| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
| Mieloma múltiple recidivante/refractario |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma is a cancer formed by malignant plasma cells that starts in the bone marrow (the spongy tissue inside the bones). |
El mieloma múltiple es un cáncer formado por células plasmáticas malignas que empieza en la médula ósea (el tejido esponjoso de dentro
de los huesos). |
|
| 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 | 21.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate the efficacy of cevostamab based on investigator assessed Objective response rate (ORR)
• To evaluate the safety and tolerability of cevostamab |
• Evaluar la eficacia de cevostamab en base a la tasa de respuesta objetiva (TR) evaluada por el investigador
• Evaluar la seguridad y la tolerabilidad de cevostamab |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of cevostamab based on IRC assessed ORR, DOR, CR or better, rate of VGPR or better, OS, PFS, time to first response, time to best response, MRD negative rate, proportion of participants experiencing a clinically meaningful improvement and time to deterioration assessed by EORTC QLQ-C30 and EORTC QLQ-MY20
• To characterize the PK of cevostamab in participants with MM
• To evaluate the immune response to cevostamab, potential relationships between cevostamab exposure and pharmacodynamic biomarkers
• To make a preliminary assessment of the efficacy of tocilizumab in ameliorating the symptoms of CRS following treatment with cevostamab
• To identify biomarkers that may be:
o Able to provide evidence of cevostamab activity and to increase the knowledge and understanding of disease biology
o Predictive of response to cevostamab
o Associated with progression to a more severe disease state, acquired resistance to cevostamab and susceptibility to developing AEs |
• Evaluar la eficacia de cevostamab en base a TRO según la evaluación del CRI, DR, tasa de RC, tasa de RPMB, SG, SLP, tiempo hasta la primera respuesta, tiempo hasta la mejor respuesta, tasa de EMR negativa, proporción de participantes que experimentan una mejoría clínicamente significativa y tiempo hasta el deterioro en el EORTC QLQ-C30 y EORTC QLQ-MY20
• Definir la FC de cevostamab en participantes con MM
• Evaluar la respuesta inmune a cevostamab, evaluar relaciones potenciales entre la exposición a cevostamab y los biomarcadores farmacodinámicos
• Identificar marcadores que puedan:
o Ser capaces de proporcionar evidencia de la actividad de cevostamab y aumentar los conocimientos y la comprensión de la biología de la enfermedad
o Predecir la respuesta a cevostamab
o Estar asociados con la progresión a un estado más severo de la enfermedad, estar asociados con la resistencia adquirida a cevostamab y la propensión a manifestar acontecimientos adversos |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age >= 18 years
• Documented diagnosis of multiple myeloma (MM) based on standard International Myeloma Working Group (IMWG) criteria
• Evidence of progressive disease based on investigators determination of response by IMWG criteria on or after their last dosing regimen
• Prior B cell maturation antigen (BCMA) antibody-drug conjugate (ADC) or chimeric antigen receptor T (CAR-T) Cohort: participants who have received a BCMA-targeted CAR-T or ADC therapy and are triple-class refractory
• Prior BCMA Bispecific Cohort: participants who have received a BCMA-targeting T-cell-dependent bispecific (TDB) antibody and are triple-class refractory
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Life expectancy is at least 12 weeks
• Agreement to protocol-specified assessments, including bone marrow biopsy and aspirate samples as detailed in the protocol
• Resolution of adverse events from prior anti-cancer therapy to Grade =< 1
• Measurable disease, defined as at least one of the following:
– Serum M-protein >= 0.5 g/dL (>= 5 g/L)
– Urine M-protein >= 200 mg/24 hours
– Serum free light chain (sFLC) assay: involved sFLCs >= 10 mg/dL (>=100 mg/L) and an abnormal sFLC ratio (< 0.26 or > 1.65)
• Adequate laboratory values
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 2 months after the final dose of cevostamab and for 3 months after the last dose of tocilizumab was administered
• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm during the treatment period and for at least 2 months after the final dose of cevostamab or tocilizumab (if applicable) to avoid exposing the embryo |
• Tener ≥ 18 años
• Diagnóstico documentado de MM basándose en los criterios estándar del IMWG
• Evidencia de progresión de la enfermedad basándose en la determinación de la respuesta realizada por el investigador de acuerdo con los criterios del IMWG durante o después de la última pauta de tratamiento
• Cohorte tratada previamente con un ADC o CART-T dirigidos a BCMA: participantes que han recibido terapia CAR-T o con un ADC dirigidos a BCMA y son triple refractarios
