| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Indolent B-Cell Non-Hodgkin Lymphoma |
| linfoma no hodgkiniano de linfocitos B de escasa malignidad |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Hodgkin Lymphoma (cancer) |
| linfoma no hodgkiniano (cáncer) |
|
| 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 | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
-Assess the safety and tolerability profile of BI-1206 when administered in combination with rituximab in subjects with indolent relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).
-Select the recommended Phase 2 dose (RP2D) by establishing the maximum tolerated dose (MTD) of BI-1206 given once weekly for 4 weeks, via intravenous infusion in combination with rituximab. |
-Evaluar el perfil de seguridad y tolerabilidad de BI-1206 cuando se administra en combinación con rituximab en personas con linfoma no hodgkiniano (LNH) de linfocitos B de escasa malignidad recidivante o resistente.
-Elegir la dosis recomendada para la fase II (DRFII) mediante la determinación de la dosis máxima tolerada (DMT) de BI-1206 administrado una vez a la semana durante 4 semanas mediante infusión intravenosa en combinación con rituximab. |
|
| E.2.2 | Secondary objectives of the trial |
-Study the pharmacokinetic (PK) profile of BI-1206 when administered in combination with rituximab in subjects with indolent relapsed or refractory B-cell NHL.
-Study the PK profile of rituximab when administered in combination with BI-1206.
-Assess the immunogenicity of BI-1206 when administered in combination with rituximab.
-Evaluate the effect of BI-1206 administered in combination with rituximab on the depletion of B-cells.
-Assess possible anti-tumor activity of BI-1206 administered in combination with rituximab at Week 6 after first dose of BI-1206 and during maintenance therapy for subjects who continue. |
-Estudiar el perfil FC de BI-1206 cuando se administra en combinación con rituximab en personas con LNH de linfocitos B de escasa malignidad recidivante o resistente.
-Estudiar el perfil FC del rituximab cuando se administra en combinación con BI-1206.
-Evaluar la inmunogenia de BI-1206 cuando se administra en combinación con rituximab.
-Evaluar el efecto de BI-1206 administrado en combinación con rituximab sobre la reducción del número de linfocitos B.
-Evaluar la posible actividad antitumoral de BI-1206 administrado en combinación con rituximab en la semana 6 después de la primera dosis de BI-1206 y durante el tratamiento de mantenimiento en el caso de los pacientes que continúen. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Are > o = 18 years of age by initiation of study treatment.
• Provide written (signed and dated) informed consent.
• Are capable of cooperating with treatment and follow-up.
• Have B-cell NHL proven by histology, with histological subtypes limited to FL (except FL3B), MCL and MZL.
• Have measureable nodal disease, defined as the presence of > o = 1 nodal lesion that measures > o = 1.5 cm in a single dimension as assessed by computerized tomography (CT) or magnetic resonance imaging (MRI).
• Are willing to undergo lymph node biopsies or biopsies of other involved tissue (besides bone marrow). However, if the investigator feels that a tissue biopsy is not technically feasible, then the subject will not be required to undergo biopsies. If viable frozen tissue (not formalin-fixed) from a previous standard of care biopsy in the previous 8 weeks prior to consent is available, a new biopsy at screening is not required.
• Have relapsed disease or disease refractory to conventional treatment or for which no standard therapy exists, the investigator judges available standard therapy as not being appropriate for the subject, or is declined by the subject. Rituximab refractory disease is defined as:
o Lack of CR or PR during rituximab-containing treatment comprising > o = 2 doses of > o = 375 mg/m2, or
o Occurrence of progressive disease after completion of a regimen of rituximab-containing therapy comprising > o = 2 doses of > o = 375 mg/m2, or
o Occurrence of progressive disease during rituximab maintenance therapy or within 6 months of completion of rituximab maintenance therapy.
• Have received at least one line of conventional previous therapy which must include at least one rituximab-based regimen.
• Have a life expectancy of at least 12 weeks on the day of the first infusion of BI- 1206.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 11. Have CD20+ malignancy as demonstrated by IHC or flow cytometry prior to first dose of BI-1206. Analysis must have been performed on tissue obtained within 6 months of signature of the informed consent form (ICF); otherwise, a new biopsy is required.
