcurrido más de 12 meses desde el comienzo de la menopausia, presencia de una prueba de embarazo en suero negativa durante el período de selección.
9. Presencia de una reserva medular, hepática y renal adecuada, manifestada por:
- Concentración de hemoglobina >= 8 g/dl.
- Recuento absoluto de neutrófilos (RAN) >= 1500/mm3.
- Recuento de plaquetas >= 75.000/mm3.
- Concentración de bilirrubina total <= 2,0 mg/dl.
- Concentración de aspartato aminotransferasa y alanina aminotransferasa <= 3 veces el límite superior de la normalidad (LSN) del laboratorio de referencia (<= 5 veces el LSN del laboratorio de referencia con afectación hepática conocida por el linfoma).
- Concentración de creatinina sérica <= 1,5 veces el LSN del laboratorio de referencia o aclaramiento de creatinina calculado con la ecuación de Cockcroft-Gault (Rostoker y cols. 2007) >= 50 ml/min.
10. El paciente es capaz de comprender instrucciones verbales y escritas y de cumplir todos los requisitos del estudio.
11. El paciente ha sido informado, ha tenido tiempo suficiente y se le ha brindado la oportunidad de leer y entender lo que conlleva su participación en el estudio y ha firmado y fechado el DCI por escrito. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Patient has received rituximab (or a rituximab biosimilar), cyclophosphamide, or vincristine.
2. Patient has allergies or hypersensitivity to murine, chimeric, human or humanised proteins, cyclophosphamide, vincristine, or prednisone.
3. Patient has evidence of histological transformation to high-grade or diffuse large B-cell lymphoma.
4. Patient has known central nervous system involvement.
5. Patient has received previous treatment for NHL:
- Previous treatment including chemotherapy, radiotherapy, immunotherapy, and/or surgery (except previous biopsy)
- All doses of corticoid therapy for treatment of NHL
- Corticoid therapy during the previous 4 weeks from Day 1 of Cycle 1 with prednisone >20 mg per day for the treatment for any purpose
6. Patient has a current diagnosis of active tuberculosis (TB) defined by chest x-ray or other severe infections, such as sepsis, abscesses, or opportunistic infections.
7. Patient has a known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. (Carriers of hepatitis B are not permitted to enrol into the study.)
8. Patient has New York Heart Association class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina, arrhythmias, clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within the previous 6 months before the ICF is signed.
9. Patient has any malignancy other than NHL, except adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ, within the previous 5 years before the ICF is signed.
10. Patient has a current or recent (within 30 days before the ICF is signed) treatment with any other investigational medicinal product or device.
11. Patient has uncontrolled diabetes mellitus, even after insulin treatment.
12. Patient is pregnant or lactating. Patients who are planning to be pregnant or to breastfeed before, during, or within 12 months after the last infusion of study treatment are not permitted to enrol into the study.
13. Patient is taking a live, live-attenuated, or nonlive vaccine within 4 weeks before Day 1 of Cycle 1 of study treatment.
14. Patient has evidence of any other coexisting disease or medical or psychological condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational product, or patient is a high risk for treatment complications. |
Se excluirá del estudio a todos los pacientes que cumplan alguno de los criterios siguientes.
1. Tratamiento previo con rituximab (o un biosimilar de rituximab), ciclofosfamida o vincristina.
2. Alergia o hipersensibilidad a proteínas murinas, quiméricas, humanas o humanizadas, ciclofosfamida, vincristina o prednisona.
3. Evidencia de transformación histológica a un linfoma de alto grado de malignidad o linfoma difuso de células B grandes.
4. Antecedentes de afectación del sistema nervioso central.
5. Tratamiento previo contra el LNH:
- El tratamiento previo comprende quimioterapia, radioterapia, inmunoterapia o cirugía (excepto una biopsia previa).
- Todas las dosis de corticoides para tratar el LNH.
- Tratamiento con corticoides durante las 4 semanas previas al día 1 del ciclo 1, con > 20 mg al día de prednisona para cualquier fin.
6. Diagnóstico presente de tuberculosis (TB) activa, definida mediante radiografía de tórax, u otras infecciones graves, como sepsis, abscesos o infecciones oportunistas.
7. Infección conocida por el virus de la inmunodeficiencia humana (VIH), hepatitis B o hepatitis C. (Los portadores de hepatitis B no podrán participar en el estudio.)
8. Insuficiencia cardíaca en clase III o IV de la New York Heart Association, cardiopatía grave no controlada (angina inestable, arritmias, anomalías electrocardiográficas [ECG] clínicamente significativas) o infarto de miocardio en los 6 meses previos a la firma del DCI.
9. Presencia de cualquier neoplasia maligna distinta del LNH, excepto un carcinoma espinocelular o basocelular de piel o un carcinoma de cuello uterino in situ debidamente tratado, en los 5 años previos a la firma del DCI.
10. Tratamiento actual o reciente (en los 30 días previos a la firma del DCI) con cualquier otro medicamento o producto sanitario en investigación.
11. Presencia de diabetes mellitus no controlada, incluso después del tratamiento con insulina.
12. Paciente embarazada o lactante. Las pacientes que tengan previsto quedarse embarazadas o amamantar antes, durante o en los 12 meses siguientes a la última infusión del tratamiento del estudio no podrán participar en el estudio.