• Cohorte tratada previamente con un anticuerpo biespecífico dirigido a BCMA: participantes que han recibido un anticuerpo TDB dirigido a BCMA y son triple refractarios
• Estado funcional del Eastern Cooperative Oncology Group (ECOG) 0 o 1
• Esperanza de vida de al menos 12 semanas
• Estar de acuerdo en someterse a las evaluaciones especificadas en el protocolo, incluyendo la biopsia y el aspirado de médula ósea, conforme se describe en el protocolo
• Resolución a grado <= 1 de los acontecimientos adversos resultantes de una terapia anticancerosa previa
• Enfermedad medible, definida por al menos uno de los valores siguientes: -Proteína M en suero ≥ 0,5 g/dl (≥ 5 g/l) - Proteína M en orina ≥ 200 mg/24 h - Prueba de SFLC: SFLC implicadas ≥10 mg/dl (≥ 100 mg/l) y cociente SFLC anormal (< 0,26 o > 1,65)
• Valores de las pruebas de laboratorio adecuados
• Las mujeres participantes potencialmente fértiles deben comprometerse a practicar la abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o a usar métodos anticonceptivos durante el período de tratamiento y como mínimo hasta 2 meses después de la administración de la última dosis de cevostamab y hasta 3 meses después de la última dosis de tocilizumab
• Los varones participantes deben comprometerse a practicar la abstinencia sexual (abstenerse de mantener relaciones heterosexuales) o usar preservativo durante el período de tratamiento y como mínimo hasta 2 meses después de la administración de la última dosis de cevostamab o tocilizumab |
|
| E.4 | Principal exclusion criteria |
• Inability to comply with protocol-mandated hospitalization
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 3 months after the final dose of cevostamab or tocilizumab
• Prior treatment with cevostamab or another agent with the same target
• Prior BCMA ADC or CAR-T Cohort: prior treatment with any TDB antibody
• Prior BCMA Bispecific Cohort: treatment with TDB antibody within 12 weeks prior to enrollment in the study
• Prior use of any monoclonal antibody (mAb), radioimmunoconjugate, or ADC as anti-cancer therapy within 4 weeks before first study treatment, except for the use of non-myeloma therapy
• Prior treatment with systemic immunotherapeutic agents, including but not limited to, cytokine therapy and anti- Cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), anti- Programmed cell death protein 1 (PD-1), and anti- Programmed death-ligand 1 (PD-L1) therapeutic antibodies within 12 weeks or 5 half-lives of the drug, whichever is shorter, before first study treatment
• Prior treatment with CAR-T cell therapy within 12 weeks before first cevostamab infusion
• Known treatment-related, immune-mediated adverse events associated with prior checkpoint inhibitors as follows:
– Prior PD-L1/PD-1 or CTLA-4 inhibitor: Grade >= 3 adverse events with the exception of Grade 3 endocrinopathy managed with replacement therapy
– Grade 1-2 adverse events that did not resolve to baseline after treatment discontinuation
• Treatment with radiotherapy, any chemotherapeutic agent, or treatment with any other anti-cancer agent within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first study treatment
• Autologous stem cell transplantation (SCT) within 100 days prior to first study treatment
• Prior allogeneic SCT
• Circulating plasma cell count exceeding 500/ microliter (µL) or 5% of the peripheral blood white cells
• Prior solid organ transplantation
• History of autoimmune disease
• History of confirmed progressive multifocal leukoencephalopathy
• History of severe allergic or anaphylactic reactions to mAb therapy
• Known history of amyloidosis
• Lesions in proximity of vital organs that may develop sudden decompensation/deterioration in the setting of a tumor flare
• History of other malignancy within 2 years prior to screening, except those with negligible risk of metastasis or death, such as ductal carcinoma in situ not requiring chemotherapy, appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer not requiring treatment or appropriately treated Stage I uterine cancer
• Current or past history of central nervous system (CNS) disease, such as stroke, epilepsy, CNS vasculitis, neurodegenerative disease, or CNS involvement by MM
• Significant cardiovascular disease that may limit a potential participant’s ability to adequately respond to a cytokine release syndrome (CRS) event
• Symptomatic active pulmonary disease or requiring supplemental oxygen
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection at study enrollment, or any major episode of infection requiring treatment with IV (intravenous) antibiotics or antivirals for coronavirus disease 2019 (COVID-19) where the last dose of treatment was given within 14 days prior to first study treatment
• Known or suspected chronic active Epstein-Barr virus (EBV) infection
• Known history of hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS)
• Recent major surgery within 4 weeks prior to first study treatment