• Have hematological and biochemical indices within the ranges shown below. These measurements must be performed within 1 week and assessed by the Investigator before their first dose of BI-1206. |
1. Tener > o = 18 años de edad al inicio del tratamiento del estudio.
2. Tener LNH de linfocitos B demostrado mediante histología, de los subtipos histológicos LF (excepto LF3B), LCM y LZM.
3. Tener afectación ganglionar mensurable, definida por la presencia de > o = 1 lesión ganglionar de > o = 1,5 cm en una sola dimensión y evaluada mediante tomografía computarizada (TC) o resonancia magnética (RM).
4. Estar dispuesto/a a someterse a biopsias de los ganglios linfáticos. Sin embargo, si el investigador considera que hacer una biopsia de los ganglios linfáticos no es técnicamente viable, no será necesario que el paciente se someta a la misma.
5. Tener un cáncer recidivante, resistente al tratamiento convencional, para el que no exista tratamiento convencional, que el investigador considere que el tratamiento convencional disponible no es adecuado para el paciente o cuyo tratamiento haya sido rechazado por el/la paciente.
6. Haber recibido al menos una línea de tratamiento convencional con al menos una pauta basada en rituximab.
7. Tener una esperanza de vida de al menos 12 semanas el día de la primera infusión de BI-1206.
8. Tener un estado funcional del Grupo colaborador de oncología del este de los EE. UU.
(Eastern Cooperative Oncology Group, ECOG) de 0-2.
9. Tener una neoplasia maligna CD20+ demostrada mediante inmunohistoquímica o citometría de flujo antes de la primera dosis de BI-1206. El análisis debe haberse realizado en los 6 meses previos a la firma del formulario de consentimiento informado (FCI).
10. Tener los valores hematológicos y bioquímicos dentro de los intervalos especificados previamente. Estas evaluaciones deben realizarse en el periodo de una semana antes del tratamiento con BI-1206. |
|
| E.4 | Principal exclusion criteria |
• Have had an allogenic bone marrow or stem cell transplant within 12 months prior to the first dose of BI-1206.
• Have presence of active chronic graft versus host disease of any grade/severity.
• Have current leptomeningeal lymphoma or compromise of the central nervous system.
• Have transformed lymphoma from a pre-existing indolent lymphoma. Subjects with a previous history of transformation, but on this disease episode have a biopsy proven indolent recurrence, may be included. Subjects with proven or suspected Richter transformation are not eligible.
• Have Waldenstrom’s Macroglobulinemia or FL3B, due to the high risk of transformation while on study.
• Need systemic doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the study other than as pre-medication. During the screening period, doses of up to 20 mg/day may be given but the dose must be reduced to 10 mg/day by Cycle 1 Day 1. Inhaled or intranasal steroids are permissible.
• Have known or suspected hypersensitivity to rituximab or BI-1206. Previous isolated IRRs are not to be considered a reason for exclusion.
• Have cardiac or renal amyloid light-chain amyloidosis.
• Have received any of the following:
o Chemotherapy or small molecule products with 2 weeks of first dose of BI- 1206 and/or Radiotherapy (except for focal symptomatic control of lymphadenopathy) within 4 weeks of first dose of BI-1206 and/or
o Immunotherapy within 8 weeks prior to the first dose of BI-1206.
• Have ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator should not exclude the subject.
• Have the ability to become pregnant (or already pregnant or lactating/breastfeeding). However, those female subjects who have a negative serum pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial and for 12 months after last dose of BI 1206 are considered eligible. Highly effective methods of birth control include:
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation
• Progestogen-only hormonal contraception associated with inhibition of ovulation
• Intrauterine device
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence
• Are male subjects with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception (condom plus spermicide gel) during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the fetus or neonate.
• Have had major surgery from which the subject has not yet recovered.
• Are at high medical risk because of non-malignant systemic disease including active infection on treatment with antibiotics, antifungals or antivirals.
• Are serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
• Have an active, known or suspected autoimmune disease. However, subjects with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia not requiring systemic treatment), or conditions not expected to recur in the absence of an external trigger will be permitted to participate.
• Have concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), history of clinically significant cardiac ischemia or cardiac arrhythmia in the past 6 months.
• Have ongoing alcohol or drug addiction, as judged by the Investigator.
• Have any other condition which in the Investigator’s opinion would not make the subject a good candidate for the clinical trial.
• Are participating or plan to participate in another interventional clinical study, while taking part in this Phase 1/2a study of BI-1206. Participation in an observational non-interventional study is acceptable.
• Have current malignancies of other types, with the exception of:
o adequately treated cone-biopsied in situ carcinoma of the cervix uteri
o basal or squamous cell carcinoma of the skin
o asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for >1 year prior to start of study therapy.
Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for ≥ 3 years and are deemed at negligible risk for recurrence, are also eligible for the trial. |
1. Haber recibido un trasplante alogénico de médula ósea en los 12 meses anteriores a la primera dosis de BI-1206.
2. Presentar enfermedad de injerto contra huésped crónica.
3. Tener linfoma leptomeníngeo o tener afectado el sistema nervioso central.
4. Tener un linfoma transformado procedente de un linfoma de escasa malignidad preexistente. Los pacientes con antecedentes de transformación, pero con recidiva de escasa malignidad demostrada mediante biopsia en este episodio de la enfermedad, pueden incluirse. Los pacientes con transformación de Richter (sospechada o demostrada) no pueden participar.
5. Tener una macroglobulinemia de Waldenström o LF3B.
6. Necesidad de prednisolona a dosis >10 mg al día (o dosis equipotentes de otros corticosteroides) durante el ensayo, aparte de la empleada como medicación previa. Durante el período de selección, pueden administrarse hasta 20 mg/día, pero la dosis debe reducirse a 10 mg/día en el día 1 del ciclo 1.
7. Tener hipersensibilidad (conocida o sospechada) al rituximab o a BI-1206. La aparición previa y aislada de RRI no debe considerarse un motivo de exclusión.
8. Tener amiloidosis de cadena ligera cardíaca o renal.
9. Haber recibido lo siguiente:
o Quimioterapia o fármacos tradicionales en las 2 semanas previas a la primera dosis de BI-1206 o Radioterapia (excepto para el control sintomático focal de una linfadenopatía) en las 4 semanas anteriores a la primera dosis de BI-1206
o Inmunoterapia en las 8 semanas previas a la primera dosis de BI-1206.
10. Seguir presentando manifestaciones de reacciones adversas a tratamientos anteriores. Las excepciones a ello son la alopecia o determinadas reacciones adversas de grado 1 que, en opinión del investigador, no deben ser la causa de exclusión de un paciente.
11. Poder quedarse embarazada (o estar ya embarazada o en período de lactancia). Sin embargo, las mujeres con un resultado negativo en una prueba de embarazo en suero u orina antes de la inclusión y que acepten usar métodos anticonceptivos aprobados médicamente durante las 4 semanas previas a la entrada en el ensayo, durante el ensayo y durante los 12 meses
posteriores a la última dosis de BI-1206 se consideran aptas para participar.
12. Ser hombre con una pareja con posibilidades de quedarse embarazada (a menos que acepte tomar medidas para no procrear mediante un método anticonceptivo muy eficaz durante el
ensayo y durante los 12 meses posteriores a la finalización del tratamiento). Se debe
aconsejar a los hombres cuya pareja esté embarazada o en período de lactancia que utilicen
métodos anticonceptivos de barrera para evitar la exposición al feto o al neonato.
13. Haberse sometido a una intervención de cirugía mayor y no haberse recuperado todavía de la misma.
14. Tener un riesgo médico elevado debido a una enfermedad sistémica no maligna, incluida una infección activa que se esté tratando con antibióticos, antifúngicos o antivíricos.
15. Presentar un resultado positivo en suero para los virus de la hepatitis B, la hepatitis C o la inmunodeficiencia humana (VIH).
16. Tener conocimiento del padecimiento de una enfermedad autoinmunitaria activa o sospechar de la existencia de la misma. Sin embargo, podrán participar los pacientes con diabetes mellitus de tipo I, hipotiroidismo que solo requiere hormonoterapia de reposición, trastornos cutáneos (como vitiligo, psoriasis o alopecia que no requieran tratamiento sistémico) o afecciones de las que no se espere una reaparición en ausencia de un desencadenante externo.
17. Tener insuficiencia cardíaca congestiva concurrente, antecedentes de cardiopatía de clase III/IV (New York Heart Association [NYHA]), antecedentes de isquemia cardíaca o antecedentes de arritmia cardíaca.
