E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed CD37+ non-Hodgkin B-cell follicular lymphoma |
Linfoma linfocítico B folicular no hodgkiniano CD37+ recidivante |
|
E.1.1.1 | Medical condition in easily understood language |
Cancer of the white blood cells |
Cancer de las celulas blancas |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029547 |
E.1.2 | Term | Non-Hodgkin's lymphoma |
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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003902 |
E.1.2 | Term | B-cell lymphoma recurrent |
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 |
- Part 1: To identify the optimal dose of Betalutin in terms of overall response rate (ORR), assessed with the use of standard criteria for Lymphoma.
- Part 2: To assess the ORR assessed with the use of standard criteria for Lymphoma |
- Parte 1: Identificar la dosis óptima de Betalutin en términos de tasa de respuesta global (TRG), evaluada aplicando criterios normalizados para linfoma.
- Parte 2: Evaluar la TRG aplicando los criterios normalizados para linfoma |
|
E.2.2 | Secondary objectives of the trial |
- To assess the best overall response rate - To assess the duration of response - To estimate progression free survival (PFS) - To assess the time to next treatment - To estimate overall survival (OS) - To investigate Quality of Life (QoL) - To investigate safety and toxicity of Betalutin |
- Evaluar la tasa de mejor respuesta global - Evaluar la duración de la respuesta - Calcular la supervivencia sin progresión (SSP) - Evaluar el tiempo hasta el siguiente tratamiento - Calcular la supervivencia global (SG) - Investigar la calidad de vida (CdV) - Investigar la seguridad y la toxicidad de Betalutin |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically confirmed (by World Health Organization [WHO] classification) follicular lymphoma (follicular grade I-IIIA)
2. Relapsed after 2 or more prior systemic regimens
3. Requiring initiation of treatment for the NHL
4. Age >=18 years
5. ECOG performance status of 0-2
6. Life expectancy of at least 3 months
7. Bone marrow tumour infiltration <25% tumour cells
8. CD37-positive; re-biopsy or test existing tumour material if not known
9. Negative HAMA test
10. Laboratory values within 15 days before study enrolment: a) Absolute Neutrophil Counts >= 1.5 x 109/l b) Platelet count >= 150 x 109 /l c) Total bilirubin <= 1.5 x upper limit of normal d) Alkaline Phosphatase <= 4x normal level e) ALAT <= 4x normal level f) Creatinine <=110 ?mol/L (men), 90 ?mol/L (women)
11. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (according to standard criteria: at least one bi-dimensionally measurable lesion (>1.5 cm in its largest dimension by CT scan).
12. Women of childbearing potential must: a. understand that the study medication is expected to have teratogenic risk b. have a negative serum pregnancy test at screening and before Betalutin injection c. commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control with a Pearl-Index <= 1%. without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 5 months after end of study drug therapy, even if she has amenorrhoea
13. Male subjects must agree to use condoms during intercourse throughout study drug therapy and the following 5 months
14. The patient has been fully informed about the study and has signed the informed consent form
15. The patient is willing and able to comply with the protocol and agrees to return to the hospital for follow-up visits and examination |
1. Linfoma folicular (estadio I-IIIA) histologicamente confirmado (segun clasificacion de la Organizacion Mundial de la Salud [OMS])
2. Recidiva despues de 2 o mas tratamientos sistemicos anteriores
3. Necesidad de inicio de tratamiento para el LNH.
4. Edad >=18 años
5. Estado funcional del Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0-2
6. Esperanza de vida de al menos 3 meses
7. Células tumorales con infiltración tumoral <25 % en la médula ósea
8. Tumor positivo para CD37; repetición de la biopsia o análisis de material tumoral existente si se desconoce
9. Resultado negativo para análisis de anticuerpos humanos contra las Ig murinas (HAMA)
10. Valores de laboratorio en los 15 días anteriores al reclutamiento en el estudio: a) Cifra absoluta de neutrófilos >=1,5 x 109/l b) Cifra total de trombocitos >=150 x 109/l c) Bilirrubina total <1,5 veces el límite superior de la normalidad d) Fosfatasa alcalina <= 4 veces el límite superior de la normalidad e) Alanina aminotransferasa <=4 veces el límite superior de la normalidad f) Creatinina <=110 ?mol/l (hombres), 90 ?mol/l (mujeres)
11. Presencia de neoplasia maligna linfoide extraganglionar o linfadenopatía medible radiográficamente (con arreglo a criterios normalizados: como mínimo una lesión medible bidimensionalmente (>1,5 cm en su dimensión más larga medida mediante tomografía axial computerizada (TAC)).