• Positive serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection
• Acute or chronic hepatitis C virus (HCV) infection
• Known history of human immunodeficiency virus (HIV) seropositivity
• Administration of a live, attenuated vaccine within 4 weeks before first study treatment or anticipation that such a live attenuated vaccine will be required during the study
• Treatment with systemic immunosuppressive medications, with the exception of corticosteroid treatment <= 10 mg/day prednisone or equivalent, within 2 weeks prior to first study treatment
• History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
• Any medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results |
•Incapacidad para cumplir la hospitalización requerida en el protocolo
•Mujeres embarazadas o en período de lactancia o que tengan intención de quedarse embarazadas durante el estudio o en los 3 meses siguientes a la administración de la última dosis de cevostamab o tocilizumab
•Tto previo con cevostamab u otro agente dirigido a la misma diana
•Cohorte con un ADC o CAR-T dirigidos a BCMA previo: tto previo con cualquier anticuerpo TDB
•Cohorte con un anticuerpo biespecífico dirigido a BCMA previo: tto con un anticuerpo TDB en las 12 semanas previas a la inclusión en el estudio
•Uso previo de cualquier mAb, radioinmunoconjugado o ADC para el tto del cáncer en las 4 semanas previas a la administración del primer tto del estudio, exceptuando terapia no específica para el mieloma
•Tto previo con agentes inmunoterapéuticos sistémicos incluyendo, aunque no exclusivamente, terapia con citoquinas y anticuerpos terapéuticos anti-CTLA4, anti-PD-1 y anti-PD-L1 en las 12 semanas, o durante el equivalente a 5 semividas del fármaco, previas a la administración del primer tto del estudio, lo que sea más corto
•Tto previo con terapia celular CAR-T en las 12 semanas previas a la administración de la primera infusión de cevostamab
•Acontecimientos adversos inmunomediados conocidos relacionados con el tto, asociados con la administración previa de inhibidores de puntos de control inmunitario, como los siguientes:
•Inhibidores de PD-L1/PD-1 o CTLA-4 previos: Acontecimientos adversos de grado ≥ 3, exceptuando endocrinopatía de grado 3 controlada con terapia de reemplazo
•Acontecimientos adversos de grado 1-2 que no han remitido al grado basal después de suspender el tto
•Tto con radioterapia, cualquier agente quimioterápico u otro agente anticanceroso (en investigación o no) en las 4 semanas, o durante el equivalente a 5 semividas del fármaco, previas a la administración del primer tto del estudio, lo que sea más corto
•Trasplante autólogo de cél madre en los 100 días previos a la administración del primer tto del estudio
•Trasplante alogénico de cél madre previo
•Recuento de céls plasmáticas circulantes superior a 500/µL o 5% de leucocitos en sangre periférica
•Trasplante previo de órganos sólidos
•Historial de enfermedades autoinmunes
•Historial de leucoencefalopatía multifocal progresiva confirmada
•Historial de reacciones alérgicas graves o anafilácticas a tto con mAb
•Historial conocidos de amiloidosis
•Lesiones en la proximidad de órganos vitales que puedan causar una descompensación o deterioro repentinos en caso de exacerbación tumoral
•Historial de otras neoplasias malignas en los 2 años previos a la selección, exceptuando aquellas que tengan un riesgo insignificante de metástasis o muerte tales como carcinoma ductal in situ que no requiere QT, carcinoma in situ de cérvix tratado de manera apropiada, carcinoma de piel no melanoma, cáncer de próstata localizado de bajo grado que no requiere tto o cáncer de útero en estadio I tratado adecuadamente
•Enfermedad del SNC en la actualidad o en el pasado, como ictus, epilepsia, vasculitis del SNC, enfermedad neurodegenerativa o afectación del SNC por MM
•Enfermedades cardiovasculares significativas que puedan limitar la capacidad de un participante potencial para responder adecuadamente a un episodio de SLC
•Enfermedad pulmonar sintomática activa o que requiera oxígeno suplementario
•Infección activa documentada de etiología bacteriana, viral, micótica, micobacteriana, parasitaria u otras en el momento de la inclusión en el estudio o cualquier episodio importante de infección que haya requerido tto con antibióticos IV o antivirales para COVID-19 y la última dosis se haya administrado en los 14 días previos al primer tto del estudio
•Infección crónica activa, documentada o presuntiva, por virus de Epstein-Barr
•Historial conocidos de linfohistiocitosis hemofagocítica o síndrome de activación macrofágica
•Intervención de cirugía mayor reciente en las 4 semanas previas a la administración del primer tto del estudio
•Serología o PCR positivas para infección por virus de hepatitis B aguda o crónica
•Infección por virus de hepatitis C aguda o crónica
•Historial conocidos de seropositividad por VIH
•Administración de una vacuna de microorganismos vivos atenuados en las 4 semanas previas al primer tto del estudio o que se requiera previsiblemente durante el estudio