13. Recepción de una vacuna de microorganismos vivos, vivos atenuados o muertos en las 4 semanas previas al día 1 del ciclo 1 del tratamiento del estudio.
14. Presencia de signos de cualquier otra enfermedad concomitante o de un trastorno médico o psicológico, disfunción metabólica, hallazgo en la exploración física o resultado analítico que depare sospechas razonables de una enfermedad o proceso que contraindique el uso de un producto en investigación o el paciente corre un riesgo elevado de presentar complicaciones del tratamiento. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- PART 1: Pharmacokinetics: the primary endpoints will be AUCtau and CmaxSS
- PART 2: Efficacy: the primary endpoints will be overall response rate (CR + CRu + PR) according to the 1999 International Working Group (IWG) criteria in previously untreated patients with advanced (stage III-IV) CD20+ FL |
- PARTE 1: Farmacocinética: la variable principal será AUCtau y CmaxSS
- PARTE 2: Eficacia: las variables principals serán la tasa de respuesta global (RC + RCnc + RP) conforme a los criterios International Working Group (IWG) 1999 en pacientes con LF CD20+ avanzado (estadio III-IV) sin tratamiento previo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- PART 1: Pharmacokinetics: in the Core Study Period (12 weeks) of study treatment
- PART 2: Efficacy: 8 cycles in the Core Study Period (24 weeks) of study treatment |
- PARTE 1: Farmacocinética: en el período principal del estudio (12 semanas) del tratamiento del estudio.
- PARTE 2: Eficacia: 8 ciclos en el período principal del estudio (24 semanas) de tratamiento del estudio |
|
| E.5.2 | Secondary end point(s) |
- PART 1: Pharmacokinetics: to evaluate other PK parameters of CT-P10 in comparison with Rituxan as determined by maximum serum concentration (Cmax), trough serum concentration (Ctrough), average concentration (Cav), time to maximum serum concentration (Tmax), volume of distribution (Vd), total clearance (CL), terminal elimination half-life (T1/2), mean residence time (MRT), peak to trough fluctuation ratio (PTF), and terminal elimination rate constant (Landaz).
- PART 2:
- To demonstrate overall response rate (CR + PR) over 8 cycles (Core Study Period) according to the 2007 IWG criteria.
- To evaluate additional efficacy parameters (PFS, TTP, time to treatment failure [TTF], response duration, disease-free survival [DFS], and OS) according to the 1999 IWG criteria and 2007 IWG criteria for patients who underwent positron emission tomography-computed tomography (PET-CT).
- To evaluate pharmacodynamics (B-cell kinetics, including depletion and recovery), overall safety, and biomarkers of CT-P10 in comparison with Rituxan. |
- PARTE 1:Farmacocinética: Evaluar otros parámetros farmacocinéticos (FC) de CT-P10 en comparación con Rituxán, según lo determinado mediante la concentración sérica máxima (Cmax), concentración sérica mínima (Cmin), concentración promedio (Cprom), tiempo hasta la concentración sérica máxima (Tmax), volumen de distribución (Vd), aclaramiento total (CL), semivida de eliminación terminal (T1/2), tiempo medio de permanencia (TMP), cociente de fluctuación entre concentración máxima y mínima (FMM) y constante de velocidad de eliminación terminal (Lz).
- PARTE 2:
- Demostrar la tasa de respuesta global (RC + RP) durante 8 ciclos (período principal del estudio) conforme a los criterios IWG 2007.
- Evaluar otros parámetros de eficacia (supervivencia sin progresión, tiempo hasta la progresión, tiempo hasta el fracaso del tratamiento, duración de la respuesta, supervivencia sin enfermedad y supervivencia global) conforme a los criterios IWG 1999 y los criterios IWG 2007 en los pacientes que se hayan sometido a una tomografía por emisión de positrones-tomografía computarizada (PET-TC).
- Evaluar la farmacodinamia (cinética de linfocitos B, incluidas depleción y recuperación), seguridad global y biomarcadores de CT-P10 en comparación con Rituxán. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PART 1: Pharmacokinetics: 4 cycles in the Core Study Period (12 weeks) of study treatment
- PART 2: Efficay: secondary endpoints include additional efficay parameters, pharmacodynamics and safety during the Core Study Period, Maintenance Study Period, and Follow-up Period |
- PARTE 1: Farmacocinética: 4 ciclos en el período principal del estudio (12 semanas) de tratamiento del estudio.
- PARTE 2: Eficacia: las variables secundarias incluyen los parámetros adicionales de eficacia, farmacodinamia y seguridad durante el período principal del estudio, el período de mantenimiento y el período de seguimiento. |
|
| 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 | 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 | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Biosimilar study |
| Estudio biosimilar |
|
| 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 | 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) | 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 | 46 |
| 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 |
| Bulgaria |
| Greece |
| Italy |
| Netherlands |
| Portugal |
| Romania |
| Belarus |
| Brazil |
| Georgia |
| India |
| Korea, Republic of |
| Spain |
| Mexico |
| Poland |
| Russian Federation |
| Serbia |
| South Africa |
| Taiwan |
| Turkey |
| Ukraine |
| 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
|
| The end of the study is defined as the date on which the last patient completes the last visit. |
| El final del estudio se define como la fecha en la que el último paciente completa la última visita. |
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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