12. Las mujeres fértiles deben: a) entender que se prevé que la medicación del estudio entrañará riesgo teratogénico b) realizar una prueba de embarazo en sangre con resultado negativo en el período de selección y antes de la inyección de Betalutin c) comprometerse a practicar la abstinencia heterosexual continuada o empezar a utilizar dos métodos anticonceptivos aceptables con un índice de falibilidad <=1 % sin interrupción 4 semanas antes del inicio de la administración del fármaco del estudio, durante la terapia con el fármaco del estudio y durante 5 meses tras la finalización de la terapia con el fármaco del estudio, aunque tenga amenorrea
13. Los sujetos masculinos deben comprometerse a utilizar preservativos en sus relaciones sexuales durante la terapia con el fármaco del estudio y los 5 meses posteriores
14. El paciente ha recibido información detallada sobre el estudio y ha firmado el formulario de consentimiento informado
15. El paciente puede y quiere cumplir el protocolo y se compromete a volver al hospital para completar las visitas de seguimiento y las exploraciones |
|
E.4 | Principal exclusion criteria |
1. Evidence of severe or uncontrolled systemic diseases: a) Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment b) Known to be HIV positive c) Pulmonary conditions e.g. unstable or uncompensated respiratoryd) Hepatic conditions e) Renal conditions f) Neurological conditions g) Psychiatric conditions h) Metabolic conditions i) History of erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome j) Cardiac conditions, including i. History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks ii. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system iii. Known uncontrolled arrhythmias (except sinus arrhythmia) in the past 24 weeks.
2. Bulky disease defined as the presence of one or more nodes with at least one dimension of 10 cm or more.
3. Ongoing immunosuppressive therapy, including systemic corticosteroids. Patients may be using topical or inhaled corticosteroids
4. Known or suspected central nervous system involvement of lymphoma
5. Previous total body irradiation, or irradiation of >25% of the patient?s bone marrow
6. Investigational drug, chemotherapy, or immunotherapy received within the last 4 weeks prior to start of study treatment, except for the pre-treatment used in this study
7. Pregnant or lactating women
8. Prior hematopoietic allogenic stem cell transplantation
9. Prior autologous stem cell transplantation <=2 years ago
10. History of a non-lymphoma malignancy except for the following: a) adequately treated local basal cell or squamous cell carcinoma of the skin b) cervical carcinoma in situ c) superficial bladder cancer d) localized prostate cancer e) other adequately treated Stage 1 or 2 cancer currently in complete remission f) or any other cancer that has been in complete remission for >= 5 years
11. Allergy to X ray contrast agents |
1. Evidencia de enfermedades sistémicas graves o descontroladas: a) Infección descontrolada con evidencia de infección vírica, fúngica o bacteriana sistémica en curso (sin incluir infecciones víricas en las vías respiratorias altas) en el momento de iniciar el tratamiento del estudio b) Sujetos seropositivos para VIH c) Afecciones pulmonares, como afección respiratoria inestable o descompensada d) Afecciones hepáticas e) Afecciones renales f) Afecciones neurológicas g) Afecciones psiquiátricas h) Afecciones metabólicas i) Antecedentes de eritema multiforme, necrólisis epidérmica tóxica o síndrome de Stevens-Johnson j) Afecciones cardíacas, incluyendo i. Antecedentes de síndromes coronarios agudos (incluida angina inestable), angioplastia coronaria o prótesis intravascular en las últimas 24 semanas ii. Insuficiencia cardíaca de clase II, III o IV según definición del sistema de clasificación funcional de la New York Heart Association (NYHA) iii. Arritmias conocidas descontroladas (salvo arritmia sinusal) en las últimas 24 semanas
2. Neoplasia maligna con gran masa tumoral, como presencia de una o más metástasis ganglionares que midan 10 cm o más