•Administración de medicaciones inmunosupresoras sistémicas excepto corticosteroides en dosis <=10 mg/día de prednisona o equivalente en las 2 semanas previas al primer tto del estudio
•Historial de abuso de drogas o alcohol en los 12 meses previos a la selección, de acuerdo con el investigador
•Cualquier trastorno o anomalía observados en las pruebas de laboratorio clínico, que, de acuerdo con el investigador, impida al paciente participar y completar el estudio con seguridad o que pudiera afectar al cumplimiento con el protocolo o la interpretación de los resultados |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. ORR, defined as the proportion of participants with an objective response [stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR)], based on investigator-assessed response, according to IMWG criteria
2. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) CRS grading scale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1-2. Up to approximately 2 years |
| 1-2. Hasta aproximadamente 2 años |
|
| E.5.2 | Secondary end point(s) |
1. ORR, defined as the proportion of participants with an objective response based on independent review committee (IRC)-assessed response
2. Duration of response (DOR), defined as the time from the first occurrence of an objective response until the date of disease progression or death from any cause (whichever occurs first), as determined separately by the IRC and the investigator
3. Rate of CR or better, defined as the proportion of participants who achieve a response of sCR or CR, as assessed separately by IRC and the investigator
4. Rate of VGPR or better, defined as the proportion of participants who achieve a response of VGPR or better, as assessed separately by IRC and the investigator
5. Overall survival (OS), defined as the time from initiation of study treatment to death from any cause
6. Progression-free survival (PFS), defined as the time from initiation of study treatment to the first occurrence of disease progression, relapse, or death from any cause (whichever occurs first), as assessed separately by IRC and the investigator
7. Time to first response (for participants who achieve an objective response), defined as time from initiation of study treatment to first achieving an objective response (separate analyses by IRC and investigator)
8. Time to best response (for participants who achieve an objective response), defined as time from initiation of study treatment to achieving the deepest response (separate analyses by IRC and investigator)
9. Minimal residual disease (MRD) negative rate, defined as proportion of participants achieving MRD negativity (< 10-5), as defined by next-generation sequencing (NGS) in bone marrow aspirate per IMWG criteria (Kumar 2016) among participants with a response of CR or better (separate analyses for CR by IRC and investigator)
10. Proportion of participants experiencing a clinically meaningful improvement in the fatigue domain of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core-30 Questionnaire (QLQ-C30) and EORTC QLQ-MY20
11. Time to deterioration in the fatigue domain of the EORTC QLQ-C30 and/or disease symptoms domain of the EORTC QLQ-MY20
12. Serum concentration of cevostamab at specified timepoints
13. Pharmacokinetics (PK) parameters of cevostamab, as data allow
14. Prevalence of anti-drug antibodies (ADAs) against cevostamab at baseline and incidence of ADAs against cevostamab during the study
15. CRS outcome following administration of tocilizumab (e.g., time to CRS resolution, doses of tocilizumab administered, relationship between serum concentration or other PK parameters for tocilizumab and pharmacodynamic biomarkers)
16. Relationship between serum concentration or other PK parameters for cevostamab and pharmacodynamic biomarkers, including, but not limited to, cytokine release, T cell number, and T-cell activation state
17. Relationship between biomarkers in blood, bone marrow biopsies and aspirates, and tumor tissue and efficacy, safety, PK, immunogenicity, or other biomarker endpoints |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-11. Up to approximately 2 years
12-14. At Cycles 1, 2, 3, 4, 6, 8 and every other cycle until the end of treatment
15-17. Up to approximately 2 years |
|
| 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 | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Brazil |
| Canada |
| Israel |
| United States |
| France |
| Netherlands |
| Spain |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| United Kingdom |
|
| 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 o la fecha en que se reciban los últimos datos necesarios para el análisis estadístico o la vigilancia de la seguridad definida en el protocolo del último paciente, lo que ocurra más tarde |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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