| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Multiple Myeloma |
| Mieloma múltiple en recaída y/o refractario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bone marrow Cancer |
| Cáncer de médula ósea |
|
| 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 | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase 1b
• Establish the safety and tolerability of AMG 420 at dose levels of 400 µg/day and 600 µg/day in subjects with relapsed and/or refractory multiple myeloma (RRMM).
Phase 2
• Estimate overall response rate (ORR) per IMWG response criteria (stringent complete response [sCR], complete response [CR], very good partial response [VGPR], partial response [PR]) in subjects with RRMM. |
Fase 1b
• Establecer la seguridad y tolerabilidad de AMG 420 a unos niveles de dosis de 400 μg/día y 600 μg/día en sujetos con mieloma múltiple en recaída y/o refractario (MMRR).
Fase 2
• Estimar la TRG conforme a los criterios de respuesta del IMWG
(respuesta completa estricta [RCe], respuesta completa [RC], respuesta parcial muy buena [RPMB], respuesta parcial [RP]) en sujetos con MMRR. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b
Key Secondary
• Estimate ORR and duration of response (DOR) of AMG 420 in subjects with RRMM
• Evaluate the rate of minimal residual disease (MRD)-negativity at the time of CR
Secondary
• Establish the safety and tolerability of AMG 420 in subjects with extramedullary relapsed multiple myeloma
•Characterize the pharmacokinetics of AMG 420 when administered as 4- week continuous intravenous (cIV) infusion
•Evaluate other measures of anti-myeloma activity of AMG 420 in subjects with RRMM:
−Time to response
−Progression-free survival (PFS)
−Overall survival (OS)
−Treatment-free interval (TFI)
−Best overall response (BOR)
Phase 2
Key Secondary
• Estimate DOR of AMG 420 in subjects with RRMM
• Evaluate the rate of MRD-negative disease at the time of CR
Secondary
• Evaluate other measures of anti-myeloma activity of AMG 420 in subjects with RRMM:
−Time to response
−PFS
−OS
−TFI
−BOR
• Establish the safety and tolerability of AMG 420 in subjects with RRMM |
Fase1b
•Estimar la tasa de respuesta global y la duración de la respuesta deAMG420 en los sujetos conMMRR
•Evaluar la tasa de enfermedad residual mínima(ERM)negativa en el momento de laRC
Secundarios
•Establecer la seguridad y tolerabilidad de AMG420 en sujetos con MM en recaída extramedular
•Caracterizar la farmacocinética de AMG420 cuando se administra mediante perfusión intravenosa continua(IVc) durante 4 semanas
•Evaluar otras medidas de actividad antimieloma deAMG420 en sujetos conMMRR:
-Tiempo hasta la respuesta
-Supervivencia libre de progresión(SLP)
-Supervivencia global(SG)
-Intervalo sin tratamiento(IST)
-Mejor respuesta global(MRG)
Fase2
Secundarios clave
•Estimar la DR deAMG420 en sujetos conMMRR
•Evaluar la tasa de ERM negativa en el momento de la RC
Secundarios
•Evaluar otras medidas de actividad antimieloma deAMG420 en sujetos conMMRR:
-Tiempo hasta la respuesta
-SLP
-SG
-IST
-MRG
•Establecer la seguridad y tolerabilidad deAMG420 en sujetos conMMRR |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject has provided informed consent prior to initiation of any study specific activities/procedures.
Age ≥ 18 years at the time of the signing of informed consent.
Multiple myeloma meeting the following criteria:
•Pathologically-documented diagnosis of multiple myeloma that is relapsed or is refractory as defined by the following:
−Relapsed after ≥ 3 lines of prior therapy that must include a PI, an IMiD, and a CD38-directed monoclonal antibody in any order during the course of treatment OR refractory to PI, IMiD, and CD38-directed monoclonal antibody.
•Measurable disease, defined by 1 or more of the following at time of screening:
−serum M-protein > 0.5 g/dL measured by serum protein electrophoresis (SPEP)
−urinary M-protein excretion > 200 mg/24 hours
−Involved sFLC measurement > 10 mg/dL, provided that the sFLC ratio is abnormal (< 0.26 or > 1.65) as per IMWG response criteria.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
Life expectancy of at least 3 months as per investigator`s judgment at time of screening.
Hematological function without transfusion support (within 7 days from screening assessment) as follows:
•ANC ≥ 1.0 x 109/L (without growth factor support)
•platelet count ≥ 25 x 109/L (without transfusions)
•hemoglobin ≥ 7.0 g/dL (transfusions permitted no later than 48 hours before screening).
Renal function as follows:
• calculated or measured creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation or via 24-hour urine collection with plasma and urine creatinine concentrations, respectively.