3. Terapia inmunosupresora en curso, incluidos corticosteroides sistémicos. Los pacientes pueden estar recibiendo corticosteroides de administración tópica o inhalada
4. Linfoma con afectación conocida o presunta del sistema nervioso central
5. Irradiación corporal total previa o irradiación de >25 % de la médula ósea del paciente
6. Fármaco experimental, quimioterapia o inmunoterapia recibidos en las 4 semanas anteriores al inicio del tratamiento del estudio, salvo el pretratamiento administrado en este estudio
7. Mujeres embarazadas o en período de lactancia
8. Alotrasplante hematopoyético previo
9. Autotrasplante de hemocitoblastos <=2 años
10. Antecedentes de neoplasia maligna no linfoma, excepto: a) carcinoma espinocelular o basocelular local adecuadamente tratado en la piel b) cáncer de cuello uterino in situ c) cáncer vesical superficial d) cáncer de próstata localizado e) otro carcinoma en estadio I o II tratado suficientemente en remisión completa f) o cualquier otro carcinoma en remisión completa durante >=5 años
11. Alergia a agentes de contraste radiográficos |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR), defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) assessed with the use of standard criteria for lymphoma; in part 2 of the study, responses will be assessed by the independent image review committee. ORR scored at 3 months will be used for primary efficacy end-point. |
TRG, definida como la proporción de pacientes que consiguen remisión completa (RC) o remisión parcial (RP) evaluada aplicando criterios normalizados para linfoma; en la Parte 2 del estudio las respuestas serán evaluadas por el Comité independiente de revisión de imágenes. La TRG calificada a los 3 meses se utilizará para determinar el criterio principal de valoración de la eficacia. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 3 months |
A los 3 meses |
|
E.5.2 | Secondary end point(s) |
1. Best overall response rate
2. Duration of tumour response (DOR)
3. PFS (Performance Status)
4. Time to next treatment
5. OS (Overall Survival) |
1. Tasa de mejor respuesta global
2. Duración de la remisión tumoral (DRT)
3. SSP.
4. Tiempo hasta el siguiente tratamiento
5. La SG |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. 5 years
2. Time from the date of the onset of response to the first documentation of relapse or progressive disease, whichever occurs first.
3. Defined as the interval from Betalutin administration and date of: relapse (new or enlarged lesions after CR); progression (new or enlarged lesions after PR or stable disease [SD]), or death from any cause. If none of the above events are observed, PFS should be censored at the date of the last assessment (i.e. last CT scan). Cheson criteria is used for definition of new or enlarged lesion.
4. The time from Betalutin administration to the start of the next anti-cancer therapy.
5. From the date of study entry until the date of death of any cause. |
1. 5 años 2. Tiempo transcurrido entre fecha de inicio de remisión y primera documentación de recidiva o progresión tumoral, lo que primero suceda 3. SSP definida como intervalo entre administración de Betalutin y fecha de: recidiva (lesiones nuevas o agrandadas tras RC); progresión (lesiones nuevas o agrandadas tras RC o enfermedad estable) o muerte por cualquier causa. Si no se observa ninguno de los acontecimientos anteriores, SSP será objeto de censura estadística a fecha de la última evaluación (es decir, último TAC). Los criterios de Cheson se utilizan para definición de lesión nueva o agrandada 4. Tiempo transcurrido entre administración de Betalutin e inicio de siguiente terapia antineoplásica 5. Tiempo desde fecha entrada en el estudio a fecha de muerte por cualquier causa |
|
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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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 |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Norway |
Poland |
Russian Federation |
Spain |
Sweden |
Turkey |
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
|
LSLV |
Última visita del último paciente |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 18 |