18. Tener, en la actualidad, neoplasias malignas de otros tipos, con la excepción de las siguientes (tratadas de manera satisfactoria):
- Carcinoma de cuello uterino in situ al que se le ha practicado una conización
- Carcinoma de piel basocelular o espinocelular
- Cáncer de próstata asintomático sin metástasis conocidas y sin necesidad de tratamiento o que requiere solo hormonoterapia de reposición y con una concentración normal de antígeno prostático específico durante >1 año antes del inicio del tratamiento del estudio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Endpoints include time to objective response, duration of response, progression-free survival (PFS), and overall survival (OS). Efficacy will be based on assessment of overall response rate (ORR) according to the response criteria for malignant lymphoma (Cheson, 2014). |
La valoración de la eficacia se basará en la evaluación de la tasa de respuesta
objetiva (TRO), la duración de la respuesta, la supervivencia sin progresión (SSP) y la supervivencia global (SG). La eficacia se basará en la evaluación de la tasa de respuesta global (TRG) según los criterios de respuesta del linfoma maligno (Cheson, 2014). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Documenting AEs and SAEs (graded according to National Cancer Institute [NCI] CTCAE version 4.03) and determining causality in relation to BI-1206 and/or rituximab. Causality of AEs/SAEs will be assessed by the Investigator.
2.Determining the MTD of BI-1206, with no more than 1 of up to 6 subjects at the same dose level experiencing a BI-1206- or rituximab-related (i.e., related or possibly related) dose-limiting toxicity (DLT) during the 28-day treatment period on induction therapy (i.e., by Day 29/Week 5). |
1. Docuementación de AA y AAG (graduación según NCI-CTCAE) y determinación de la causalidad en relación con BI-1206 y/o rituximab. La causalidad de los AA/AAG se evaluará por el investigador
2. Determinación de la DMT de BI-1206, con no más de 1 a 6 sujetos en el mismo nivel de dosis que experimenten TLD relacionadas con BI-1206 o rituximab (es decir, posiblemente relacionadas) durante los 28 días de tratamiento en la terapia de inducción (es decir, día 29/Semana 5) |
|
| E.5.2 | Secondary end point(s) |
1. Evaluation of PK parameters for BI-1206 during the BI-1206 treatment period.
2. Evaluation of PK parameters for rituximab during the BI-1206 treatment period.
3. Evaluation of ADA response to BI 1206.
4. Measurement of B cell depletion.
5. Assessment of overall response rate (ORR) according to the response criteria for malignant lymphoma (Cheson, 2014). Other endpoints will include time to objective response, duration of response, PFS, and OS.
6. CD32b protein expression levels. |
1. Evaluación de parámetros de FC de BI-1206 durante el tratamiento con BI-1206
2. Evaluación de parámetros de FC de rituximab durante el tratamiento con BI-1206
3. Evaluación de respuesta ADA a BI-1206
4. Determinación de la reducción de linfocitos B
5. Evaluación de la tasa de respuesta global (TRG) según los criterios de respuesta del linfoma maligno (Cheson, 2014). Otras variables incluirán la tasa de respuesta objetiva (TRO), la duración de la respuesta, la supervivencia sin progresión (SSP) y la supervivencia global (SG).
6. Niveles de expresión de la proteina CD32b |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Blood serum samples will be collected for PK assessments of BI-1206 and rituximab at prespecified time points. Blood samples will be collected for PD assessments of BI-1206 at prespecified time points. Bone marrow will be collected at screening. If signs of disease are observed, another sample will be collected at Week 6 to assess for response and as clinically indicated thereafter. A portion of each available bone marrow sample will also be used for PD analysis. Lymph node biopsy samples will also be used for PD analysis, as available. B-lymphocyte levels will be assessed and reported at each site as part of the regular hematology assessment to determine the level of peripheral blood B-lymphocyte depletion. CD32b protein expression levels and CD32b receptor occupancy will be evaluated. |
| Se obtendrán muestras de sangre para evaluar la FC de BI-1206 y rituximab en momentos específicos. Se obtendrán muestras para análisis de FD en momentos específicos. Se obtendrán muestras de médula ósea en la selección. Si se observan signos de cáncer, se obtendrá otra muestra en la semana 6 para evaluar la respuesta, así como más adelante si está clínicamente indicado.Una parte de cada muestra de médula ósea disponible también se empleará para el análisis FD. Las biopsias de los ganglios linfáticos también se utilizarán para el análisis FD. El nº de linfocitos B se evaluará y notificará ecada centro de investigación como parte de la evaluación hematológica habitual para determinar la reducción linfocitos B . Se evaluará el nivel de expresión de CD32b y la ocupación de los receptores CD32b |
|
| 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 | 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) | 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 |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Escalado de dosis, cohortes consecutivas |
| Dose escalation, consecutive-cohort |
|
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Poland |
| Spain |
| 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
|
| LVLS |
| 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 | 2 |
| 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 | 2 |
| 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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