Hepatic function as follows:
•aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN)
• total bilirubin (TBIL) < 1.5 x ULN (unless considered due to Gilbert’s syndrome). |
El sujeto ha proporcionado su consentimiento informado antes de iniciar
cualquier procedimiento/actividad específicos del estudio.
Edad ≥ 18 años en el momento de firmar el consentimiento informado.
Mieloma múltiple que cumple los criterios siguientes:
•Diagnóstico documentado anatomopatológicamente de mieloma múltiple
en recaída o refractario definido por lo siguiente:
- Recaída después de ≥ 3 líneas previas de tratamiento, que deben incluir (en cualquier orden) un IP, un IMiD y un anticuerpo monoclonal dirigido contra CD38, durante el tratamiento, o enfermedad refractaria al tratamiento con IP, IMiD y anticuerpos monoclonales dirigidos contra CD38.
•Enfermedad medible, definida por 1 o más de los criterios siguientes en el momento de la selección:
- Proteína M en suero > 0,5 g/dl determinada mediante electroforesis de proteínas en suero (SPEP).
- Excreción de proteína M en la orina > 200 mg/24 horas.
- Determinación de la sFLC afectada > 10 mg/dl, siempre que la proporción de sFLC sea anormal (< 0,26 o > 1,65) según los criterios de respuesta del IMWG.
Estado funcional ECOG (Eastern Cooperative Oncology Group) de ≤ 2.
Esperanza de vida de al menos 3 meses, según el criterio del investigador, en el momento de la selección.
La función hematológica siguiente, sin transfusión de apoyo (en los 7 días
previos a la evaluación de la selección):
•RAN ≥ 1,0 x 109/l (sin apoyo con factor de crecimiento).
•Recuento plaquetario ≥ 25 x 109/l (sin transfusiones).
•Hemoglobina ≥ 7,0 g/dl (se permiten transfusiones hasta 48 horas antes de la selección).
La función renal siguiente:
•Aclaramiento de creatinina ≥ 30 ml/min calculado con la ecuación de Cockcroft-Gault o medido mediante la recogida de una muestra de orina de 24 horas para determinar las concentraciones de creatinina en plasma y orina.
La función hepática siguiente:
•Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) < 3 x límite superior de la normalidad (LSN).
•Bilirrubina total (BiT) < 1,5 x LSN (salvo que se considere debida a síndrome de Gilbert). |
|
| E.4 | Principal exclusion criteria |
Disease Related:
Known central nervous system involvement by multiple myeloma.
Evidence of primary or secondary plasma cell leukemia at the time of screening.
Waldenstrom’s macroglobulinemia.
Unresolved toxicities from prior anticancer therapy.
Other Medical Conditions
History of other malignancy within the past 3 years, with the following exceptions:
•malignancy treated with curative intent and with no known active disease present for ≥ 1 year before enrollment and felt to be at low risk for recurrence by the treating physician
•adequately-treated non-melanoma skin cancer or lentigo maligna without evidence of disease
•adequately-treated cervical carcinoma in situ without evidence of disease
•breast ductal carcinoma in situ with full surgical resection (ie, negative margins) and without evidence of disease
•prostate cancer with a Gleason score < 6 with undetectable prostate specific antigen (PSA) over 12 months
•treated medullary or papillary thyroid cancer
•adequately-treated urothelial papillary noninvasive carcinoma or carcinoma in situ
•similar neoplastic conditions with an expectation of > 95% five-year disease-free survival
• see exclusion criterion 202 (Evidence of primary or secondary plasma cell leukemia at the time of screening) for exclusion of subjects with evidence of primary or secondary plasma cell leukemia at the time of screening.
Known history of amyloidosis.
Current or known history of autoimmune diseases requiring systemic treatment in past 5 years except vitiligo, resolved childhood asthma/atopy, or subjects with history of hypothyroidism after completing treatment for autoimmune thyroid disease, stable on hormone replacement therapy.
Clinically not-controlled chronic or ongoing infectious disease requiring treatment at the time of study day 1 or within the 14 days before study day 1
Symptomatic peripheral sensory or motor neuropathy of grade ≥ 3.
History or presence of clinically relevant central nervous system (CNS) pathology as uncontrolled epilepsy or seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, and psychosis.
Active hepatitis B and C based on the following results:
•Positive for hepatitis B surface antigen (HepBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B).
•Negative HepBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B.
•Positive Hepatitis C virus antibody (HepCAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C.
Known or suspected HIV infection or subjects who are HIV seropositive.
Baseline ECG QTc > 470 msec (applying Fridericia correction), defined as the average of individual baseline ECGs.
Prior/Concomitant Therapy
Previously received an allogeneic stem cell transplant and the occurrence of 1 or more of the following:
•received the transplant within 6 months prior to study day 1
•received immunosuppressive therapy within the last 3 months prior to study day 1
•any active acute graft versus host disease (GvHD), grade 2 to 4, according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
•any systemic therapy against GvHD within 2 weeks prior to start of investigational product treatment.
Autologous stem cell transplantation < 90 days prior to study day 1.
Treatment with systemic immune modulators including, but not limited to, nontopical systemic corticosteroids (unless the dose is ≤ 10 mg/day prednisone or equivalent), cyclosporine, and tacrolimus within 2 weeks before study day 1.
Last anticancer treatment (chemotherapy, IMiD, PI, molecular targeted therapy) < 2 weeks prior to study day 1.
Last treatment with a therapeutic antibody less than 4 weeks prior to study day 1.
Systemic radiation therapy within 28 days prior to study day 1. Focal radiotherapy within 14 days prior to study day 1.
Major surgery defined as surgery requiring general anesthesia with endotracheal intubation within 28 days prior to study day 1, unless discussed with and eligibility approved by Amgen medical monitor.
Prior treatment with any drug that specifically targets BCMA on tumor cells (eg, other bi-specific antibody constructs, antibody drug conjugates, or CAR T-cells, except for subjects who were previously treated with AMG 420 in this study and who are candidates for second-course treatment.
Treatment with medications known to cause QTc interval prolongation within the washout periods unless approved by the Amgen medical monitor.
Prior/Concurrent Clinical Study Experience
Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). |
Relacionados con la enferm.
Afectación conocida del SNC el MM
Evid. de leucemia de cél. asmáticas primaria o secund. en el momento de la selec.
Macroglobulinemia de Waldenström
Toxi. no resueltas derivadas de un trt. anticanceroso prev.
Otras enferm.
Antecedentes de otras neoplasias malignas en los últimos 3años con las excepciones siguientes:
•Tumor maligno tratado con intención curativa y sin presencia de enferm. activa confirmada durante≥1año antes de la inclusión y que el médico responsable del trt. considere de bajo riesgo de recurrencia
•Cáncer de piel no melanomatoso o lentigo maligno tratados adecuadamente sin evid. de enferm.
•Carcinoma cervicouterino insitu tratado adecuad. in evid. de enferm.
•Carcinoma ductal de la mama insitu con resección quirúrgica completa(márgenes negativos)y sin evid. de enferm.
•Cáncer de próstata con puntuación de Gleason<6 con antígeno (Ag) específ. de la próstata(PSA)indetectable durante12meses
•Cáncer papilar o medular de tiroides tratado
•Carcinoma urotelial papilar no invasivo o carcinoma insitu tratados adecua.
•Una enferm. neoplásica similar con una expectativa de supervivencia libre de enferm. durante5años>95%
•Véase el criterio de exclus. 202 sobre la exclus. de sujetos con evid. de leucemia de cél.plasmáticas primaria o secund. en el momento de la selec.
Antecedentes conocidos de amiloidosis
Presencia o antecedentes de enferm. autoinmun. que precisaron trt. sistémico en los últimos 5años excepto vitiligo o asma/atopia resuelta en la infancia o sujetos con antecedentes de hipotiroidismo tras completar el trt. para una enferm. tiroidea autoinmun. que se hubiera mantenido estable con el trt. hormonal sustitutivo
Enferm. infecciosa crónica o presente no controlada clínic. que precisa trt. el día1 del estudio o en los 14d prev. al día1 del estudio
Neuropatía motora o sensorial periférica sintomática de grado≥3
Antecedentes/presencia de una patología del SNC clínic. relevante como epilepsia o trast. epiléptico sin controlar paresia afasia ictus lesiones cerebrales graves demencia enferm. de Parkinson enferm. del cerebelo síndrome orgánico cerebral y psicosis
HepatitisByC activas según los siguientes resultados:
•+para el Ag de superficie de la hepB(HepBsAg)(indica hepB crónica o hepB aguda reciente)
•- ara HepBsAg y + para anticuerpo (Ab) del núcleo de la hepB: debe determ. el ADN del virus de la hepB mediante la reacción en cadena de la polimerasa.El ADN del virus dela hepB detectable sugiere una hepB oculta
•+ ara Ab del virus de la hepC: debe determ. el ARN del virus de la hepC mediante RCP. El ARN del virus de la hepC detectable sugiere una hepC crónica
Se sabe o se sospecha que el sujeto está infect. por elVIH o sujetos seropositivos para elVIH
ECGbasal con un intervalo QTc>470 ms(tras aplicar la corrección de Fridericia), determ. mediante el promedio de losECGbasales individuales
Trt. prev./concomitante
Haber recibido anteriormente un traspl. alogénico de cél. progenitoras y 1 o más de los siguientes casos:
•Haber recibido el traspl. en los6meses anteriores al día1 del estudio
•Haber recibido trt. con inmunosupr. en los3meses anteriores al día1 del estudio
•Enferm. del injerto contra el huésped(EICH)activa aguda de grado2a4 según los criterios de Glucksberg, o EICH activa crónica que precisa trt. sistémico
•Administración de cualquier trt. sistémico para laEICH en las 2semanas previas al inicio del trt. con el prod. en investig.
Traspl. autólogo de cél. progenitoras<90d antes del día1 del estudio
Trt. con inmunomoduladores sistémicos como corticosteroides sistémicos no tópicos (a no ser que la dosis sea≤10 mg/día de prednisona o equivalente), ciclosporina o tacrólimus, entre otros, en las 2semanas previas al día1 del estudio
Último trt. anticanceroso recibido<2 semanas antes del día1 del estudio
Último trt. con un Ab terapéutico recibido menos de 4semanas antes del día1 del estudio
Radioterapia sistémica en los 28d anteriores al día1 del estudio.Radioterapia focal en los 14d anteriores al día1 del estudio
Cirugía mayor: cualquier cirugía que precise anestesia general con intubación endotraqueal, en los 28d anteriores al día1 del estudio a no ser que se comente con el monitor médico de Amgen y se acuerde su elegibilidad
Trt. Prev. con cualquier fármaco dirigido específicamente contra el BCMA de las cél. tumorales (p.ej otros constructos de Ab biespecíf. conjug. Ab-fármaco o cél.T-CAR excepto para los sujetos que recibieran trt. Prev. con AMG420 en este estudio y que sean candidatos a una segunda tanda de trt.
Trt. con medicamentos que prolongan el intervalo QTc teniendo en cuenta los períodos de lavado a no ser que se obtenga la aprobación del monitor médico de Amgen
Experiencia previa/concomitante en EC
Estar recibiendo actualmente trt. en otro estudio de un fármaco o prod. sanitario en investig. o que hayan transcurrido menos de 30d desde el fin del trt. en otro estudio de un fármaco o prod. sanitario en investig. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
• Dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests
Phase 2
• ORR according to IMWG response criteria, per IRC assessment |
Fase 1b
• Toxicidades limitantes de la dosis (TLD), acontecimientos adversos queaparecen durante el tratamiento,
acontecimientos adversos relacionados con el tratamiento, acontecimientos relacionados con la enfermedad y cambios en las constantes vitales, los electrocardiogramas (ECG) y las pruebas analíticas clínicas
Fase 2
• TRG conforme a los criterios de respuesta del IMWG, evaluados por el CRI |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout study |
| Durante el estudio |
|
| E.5.2 | Secondary end point(s) |
Phase 1b
Key secondary
•ORR
•DOR
•MRD negativity at the time of CR
Secondary
•DLTs, treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, ECGs, and clinical laboratory tests
•AMG 420 PK parameters including, but not limited to, half-life (t1/2), clearance, and apparent Css
• Efficacy parameters according to International Myeloma Working Group (IMWG) response criteria, per independent review committee (IRC) assessment:
−Time to response
−PFS
−BOR
•OS
•TFI
Phase 2
Key secondary
• DOR
• MRD negativity at the time of CR
Secondary
•Efficacy parameters according to IMWG
response criteria, per IRC assessment:
−Time to response
−PFS
−BOR
•OS
•TFI
• Treatment-emergent adverse events, treatment-related adverse events, disease-related events, and changes in vital signs, ECGs, and clinical laboratory tests |
Fase 1b
Secundarios clave
•TRG
•DR
•ERM negativa en el momento de la RC
Secundarios
•TLD, acontecimientos adversos que aparecen durante el tratamiento, acontecimientos adversos relacionados con el tratamiento, acontecimientos relacionados con la enfermedad y cambios en las constantes vitales, los ECG y las
pruebas analíticas clínicas
•Parámetros FC de AMG 420, como la semivida (t1/2), el aclaramiento y la Css aparente
•Parámetros de eficacia de acuerdo con los criterios de respuesta del International Myeloma Working Group (IMWG), evaluados por el comité de revisión independiente (CRI):
- Tiempo hasta la respuesta
- SLP
- MRG
•SG
•IST
Fase 2
Secundarios clave
•DR
•ERM negativa en el momento de la RC
Secundarios
•Parámetros de eficacia conforme a los criterios de respuesta del IMWG, evaluados por el CRI:
- Tiempo hasta la respuesta
- SLP
- MRG
•SG
•IST
•Acontecimientos adversos que aparecen durante el tratamiento,acontecimientos adversos
relacionados con el tratamiento, acontecimientos relacionados con la enfermedad y cambios en las constantes vitales, los ECG y las pruebas analíticas clínicas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout study |
| Durante el estudio |
|
| 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 |
| Phase 1b: dose confirmation |
| Fase 1b: confirmación de dosis |
|
| 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Japan |
| Romania |
| Spain |
| Switzerland |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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